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Ren Y, Dong Y, Li Z, Xu K, Xu J, Li X, Zhang M, Xu C, Yang M, Lee M, Meng X, Wang J. Kidney-targeting DNA tetrahedral molecular cage synergistically inhibits acute kidney injury by clearing ROS and activating HO-1. Biomaterials 2025; 320:123237. [PMID: 40049024 DOI: 10.1016/j.biomaterials.2025.123237] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2024] [Revised: 02/04/2025] [Accepted: 03/02/2025] [Indexed: 04/06/2025]
Abstract
Acute kidney injury (AKI) is a major cause of mortality in hospitalized patients, yet effective therapeutic interventions remain underdeveloped. To address this critical need, we have employed tetrahedral framework nucleic acid (tFNA) as a carrier to self-assemble a complex incorporating G-quadruplex and hemin (G4/Hemin). This novel formulation exhibits uniform particle size, targeted delivery, and significant therapeutic efficacy for AKI. In a chemotherapy-induced AKI model, G4/Hemin-tFNA preferentially accumulated in the renal tubules, significantly mitigating drug-induced renal tubular injury. In healthy mice, G4/Hemin-tFNA was rapidly cleared from circulation due to efficient renal filtration. Safety evaluations conducted over a continuous 30-day period indicated minimal side effects associated with G4/Hemin-tFNA administration. Mechanistic studies elucidated three primary molecular mechanisms through which G4/Hemin-tFNA exerts its therapeutic effects in AKI: 1) Enhanced Renal Targeting. G4/Hemin-tFNA facilitates effective renal targeting and protection during blood circulation, leading to significant accumulation of drug within the kidneys. 2) Reactive Oxygen Species (ROS) Clearance. The complex exhibits peroxidase-like activity, enabling the rapid clearance of ROS at the site of AKI lesions, thereby inhibiting the oxidative stress progression. 3) Activation of heme oxygenase-1 (HO-1). G4/Hemin-tFNA selectively activates HO-1, enhancing the concentration of anti-inflammatory factors at inflamed sites and promoting an anti-inflammatory microenvironment. Collectively, these findings demonstrate that G4/Hemin-tFNA is a safe and effective therapeutic agent for AKI. By activating HO-1 and clearing ROS, G4/Hemin-tFNA inhibits disease progression, offering a promising approach for the development of future AKI therapies.
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Affiliation(s)
- Yu Ren
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, Institute for Liver Diseases of Anhui Medical University, School of Pharmacy, Anhui Medical University, Hefei, 230032, PR China
| | - Yuhang Dong
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, Institute for Liver Diseases of Anhui Medical University, School of Pharmacy, Anhui Medical University, Hefei, 230032, PR China
| | - Zhi Li
- Division of Oral and Systemic Health Sciences, School of Dentistry, University of California, Los Angeles, CA, 90095, United States
| | - Keying Xu
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, Institute for Liver Diseases of Anhui Medical University, School of Pharmacy, Anhui Medical University, Hefei, 230032, PR China
| | - Jiafeng Xu
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, Institute for Liver Diseases of Anhui Medical University, School of Pharmacy, Anhui Medical University, Hefei, 230032, PR China
| | - Xiangyu Li
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, Institute for Liver Diseases of Anhui Medical University, School of Pharmacy, Anhui Medical University, Hefei, 230032, PR China
| | - Mengmeng Zhang
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, Institute for Liver Diseases of Anhui Medical University, School of Pharmacy, Anhui Medical University, Hefei, 230032, PR China
| | - Changlu Xu
- Division of Oral and Systemic Health Sciences, School of Dentistry, University of California, Los Angeles, CA, 90095, United States
| | - Min Yang
- The Second Department of Critical. Care Medicine, The Second Affiliated Hospital of Anhui- Medical University, Anhui, Hefei, 230601, PR China
| | - Min Lee
- Division of Oral and Systemic Health Sciences, School of Dentistry, University of California, Los Angeles, CA, 90095, United States; Department of Bioengineering, University of California, Los Angeles, CA, 90095, United States.
| | - Xiaoming Meng
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, Institute for Liver Diseases of Anhui Medical University, School of Pharmacy, Anhui Medical University, Hefei, 230032, PR China.
| | - Jie Wang
- The Second Department of Critical. Care Medicine, The Second Affiliated Hospital of Anhui- Medical University, Anhui, Hefei, 230601, PR China.
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2
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Obeng EM, Hodge C, You J. Microplastic pollution: a review of specific blood-tissue barrier breaches and health effects. ENVIRONMENTAL POLLUTION (BARKING, ESSEX : 1987) 2025; 376:126416. [PMID: 40355068 DOI: 10.1016/j.envpol.2025.126416] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/23/2025] [Revised: 05/09/2025] [Accepted: 05/09/2025] [Indexed: 05/14/2025]
Abstract
Microplastic (1 μm - 5 mm) and nanoplastic (<1 μm) pollution is a heightening global challenge affecting the environment and the health of living creatures within. As primary precursors for plastic manufacturing, microplastics predominantly get into the environment through plastic product degradation and integrate into water, food chain and consumer products leading to potential health consequences. The mammalian system is equipped with several blood-tissue barriers with exclusive tight junctions that selectively regulate material transfer and protect vulnerable and functionally important organs. Nonetheless, emerging evidence indicates microplastics interact, traverse and compromise the integrity of these complex barriers. This review summarises the known and potential impact of microplastics on human health, focusing on specific organ barrier breaches. Evidence of microplastic traversal and deposition in distal mammalian organs are discussed. We further highlight current challenges facing both researchers and clinicians and provide an outlook for expanding our understanding of the impact of microplastic on health.
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Affiliation(s)
- Eugene M Obeng
- School of Medical Sciences, Faculty of Medicine and Health, University of Sydney, Camperdown, NSW, 2006, Australia; The University of Sydney Nano Institute (Sydney Nano), University of Sydney, Camperdown, NSW, 2006, Australia; Net Zero Institute, University of Sydney, Darlington, NSW, 2006, Australia.
| | - Christopher Hodge
- School of Medical Sciences, Faculty of Medicine and Health, University of Sydney, Camperdown, NSW, 2006, Australia; Net Zero Institute, University of Sydney, Darlington, NSW, 2006, Australia; Save Sight Institute, University of Sydney, Sydney, NSW, 2000, Australia; Vision Eye Institute, Chatswood, NSW, 2067, Australia
| | - Jingjing You
- School of Medical Sciences, Faculty of Medicine and Health, University of Sydney, Camperdown, NSW, 2006, Australia; Net Zero Institute, University of Sydney, Darlington, NSW, 2006, Australia; Vision Eye Institute, Chatswood, NSW, 2067, Australia; School of Optometry and Vision Science, University of New South Wales, Sydney, New South Wales, Australia.
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3
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Bai L, Jia Y, Ma S, Cai Q, Zhang Y, Zhu S. Albumin-seeking NIR dyes for high-sensitive imaging of glomerular filtration barrier breakdown. Biomaterials 2025; 317:123093. [PMID: 39799697 DOI: 10.1016/j.biomaterials.2025.123093] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2024] [Revised: 12/24/2024] [Accepted: 01/05/2025] [Indexed: 01/15/2025]
Abstract
The kidney, vital for metabolic balance, faces risks of severe diseases if dysfunctional. The glomerular filtration barrier (GFB), crucial for blood filtration, disrupts in conditions like diabetic nephropathy or nephritides, resulting in proteinuria or even renal failure. Monitoring GFB integrity is essential for early diagnosis or prognostic monitoring. However, current methods lack effective contrast agents for precise, non-invasive GFB imaging. As near-infrared-II (NIR-II) imaging offers promising imaging quality due to its deep tissue penetration and high resolution/contrast while albumin servers as an efficient biomarker for GFB disruption, developing NIR-II dyes with inherent albumin-targeting moiety, will provide real-time imaging of GFB disruption. Here, we adopt albumin-seeking cyanine dye to high-resolution image endogenous albumin in mouse models, facilitating detecting even mild disruptions with trace proteinuria. Notably, our strategy can determine albuminuria by real time imaging without the need to collect urine. Albumin-seeking dyes also enable fast and accurate quantitative measurement of microalbuminuria from patients. These dyes could revolutionize diagnostics, offering rapid, sensitive in vivo imaging of microalbuminuria and diverse clinical applications.
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Affiliation(s)
- Lang Bai
- Joint Laboratory of Opto-Functional Theranostics in Medicine and Chemistry, The First Hospital of Jilin University, Changchun, 130021, PR China; State Key Laboratory of Supramolecular Structure and Materials, Center for Supramolecular Chemical Biology, College of Chemistry, Jilin University, Changchun, 130012, PR China
| | - Yunlong Jia
- Joint Laboratory of Opto-Functional Theranostics in Medicine and Chemistry, The First Hospital of Jilin University, Changchun, 130021, PR China
| | - Shengjie Ma
- Department of Gastrocolorectal Surgery, General Surgery Center, The First Hospital of Jilin University, Changchun, 130012, PR China.
| | - Qing Cai
- Department of Oral Implantology, School and Hospital of Stomatology, Jilin University, Changchun, 130021, PR China.
| | - Yuewei Zhang
- Joint Laboratory of Opto-Functional Theranostics in Medicine and Chemistry, The First Hospital of Jilin University, Changchun, 130021, PR China.
| | - Shoujun Zhu
- Joint Laboratory of Opto-Functional Theranostics in Medicine and Chemistry, The First Hospital of Jilin University, Changchun, 130021, PR China; State Key Laboratory of Supramolecular Structure and Materials, Center for Supramolecular Chemical Biology, College of Chemistry, Jilin University, Changchun, 130012, PR China.
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Zhu W, Wang Q, Chen M. Identifying genes and traits associated with pre-eclampsia using summary statistics. PLoS One 2025; 20:e0323683. [PMID: 40445995 PMCID: PMC12124566 DOI: 10.1371/journal.pone.0323683] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2024] [Accepted: 04/11/2025] [Indexed: 06/02/2025] Open
Abstract
The occurrence and development of pre-eclampsia (PE) is closely related to genetics. However, multi-omics analysis does not provide sufficient evidence to define significant genes. Therefore, we aimed to identify significant genes and pathways using summary statistics from genome-wide association studies (GWAS). Based on the summary statistics, we used linkage disequilibrium score regression (LDSC) to discover genetic correlation between PE and complex traits. Leveraging summary statistics of tissue-specific expression quantitative trait loci (eQTL), we used FUSION to define significant genes, Bayesian colocalization analysis to identify pleiotropic genes, and Multi-marker Analysis of GenoMic Annotation (MAGMA) to determine the associated pathways. Specifically, considering the potential relationship between PE and tissues, we included 11 tissues, such as kidney cortex. Our integrative analysis revealed that the observed heritability of PE was 0.0179 (standard error [SE] = 0.0021, P-value < 0.001). Also, based on the Bonferroni correction, we defined 238 traits genetically correlated to PE, such as the other cardiovascular diseases (r = -0.55) and furosemide (r = 0.79). Integrating eQTL summary statistics across eleven tissues, we identified 30 significant genes, such as EIF2S1 in the uterus (TWAS. Z = 4.44, TWAS. P = 8.95 × 10-6), and PAWRP2 in ovary (TWAS. Z = 4.34, TWAS. P = 1.45 × 10-5). Based on colocalization, we identified 26 pleiotropic genes. We found that three genes, including RPS26, SULT1A2, OBSCN-AS1, and SUOX, were simultaneously defined by FUSION and colocalization. Moreover, we found that the significant enrichment was in the FOXG1_TARGET_GENES pathway regulated by the transcription factor FOXG1 (PFDR = 0.049). The findings of post-GWAS analysis for PE indicate that there are 30 significant genes and 26 pleiotropic genes. Future studies are required to investigate the efficacy of targeting pleiotropic genes to reduce the risk of PE.
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Affiliation(s)
- Wenyan Zhu
- Department of Biostatistics, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, China
| | - Qi Wang
- Department of gynecology and obstetrics, Nanjing Women and Children’s Healthcare Hospital, Women’s Hospital of Nanjing Medical University, Nanjing, China
| | - Min Chen
- Department of gynecology and obstetrics, Nanjing Women and Children’s Healthcare Hospital, Women’s Hospital of Nanjing Medical University, Nanjing, China
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Yang XD, Ma SJ, Xiang DX, Yang YY. Shenfushu granules attenuate diabetic kidney disease by inhibiting PIK3R1/protein kinase B/heparanase-mediated endothelial-mesenchymal transition. World J Diabetes 2025; 16:102196. [DOI: 10.4239/wjd.v16.i5.102196] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/12/2024] [Revised: 02/09/2025] [Accepted: 03/18/2025] [Indexed: 04/25/2025] Open
Abstract
BACKGROUND Injury to the glomerular filtration barrier causes diabetic kidney disease (DKD), and glomerular endothelial-mesenchymal transition damages the filtration barrier of glomerular endothelial cells. Shenfushu granules (SFSGs) can treat chronic renal failure; however, their role and mechanism in DKD remain unclear.
AIM To investigate the role of SFSGs in delaying DKD progression and their underlying mechanism in a streptozotocin-induced DKD mouse model.
METHODS The microalbumin content in the urine and the blood glucose, creatinine, and blood urea nitrogen levels in the serum were measured. The expression and distribution of α-smooth muscle actin (α-SMA), heparan sulfate (HS) and cluster of differentiation (CD) 31 were observed through immunofluorescence or immunohistochemistry. Western blotting was conducted to measure the expression of CD31, α-SMA, PIK3R1, protein kinase B (AKT), phospho-PIK3R1, phospho-AKT, and heparanase-1. Network pharmacology was conducted to screen and identify the core components and targets of SFSGs. Molecular docking and dynamic simulations were performed to evaluate the binding ability of the core components of SFSGs to their core targets.
RESULTS Compared with those in the model group, the 24-hour microalbuminuria (188.2 ± 20.1 and 140.4 ± 24.7 vs 323.2 ± 44.4), serum creatinine (79.4 ± 2.6 and 68.7 ± 6.0 vs 110.2 ± 4.8), blood urea nitrogen (14.4 ± 1.1 and 13.1 ± 0.5 vs 19.5 ± 1.1), and renal index (20.3 ± 1.0 and 19.6 ± 0.8 vs 25.3 ± 1.7) were significantly lower in the SFSGs (2.08 and 4.16 g/kg/day extract)-treated DKD mice. SFSGs inhibited the downregulation of CD31 and the upregulation of α-SMA in the glomerular endothelial cells of DKD mice. Additionally, SFSGs suppressed the decrease in glycocalyx thickness and the expression of its component HS. Network pharmacology revealed that PIK3R1 was the core target of SFSGs. SFSGs markedly downregulate the expression of phospho-PIK3R1, phospho-AKT, and heparanase-1. However, the PIK3R1 agonist abolished the regulatory effect of SFSGs on the expression of CD31, α-SMA, and heparanase-1.
CONCLUSION Collectively, these results suggest that SFSGs can significantly delay DKD progression and inhibit injury to the glycocalyx and the endothelial-mesenchymal transition of glomerular endothelial cells. This mechanism is related to PIK3R1/AKT/heparanase-1 signaling pathway regulation.
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Affiliation(s)
- Xi-Ding Yang
- Department of Pharmacy, The Second Xiangya Hospital of Central South University, Changsha 410011, Hunan Province, China
| | - Si-Jia Ma
- Department of Pharmacy, The Second Xiangya Hospital of Central South University, Changsha 410011, Hunan Province, China
| | - Da-Xiong Xiang
- Department of Pharmacy, The Second Xiangya Hospital of Central South University, Changsha 410011, Hunan Province, China
| | - Yong-Yu Yang
- Department of Pharmacy, The Second Xiangya Hospital of Central South University, Changsha 410011, Hunan Province, China
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Torrini F, Frigerio R, Garlipp J, Lenzen P, Normak K, Paganini C, Cretich M, Gori A, Arosio P. Affinity-Based Isolation and One-Pot Analysis of Extracellular Vesicles from Biofluids Using Phase Separated Zwitterionic Coacervates. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2025; 12:e2411653. [PMID: 40231809 PMCID: PMC12120729 DOI: 10.1002/advs.202411653] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/20/2024] [Revised: 02/25/2025] [Indexed: 04/16/2025]
Abstract
Extracellular vesicles (EVs) hold promise for liquid biopsy and drug delivery applications. However, their heterogeneous nature poses challenges for efficient and selective isolation from complex biofluids. Here, an isolation method based on phase-separated zwitterionic (ZW) coacervates is developed. These coacervates form over a wide range of pH values and ionic strengths, ensuring compatibility with all biofluids. They exhibit antifouling properties that minimize nonspecific binding, allowing for the selective isolation of EVs from biofluids upon functionalization of the polymer with a suitable affinity probe, as proved here with a membrane-sensing peptide. This strategy is applied to pull down, concentrate, and release EVs from urine samples with high yields while retaining their structural integrity. This approach effectively separates EVs from lipoproteins, a challenging task for conventional separation techniques. The power of the approach is demonstrated as a preparative step for downstream analysis and as a one-pot assay to profile EV biomarkers in complex fluids. The latter application, implemented here with flow cytometry, significantly streamlines pre-analytical workflows. Thus, functionalized ZW coacervates represent an effective strategy for the selective isolation and direct analysis of EVs from complex mixtures, paving the way for advances in large-scale manufacturing and diagnostics.
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Affiliation(s)
- Francesca Torrini
- Department of Chemistry and Applied Biosciences, Institute for Chemical and BioengineeringETH ZurichZurich8093Switzerland
| | - Roberto Frigerio
- Consiglio Nazionale delle RicercheIstituto di Scienze e Tecnologie Chimiche “Giulio Natta” (SCITEC)Milan20131Italy
| | - Jonathan Garlipp
- Department of Chemistry and Applied Biosciences, Institute for Chemical and BioengineeringETH ZurichZurich8093Switzerland
| | - Philippe Lenzen
- Department of Chemistry and Applied Biosciences, Institute for Chemical and BioengineeringETH ZurichZurich8093Switzerland
| | - Karl Normak
- Department of Chemistry and Applied Biosciences, Institute for Chemical and BioengineeringETH ZurichZurich8093Switzerland
| | - Carolina Paganini
- Department of Chemistry and Applied Biosciences, Institute for Chemical and BioengineeringETH ZurichZurich8093Switzerland
| | - Marina Cretich
- Consiglio Nazionale delle RicercheIstituto di Scienze e Tecnologie Chimiche “Giulio Natta” (SCITEC)Milan20131Italy
| | - Alessandro Gori
- Consiglio Nazionale delle RicercheIstituto di Scienze e Tecnologie Chimiche “Giulio Natta” (SCITEC)Milan20131Italy
| | - Paolo Arosio
- Department of Chemistry and Applied Biosciences, Institute for Chemical and BioengineeringETH ZurichZurich8093Switzerland
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Gao Y, Ren J, Peng H, Nasser MI, Liu C. Follistatin-like protein 1: Implications for renal disease progression. J Pharmacol Exp Ther 2025; 392:103564. [PMID: 40239460 DOI: 10.1016/j.jpet.2025.103564] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2025] [Revised: 02/22/2025] [Accepted: 03/20/2025] [Indexed: 04/18/2025] Open
Abstract
Renal diseases, including glomerulonephritis, acute kidney injury, chronic kidney failure, and kidney tumors are all current global health challenges. Lesions in other systems can cause renal diseases and can affect other systems or even the whole body. Despite ongoing advancements in pharmaceutical and technological innovations, the prognosis for end-stage renal disease, encompassing renal failure and tumors, continues to be bleak. Follistatin-like protein 1 (FSTL1) is a secreted glycoprotein produced mainly by mesenchymal cells. FSTL1 is a glycoprotein that belongs to the family of secreted, cysteine-rich acidic proteins (SPARC). It plays a pivotal role in cell survival, proliferation, differentiation, and migration, as well as in modulating inflammation and immune responses. Research has shown that FSTL1 plays a crucial role in the onset and progression of renal diseases. This review explores the functions and underlying mechanisms of FSTL1 in kidney pathology. SIGNIFICANCE STATEMENT: This review highlights the pivotal role of FSTL1 in renal diseases, particularly its involvement in renal fibrosis, inflammation, and ischemia-reperfusion injury. By elucidating its dual roles across different pathologies, this work underscores FSTL1's potential as both a biomarker and a therapeutic target, offering novel insights for managing chronic kidney disease and associated complications.
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Affiliation(s)
- Yiqi Gao
- Tangdu Hospital of the Fourth Military Medical University, Xi'an, Shaanxi, China
| | - Junyi Ren
- University of Electronic Science and Technology of China, School of Medicine, Chengdu, Sichuan, China
| | - Haoyu Peng
- University of Electronic Science and Technology of China, School of Medicine, Chengdu, Sichuan, China
| | - Moussa Ide Nasser
- Department of Cardiac Surgery, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangdong Cardiovascular Institute, Guangzhou, Guangdong, China.
| | - Chi Liu
- Department of Nephrology, Sichuan Clinical Research Center for Kidney Disease, Sichuan Provincial People's Hospital, University of Electronic Science and Technology, Chengdu, Sichuan, China.
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Chen Y, Yang H, Wang Z. A dynamic study on serum biomarkers and kidney injury in a gosling model of hyperuricemia. Poult Sci 2025; 104:105144. [PMID: 40209470 PMCID: PMC12008651 DOI: 10.1016/j.psj.2025.105144] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2025] [Revised: 03/30/2025] [Accepted: 04/06/2025] [Indexed: 04/12/2025] Open
Abstract
Hyperuricemia, a metabolic disorder characterized by elevated serum uric acid levels, poses significant challenges to poultry health and productivity. This study aimed to establish a hyperuricemia model in goslings through a multi-factorial induction approach using a high-purine, high-protein, and high-calcium diet, to investigate its dynamic progression, serological markers, and renal pathology. A total of 160 male Sanhua goslings were randomly assigned to control and model groups and fed either a basal diet or a high-purine, high-protein, and high-calcium diet for 18 days. Key findings revealed significant elevations in serum uric acid, creatinine, and urea nitrogen levels in the model group from day 5 onward, peaking on day 13 (p < 0.01). Activities of xanthine oxidase and adenosine deaminase were consistently higher in the model group, indicating enhanced purine metabolism and oxidative stress. Histopathological analysis showed progressive renal damage, including tubular degeneration, interstitial fibrosis, and glomerular injury, becoming evident by day 7 and severe by day 13. Ultrastructural examination further revealed mitochondrial dysfunction, podocyte effacement, and basement membrane disruption in the model group. Behavioral abnormalities, such as reduced mobility and the "shrinking neck" phenomenon, were observed from day 9, reflecting systemic disease severity. The dynamic expression of fibrosis-related markers, including Col-1, Col-3, and α-SMA, demonstrated the progression of renal fibrosis and extracellular matrix remodeling. These findings identify biomarkers for hyperuricemia progression and suggest potential therapeutic targets. This study establishes a comprehensive framework for understanding hyperuricemia-associated renal pathology and lays the groundwork for developing strategies to mitigate its impact on poultry health and productivity.
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Affiliation(s)
- Yuanjing Chen
- College of Veterinary Medicine, Yangzhou University, Yangzhou, PR China
| | - Haiming Yang
- College of Animal Science and Technology, Yangzhou University, Yangzhou, PR China
| | - Zhiyue Wang
- College of Veterinary Medicine, Yangzhou University, Yangzhou, PR China; College of Animal Science and Technology, Yangzhou University, Yangzhou, PR China.
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9
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Tramontano D, D'Erasmo L, Larouche M, Brisson D, Lauzière A, Di Costanzo A, Bini S, Minicocci I, Covino S, Baratta F, Pasquali M, Cerbelli B, Gaudet D, Arca M. The vicious circle of chronic kidney disease and hypertriglyceridemia: What is first, the hen or the egg? Atherosclerosis 2025; 403:119146. [PMID: 40056689 DOI: 10.1016/j.atherosclerosis.2025.119146] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/21/2024] [Revised: 02/19/2025] [Accepted: 02/20/2025] [Indexed: 03/10/2025]
Abstract
Chronic kidney disease (CKD) is documented to cause alterations in lipid metabolism, and this was considered a potent driver of increased cardiovascular risk. Among the diverse alteration of lipid traits in CKD, research endeavours have predominantly concentrated on low-density lipoproteins (LDL) in view of the potent pro-atherogenic role of these lipoprotein particles and the demonstration of protective cardiovascular effect of reducing LDL. However, few studies have focused on the metabolism of triglyceride-rich lipoproteins and even fewer on their role in causing kidney damage. Therefore, the comprehensive description of the impact of hypertriglyceridemia (HTG) in CKD pathophysiology remains largely undetermined. This reflects the difficulty of disentangling the independent role of triglycerides (TG) in the complex, bidirectional relationship between TG and kidney disease. Abnormal neutral lipid accumulation in the intrarenal vasculature and renal cells eventually due to HTG may also promote glomerular injury, throughout mechanisms including oxidative stress, mitochondrial dysfunction and proinflammatory responses. While epidemiological and experimental evidence suggests a potential role of TG in kidney damage, the causal mechanisms and their clinical relevance remain unclear, representing a significant area for future investigation. This review aims to highlight the intricate interplay between TG metabolism and kidney disease, shedding light on the mechanisms through which HTG may influence kidney functionality.
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Affiliation(s)
- Daniele Tramontano
- Department of Translational and Precision Medicine, Sapienza University of Rome, Viale Dell' Università 37, 00161, Rome, Italy
| | - Laura D'Erasmo
- Department of Translational and Precision Medicine, Sapienza University of Rome, Viale Dell' Università 37, 00161, Rome, Italy.
| | - Miriam Larouche
- Lipidology Unit, Community Genomic Medicine Center, Department of Medicine, Université de Montréal and ECOGENE-21 Clinical Research Center, Chicoutimi, QC, Canada
| | - Diane Brisson
- Lipidology Unit, Community Genomic Medicine Center, Department of Medicine, Université de Montréal and ECOGENE-21 Clinical Research Center, Chicoutimi, QC, Canada
| | - Alex Lauzière
- Lipidology Unit, Community Genomic Medicine Center, Department of Medicine, Université de Montréal and ECOGENE-21 Clinical Research Center, Chicoutimi, QC, Canada
| | - Alessia Di Costanzo
- Department of Translational and Precision Medicine, Sapienza University of Rome, Viale Dell' Università 37, 00161, Rome, Italy
| | - Simone Bini
- Department of Translational and Precision Medicine, Sapienza University of Rome, Viale Dell' Università 37, 00161, Rome, Italy
| | - Ilenia Minicocci
- Department of Translational and Precision Medicine, Sapienza University of Rome, Viale Dell' Università 37, 00161, Rome, Italy
| | - Stella Covino
- Department of Translational and Precision Medicine, Sapienza University of Rome, Viale Dell' Università 37, 00161, Rome, Italy
| | - Francesco Baratta
- Department of Clinical Internal, Anaesthesiological and Cardiovascular Sciences, Sapienza University of Rome, Rome, Italy
| | - Marzia Pasquali
- Department of Internal Medicine and Medical Specialities, Nephrology Unit, University Policlinico Umberto I Hospital, Rome, Italy
| | - Bruna Cerbelli
- Department of Medical-Surgical Sciences and Biotechnologies Sapienza University of Rome, Rome, Italy
| | - Daniel Gaudet
- Lipidology Unit, Community Genomic Medicine Center, Department of Medicine, Université de Montréal and ECOGENE-21 Clinical Research Center, Chicoutimi, QC, Canada
| | - Marcello Arca
- Department of Translational and Precision Medicine, Sapienza University of Rome, Viale Dell' Università 37, 00161, Rome, Italy
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Huang Y, Song Y, Wang S. Nature-Inspired Engineering Separation Materials and Devices. ACS NANO 2025; 19:11477-11488. [PMID: 40101135 DOI: 10.1021/acsnano.4c17912] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 03/20/2025]
Abstract
Separation is a fundamental process in natural living systems. Their separation capabilities have inspired the design of various separation materials and devices. Despite some progress having been made, a comprehensive overview is still lacking. In this Perspective, we first review the development of separation technologies. We then summarize some typical living systems exhibiting superior separation capabilities from compositions and microstructures to separation mechanisms. Next, we highlight key advancements in nature-inspired separation materials and integrated devices. Finally, we propose future research directions and opportunities, emphasizing the importance of physical and chemical design and internal and external stimulus regulation. These nature-inspired materials and devices show great potential in biomedicine, environmental remediation, energy conversion, food safety, and analysis testing.
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Affiliation(s)
- Yanling Huang
- CAS Key Laboratory of Bio-inspired Materials and Interfacial Science, Technical Institute of Physics and Chemistry, Chinese Academy of Sciences, Beijing 100190, P. R. China
| | - Yongyang Song
- CAS Key Laboratory of Bio-inspired Materials and Interfacial Science, Technical Institute of Physics and Chemistry, Chinese Academy of Sciences, Beijing 100190, P. R. China
- University of Chinese Academy of Sciences, Beijing 100049, P. R. China
| | - Shutao Wang
- CAS Key Laboratory of Bio-inspired Materials and Interfacial Science, Technical Institute of Physics and Chemistry, Chinese Academy of Sciences, Beijing 100190, P. R. China
- University of Chinese Academy of Sciences, Beijing 100049, P. R. China
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11
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Kiranmai G, Chameettachal S, Sriya Y, Duin S, Lode A, Gelinsky M, Akkineni AR, Pati F. Recent trends in the development of in vitro3D kidney models. Biofabrication 2025; 17:022010. [PMID: 39993331 DOI: 10.1088/1758-5090/adb999] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2024] [Accepted: 02/24/2025] [Indexed: 02/26/2025]
Abstract
The kidneys are vital for maintaining bodily homeostasis and are susceptible to various diseases that disrupt their function. Traditionally, research on kidney diseases has relied on animal models and simplistic two-dimensional cell cultures, which do not fully replicate human tissue pathology. To address this, recent advances focus on developing advanced 3D biomimeticin vitromodels using human-derived cells. These models mimic healthy and diseased kidney tissues with specificity, replicating key elements like glomerular and tubular structures through tissue engineering. By closely mimicking human physiology, they provide a promising platform for studying renal disorders, drug-induced nephrotoxicity, and evaluating new therapies. However, the challenges include optimizing scalability, reproducibility, and long-term stability to enhance reliability in research and clinical applications. This review highlights the transformative potential of 3D biomimeticin vitrokidney models in advancing biomedical research and clinical applications. By focusing on human-specific cell cultures and tissue engineering techniques, these models aim to overcome the limitations of conventional animal models and simplistic 2D cell cultures. The review discusses in detail the various types of biomimetic kidney models currently under development, their specific applications, and the innovative approaches used to construct them. It also addresses the challenges and limitations associated with these models for their widespread adoption and reliability in research settings.
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Affiliation(s)
- Gaddam Kiranmai
- Department of Biomedical Engineering, Indian Institute of Technology Hyderabad, Kandi, Sangareddy, Telangana 502285, India
| | - Shibu Chameettachal
- Department of Biomedical Engineering, Indian Institute of Technology Hyderabad, Kandi, Sangareddy, Telangana 502285, India
| | - Yeleswarapu Sriya
- Department of Biomedical Engineering, Indian Institute of Technology Hyderabad, Kandi, Sangareddy, Telangana 502285, India
| | - Sarah Duin
- Centre for Translational Bone, Joint and Soft Tissue Research, University Hospital and Faculty of Medicine Carl Gustav Carus, Technische Universität Dresden, Fetscherstr. 74, Dresden 01307, Germany
| | - Anja Lode
- Centre for Translational Bone, Joint and Soft Tissue Research, University Hospital and Faculty of Medicine Carl Gustav Carus, Technische Universität Dresden, Fetscherstr. 74, Dresden 01307, Germany
| | - Michael Gelinsky
- Centre for Translational Bone, Joint and Soft Tissue Research, University Hospital and Faculty of Medicine Carl Gustav Carus, Technische Universität Dresden, Fetscherstr. 74, Dresden 01307, Germany
| | - Ashwini Rahul Akkineni
- Centre for Translational Bone, Joint and Soft Tissue Research, University Hospital and Faculty of Medicine Carl Gustav Carus, Technische Universität Dresden, Fetscherstr. 74, Dresden 01307, Germany
| | - Falguni Pati
- Department of Biomedical Engineering, Indian Institute of Technology Hyderabad, Kandi, Sangareddy, Telangana 502285, India
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12
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Zhao Y, Zhuang Y, Shi J, Fan H, Lv Q, Guo X. Cathepsin B induces kidney diseases through different types of programmed cell death. Front Immunol 2025; 16:1535313. [PMID: 40129990 PMCID: PMC11930809 DOI: 10.3389/fimmu.2025.1535313] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2024] [Accepted: 02/25/2025] [Indexed: 03/26/2025] Open
Abstract
Cathepsin B (CTSB), a key cysteine protease, plays essential roles in physiological and pathological processes. As research progresses, interest in how CTSB triggers different types of programmed cell death (PCD) to induce the onset and development of diseases is increasing. Several recent studies suggest that different types of PCD mediated by CTSB play key roles in kidney diseases. In this review, we outline the fundamental mechanisms by which CTSB triggers different types of PCD in several kidney diseases and discuss the function of CTSB in various segments of the kidney. Moreover, we explore the possibilities and prospects of using CTSB as a therapeutic target for kidney diseases.
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Affiliation(s)
- Yunlong Zhao
- Institute of Disaster and Emergency Medicine, Tianjin University, Tianjin, China
- Key Laboratory for Disaster Medicine Technology, Tianjin University, Tianjin, China
- Wenzhou Safety (Emergency) Institute, Tianjin University, Wenzhou, China
| | - Yong Zhuang
- Institute of Disaster and Emergency Medicine, Tianjin University, Tianjin, China
- Key Laboratory for Disaster Medicine Technology, Tianjin University, Tianjin, China
- Wenzhou Safety (Emergency) Institute, Tianjin University, Wenzhou, China
| | - Jie Shi
- Institute of Disaster and Emergency Medicine, Tianjin University, Tianjin, China
- Key Laboratory for Disaster Medicine Technology, Tianjin University, Tianjin, China
- Wenzhou Safety (Emergency) Institute, Tianjin University, Wenzhou, China
| | - Haojun Fan
- Institute of Disaster and Emergency Medicine, Tianjin University, Tianjin, China
- Key Laboratory for Disaster Medicine Technology, Tianjin University, Tianjin, China
- Wenzhou Safety (Emergency) Institute, Tianjin University, Wenzhou, China
| | - Qi Lv
- Institute of Disaster and Emergency Medicine, Tianjin University, Tianjin, China
- Key Laboratory for Disaster Medicine Technology, Tianjin University, Tianjin, China
- Wenzhou Safety (Emergency) Institute, Tianjin University, Wenzhou, China
| | - Xiaoqin Guo
- Institute of Disaster and Emergency Medicine, Tianjin University, Tianjin, China
- Key Laboratory for Disaster Medicine Technology, Tianjin University, Tianjin, China
- Wenzhou Safety (Emergency) Institute, Tianjin University, Wenzhou, China
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13
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Zhao Z, Li P, Liu Z, Cui Y, Yao Z, Chen W, Wang M, Yu C, Xia S, Sun Y, Zhang N, Shen W. Exploring the molecular mechanisms by which secretory phospholipase a2 regulates lymphatic endothelial cell dysfunction by activating macrophages. Int J Biol Macromol 2025; 294:139038. [PMID: 39708872 DOI: 10.1016/j.ijbiomac.2024.139038] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2024] [Revised: 12/16/2024] [Accepted: 12/18/2024] [Indexed: 12/23/2024]
Abstract
This study offers new insights into the dual role of secretory phospholipase A2 (sPLA2) in lymphedema, highlighting its impact on lymphatic endothelial cell (LEC) functionality. Through transcriptomic analyses and co-culture experiments, we observed that sPLA2 has both protective and detrimental effects on human LECs (HLECs), mediated by macrophage activation. Our findings reveal that while low levels of sPLA2 promote LEC health, excessive sPLA2 leads to dysfunction, emphasizing the significance of the sPLA2/PLA2R axis and arachidonic acid metabolism (AA) in lymphedema pathology. The study suggests targeting sPLA2 and its downstream pathways as a novel therapeutic strategy for lymphedema, aiming to mitigate its progression by safeguarding HLEC integrity. This research underscores the importance of balanced sPLA2 activity in maintaining lymphatic vessel health and presents a new avenue for lymphedema management and treatment.
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Affiliation(s)
- Zimin Zhao
- Department of Lymphatic Surgery, Capital Medical University Affiliated Beijing Shijitan Hospital; Clinical Center for Lymphatic Disorders, CMU, China
| | - Peilin Li
- Department of Lymphatic Surgery, Capital Medical University Affiliated Beijing Shijitan Hospital; Clinical Center for Lymphatic Disorders, CMU, China
| | - Zhong Liu
- Department of Lymphatic Surgery, Capital Medical University Affiliated Beijing Shijitan Hospital; Clinical Center for Lymphatic Disorders, CMU, China
| | - Yonghao Cui
- Department of Lymphatic Surgery, Capital Medical University Affiliated Beijing Shijitan Hospital; Clinical Center for Lymphatic Disorders, CMU, China
| | - Zixuan Yao
- Department of Lymphatic Surgery, Capital Medical University Affiliated Beijing Shijitan Hospital; Clinical Center for Lymphatic Disorders, CMU, China
| | - Weijian Chen
- Center for Obesity and Metabolic Disease, Capital Medical University Affiliated Beijing Shijitan Hospital, Beijing, China
| | - Mengqin Wang
- Center for Obesity and Metabolic Disease, Capital Medical University Affiliated Beijing Shijitan Hospital, Beijing, China
| | - Chengyuan Yu
- Peking University Ninth Clinical School of Medicine, China
| | - Song Xia
- Department of Lymphatic Surgery, Capital Medical University Affiliated Beijing Shijitan Hospital; Clinical Center for Lymphatic Disorders, CMU, China
| | - Yuguang Sun
- Department of Lymphatic Surgery, Capital Medical University Affiliated Beijing Shijitan Hospital; Clinical Center for Lymphatic Disorders, CMU, China
| | - Nengwei Zhang
- Center for Obesity and Metabolic Disease, Capital Medical University Affiliated Beijing Shijitan Hospital, Beijing, China.
| | - Wenbin Shen
- Department of Lymphatic Surgery, Capital Medical University Affiliated Beijing Shijitan Hospital; Clinical Center for Lymphatic Disorders, CMU, China.
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14
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Haddad G, Blaine J. miR-204-5p Protects Nephrin from Enzymatic Degradation in Cultured Mouse Podocytes Treated with Nephrotoxic Serum. Cells 2025; 14:364. [PMID: 40072092 PMCID: PMC11899291 DOI: 10.3390/cells14050364] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2025] [Revised: 02/25/2025] [Accepted: 02/26/2025] [Indexed: 03/15/2025] Open
Abstract
Nephrin is an essential constituent of the slit diaphragm of the kidney filtering unit. Loss of nephrin expression leads to protein leakage into the urine, one of the hallmarks of kidney damage. Autoantibodies against nephrin have been reported in patients with minimal change disease and recurrent focal segmental glomerulosclerosis. Understanding the mechanism of nephrin loss may help improve or lead to the development of novel treatment strategies. In this study, we demonstrated the important function of miR-204-5p expression on the protection of nephrin from anti-nephrin antibodies present in nephrotoxic serum (NTS). In addition, we identified that aspartyl protease cathepsin D is one enzyme that may be involved in nephrin enzymatic degradation and that cathepsin D is a direct target of miR-204-5p gene regulation. The regulation of miR-204-5p expression was determined to be regulated by the long noncoding RNA Josd1-ps. In an NTS in vivo animal model, treatment with the pan aspartic protease inhibitor Pepstatin A ameliorated renal damage. Finally, we showed that the expression of miR-204-5p had a nephrin-protecting function in vitro. Developing a method of delivery of miR-204-5p specifically to podocytes in vivo may provide a novel method of nephroprotection against nephrin autoantibodies.
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Affiliation(s)
- George Haddad
- Division of Renal Disease and Hypertension, Department of Medicine, School of Medicine, University of Colorado, Aurora, CO 80045, USA;
| | - Judith Blaine
- Division of Renal Disease and Hypertension, Department of Medicine, School of Medicine, University of Colorado, Aurora, CO 80045, USA;
- Division of Renal Diseases and Hypertension, University of Colorado Anschutz Medical Campus, 12700 E 19th Ave, Aurora, CO 80045, USA
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15
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Wang J, Shi H, Yang Y, Gong X. Crosstalk between ferroptosis and innate immune in diabetic kidney disease: mechanisms and therapeutic implications. Front Immunol 2025; 16:1505794. [PMID: 40092979 PMCID: PMC11906378 DOI: 10.3389/fimmu.2025.1505794] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2024] [Accepted: 02/10/2025] [Indexed: 03/19/2025] Open
Abstract
Diabetic kidney disease (DKD) is a prevalent complication of diabetes mellitus (DM), and its incidence is increasing alongside the number of diabetes cases. Effective treatment and long-term management of DKD present significant challenges; thus, a deeper understanding of its pathogenesis is essential to address this issue. Chronic inflammation and abnormal cell death in the kidney closely associate with DKD development. Recently, there has been considerable attention focused on immune cell infiltration into renal tissues and its inflammatory response's role in disease progression. Concurrently, ferroptosis-a novel form of cell death-has emerged as a critical factor in DKD pathogenesis, leading to increased glomerular filtration permeability, proteinuria, tubular injury, interstitial fibrosis, and other pathological processes. The cardiorenal benefits of SGLT2 inhibitors (SGLT2-i) in DKD patients have been demonstrated through numerous large clinical trials. Moreover, further exploratory experiments indicate these drugs may ameliorate serum and urinary markers of inflammation, such as TNF-α, and inhibit ferroptosis in DKD models. Consequently, investigating the interplay between ferroptosis and innate immune and inflammatory responses in DKD is essential for guiding future drug development. This review presents an overview of ferroptosis within the context of DKD, beginning with its core mechanisms and delving into its potential roles in DKD progression. We will also analyze how aberrant innate immune cells, molecules, and signaling pathways contribute to disease progression. Finally, we discuss the interactions between ferroptosis and immune responses, as well as targeted therapeutic agents, based on current evidence. By analyzing the interplay between ferroptosis and innate immunity alongside its inflammatory responses in DKD, we aim to provide insights for clinical management and drug development in this area.
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Affiliation(s)
- Jinyang Wang
- Department of Geriatric Integrative, Second Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang, China
| | - Haonan Shi
- School of Medicine, Shanghai University, Shanghai, China
| | - Ye Yang
- Department of Geriatric Integrative, Second Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang, China
| | - Xueli Gong
- Department of Pathophysiology, School of Basic Medical Science, Xinjiang Medical University, Urumqi, Xinjiang, China
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16
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Dang Z, Zheng X, Gao Y, Du Y, Zhang Y, Zhu S. In situ albumin tagging for targeted imaging of endothelial barrier disruption. SCIENCE ADVANCES 2025; 11:eads4412. [PMID: 39951533 PMCID: PMC11827639 DOI: 10.1126/sciadv.ads4412] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/13/2024] [Accepted: 01/14/2025] [Indexed: 02/16/2025]
Abstract
The endothelial barrier (EB) is a critical component of the body's homeostatic mechanisms, thus developing effective imaging techniques to visualize its integrity is essential. The EB disruption is accompanied by the alternations in permeability and even the breakdown of tight junctions (TJs), leading to the leakage of albumin; thus, albumin can serve as a biomarker for EB disruption. Herein, we develop an albumin-specific, covalently tagged near-infrared II (NIR-II) dye, with its high selectivity for endogenous albumin, for targeted imaging EB disruption. Our albumin-tagging dye serves as a chromophore to construct NIR-II fluorescent proteins in situ, with substantially improved brightness. Thus, through in situ dye tagging of endogenous albumin as the efficient "targeting agent," we can precisely image disruptions in various endothelial barriers. Unlike the traditional exogenous targeting agents (e.g., dye-labeled antibodies) with enzymatic degradation or immune system capture issues, in situ albumin tagging demonstrates superhigh performance for targeted imaging.
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Affiliation(s)
- Zetao Dang
- State Key Laboratory of Supramolecular Structure and Materials, Center for Supramolecular Chemical Biology, College of Chemistry, Jilin University, Changchun 130012, P.R. China
- Joint Laboratory of Opto-Functional Theranostics in Medicine and Chemistry, The First Hospital of Jilin University, Changchun 130021, P.R. China
| | - Xue Zheng
- State Key Laboratory of Supramolecular Structure and Materials, Center for Supramolecular Chemical Biology, College of Chemistry, Jilin University, Changchun 130012, P.R. China
- Joint Laboratory of Opto-Functional Theranostics in Medicine and Chemistry, The First Hospital of Jilin University, Changchun 130021, P.R. China
| | - Yanli Gao
- Department of Pediatric Ultrasound, Ultrasound Diagnostic Center, The First Hospital of Jilin University, Changchun 130021, P.R. China
| | - Yijing Du
- State Key Laboratory of Supramolecular Structure and Materials, Center for Supramolecular Chemical Biology, College of Chemistry, Jilin University, Changchun 130012, P.R. China
- Joint Laboratory of Opto-Functional Theranostics in Medicine and Chemistry, The First Hospital of Jilin University, Changchun 130021, P.R. China
| | - Yuewei Zhang
- Joint Laboratory of Opto-Functional Theranostics in Medicine and Chemistry, The First Hospital of Jilin University, Changchun 130021, P.R. China
| | - Shoujun Zhu
- State Key Laboratory of Supramolecular Structure and Materials, Center for Supramolecular Chemical Biology, College of Chemistry, Jilin University, Changchun 130012, P.R. China
- Joint Laboratory of Opto-Functional Theranostics in Medicine and Chemistry, The First Hospital of Jilin University, Changchun 130021, P.R. China
- Key Laboratory of Organ Regeneration and Transplantation of Ministry of Education, Institute of Immunology, The First Hospital of Jilin University, Changchun 130021, P.R. China
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17
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May CJ, Ford NP, Welsh GI, Saleem MA. Biomarkers to predict or measure steroid resistance in idiopathic nephrotic syndrome: A systematic review. PLoS One 2025; 20:e0312232. [PMID: 39946431 PMCID: PMC11824968 DOI: 10.1371/journal.pone.0312232] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2023] [Accepted: 10/02/2024] [Indexed: 02/16/2025] Open
Abstract
In this systematic review we have sought to summarise the current knowledge concerning biomarkers that can distinguish between steroid-resistant nephrotic syndrome and steroid-sensitive nephrotic syndrome. Additionally, we aim to select biomarkers that have the best evidence-base and should be prioritised for further research. Pub med and web of science databases were searched using "steroid resistant nephrotic syndrome AND biomarker". Papers published between 01/01/2012 and 10/05/2022 were included. Papers that did not compare steroid resistant and steroid sensitive nephrotic syndrome, did not report sensitivity/specificity or area under curve and reviews/letters were excluded. The selected papers were then assessed for bias using the QUADAS-2 tool. The source of the biomarker, cut off, sensitivity/specificity, area under curve and sample size were all extracted. Quality assessment was performed using the BIOCROSS tool. 17 studies were included, comprising 15 case-control studies and 2 cross-sectional studies. Given the rarity of nephrotic syndrome and difficulty in recruiting large cohorts, case-control studies were accepted despite their limitations. We present a range of candidate biomarkers along with scores relating to the quality of the original publications and the risk of bias to inform future investigations. None of the selected papers stated whether the authors were blinded to the patient's disease when assessing the index test in the cohort. Highlighting a key problem in the field that needs to be addressed. These candidate biomarkers must now be tested with much larger sample sizes. Using new biobanks such as the one built by the NURTuRE-INS team will be very helpful in this regard.
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Affiliation(s)
- Carl J. May
- Bristol Renal, University of Bristol, Bristol, United Kingdom
| | | | - Gavin I. Welsh
- Bristol Renal, University of Bristol, Bristol, United Kingdom
| | - Moin A. Saleem
- Bristol Renal, University of Bristol, Bristol, United Kingdom
- Bristol Royal Hospital for Children, Bristol, United Kingdom
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18
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Zhang B, Zeng M, Wang R, Tie Q, Fan R, Zhang X, Zheng X, Feng W. Plantaginis Herba attenuates adriamycin-induced nephropathy: Molecular mechanism insights by integrated transcriptomic and experimental validation. JOURNAL OF ETHNOPHARMACOLOGY 2025; 341:119331. [PMID: 39778781 DOI: 10.1016/j.jep.2025.119331] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/10/2024] [Revised: 12/24/2024] [Accepted: 01/05/2025] [Indexed: 01/11/2025]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE The Chinese herbal Plantaginis Herba (PL) is one of the most widely used plants for both medicinal and dietary purposes. Plantaginis Herba is the main medicine used in a traditional Chinese prescription called Cheqiancao decoction, and it is known for its liver and kidney protective properties. AIM OF THE STUDY The aim of the present study was to explore the interventions and mechanisms of PL in ADR nephropathy by performing an integrated analysis of in vitro and in vivo experiments. MATERIALS AND METHODS The ingredients of PL were analysed by Ultra High Performance Liquid Chromatography (UPLC). The biochemical indicators of renal injury in the serum and urine were detected by a Micronumerase assay and ELISA. The renal histopathology and ultrastructure were analysed by H&E staining, Masson's trichrome staining and transmission electron microscopy (TEM), respectively. By identifying the targets of PL and ADR nephropathy, a network of PL-constituents-targets-ADR nephropathy was constructed, and a KEGG signaling pathway enrichment analysis was performed to complete the network pharmacology. A transcriptomic analysis was performed on a sequencing platform (Illumina). RESULTS Plantaginis Herba significantly decreased the levels of BUN, Scr, ALB, MAU and KIM-1. Plantaginis Herba inhibited renal histopathological injury and alleviate foot process fusion and podocyte basement membrane thickening. In addition, the results of the transcriptomic analysis and network pharmacology analysis indicated that the HIF-1, TGF-β, and PI3K/AKT signaling pathways; apoptosis; and ECM-receptor interactions might be pivotal pathways for the effect of the PL intervention on ADR nephropathy. Moreover, the validation results revealed that PL could effectively attenuate collagen fibre deposition and inhibit oxidative stress. Plantaginis Herba could regulate the expression levels of pivotal proteins in the β-catenin/TGF-β1, HIF-1, and PI3K signaling pathways in renal tissues. Plantaginis Herba could reduce the level of apoptosis and the percentage of decrease in the mitochondrial membrane potential (MMP) in primary renal cells from rats with ADR nephropathy, and regulate key proteins involved in mitochondrial apoptosis. Furthermore, Luteolin from PL had good affinity for HIF-1α, and the ability of Luteolin to ameliorate in ameliorating ADR-induced MPC-5 cell injury was attenuated by overexpressing HIF-1α. CONCLUSIONS Plantaginis Herba alleviates ADR-induced nephropathy by regulating mitochondrial apoptosis via the HIF-1α signaling pathway. Luteolin may be one of the active ingredients responsible for these effects, and these findings provide an innovative strategy for the intervention and treatment of ADR nephropathy.
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Affiliation(s)
- Beibei Zhang
- Henan University of Chinese Medicine, 156 Jinshui East Road, Zhengzhou, 450046, China; The Engineering and Technology Center for Chinese Medicine Development of Henan Province, 156 Jinshui East Road, Zhengzhou, 450046, China.
| | - Mengnan Zeng
- Henan University of Chinese Medicine, 156 Jinshui East Road, Zhengzhou, 450046, China; The Engineering and Technology Center for Chinese Medicine Development of Henan Province, 156 Jinshui East Road, Zhengzhou, 450046, China.
| | - Ru Wang
- Henan University of Chinese Medicine, 156 Jinshui East Road, Zhengzhou, 450046, China; The Engineering and Technology Center for Chinese Medicine Development of Henan Province, 156 Jinshui East Road, Zhengzhou, 450046, China.
| | - Qimei Tie
- Henan University of Chinese Medicine, 156 Jinshui East Road, Zhengzhou, 450046, China; The Engineering and Technology Center for Chinese Medicine Development of Henan Province, 156 Jinshui East Road, Zhengzhou, 450046, China.
| | - Ruyi Fan
- Henan University of Chinese Medicine, 156 Jinshui East Road, Zhengzhou, 450046, China.
| | - Xuyuan Zhang
- Henan University of Chinese Medicine, 156 Jinshui East Road, Zhengzhou, 450046, China.
| | - Xiaoke Zheng
- Henan University of Chinese Medicine, 156 Jinshui East Road, Zhengzhou, 450046, China; The Engineering and Technology Center for Chinese Medicine Development of Henan Province, 156 Jinshui East Road, Zhengzhou, 450046, China.
| | - Weisheng Feng
- Henan University of Chinese Medicine, 156 Jinshui East Road, Zhengzhou, 450046, China; The Engineering and Technology Center for Chinese Medicine Development of Henan Province, 156 Jinshui East Road, Zhengzhou, 450046, China.
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Rosales A, Blondel LO, Hull J, Gao Q, Aykun N, Peek JL, Vargas A, Fergione S, Song M, Wilson MH, Barbas AS, Asokan A. Evolving adeno-associated viruses for gene transfer to the kidney via cross-species cycling of capsid libraries. Nat Biomed Eng 2025:10.1038/s41551-024-01341-0. [PMID: 39910375 DOI: 10.1038/s41551-024-01341-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2023] [Accepted: 12/16/2024] [Indexed: 02/07/2025]
Abstract
The difficulty of delivering genes to the kidney has limited the translation of genetic medicines, particularly for the more than 10% of the global population with chronic kidney disease. Here we show that new variants of adeno-associated viruses (AAVs) displaying robust and widespread transduction in the kidneys of mice, pigs and non-human-primates can be obtained by evolving capsid libraries via cross-species cycling in different kidney models. Specifically, the new variants, AAV.k13 and AAV.k20, were enriched from the libraries following sequential intravenous cycling through mouse and pig kidneys, ex vivo cycling in human organoid cultures, and ex vivo machine perfusion in isolated kidneys from rhesus macaques. The two variants transduced murine kidneys following intravenous administration, with selective tropism for proximal tubules, and led to markedly higher transgene expression than parental AAV9 vectors in proximal tubule epithelial cells within human organoid cultures and in autotransplanted pig kidneys. Following ureteral delivery, AAV.k20 efficiently transduced kidneys in pigs and macaques. The AAV.k13 and AAV.k20 variants are promising vectors for therapeutic gene-transfer applications in kidney diseases and transplantation.
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Affiliation(s)
- Alan Rosales
- Department of Biomedical Engineering, Duke University, Durham, NC, USA
| | - Leo O Blondel
- Department of Surgery, Duke University School of Medicine, Durham, NC, USA
| | - Joshua Hull
- Department of Surgery, Duke University School of Medicine, Durham, NC, USA
| | - Qimeng Gao
- Department of Surgery, Duke University School of Medicine, Durham, NC, USA
| | - Nihal Aykun
- Department of Surgery, Duke University School of Medicine, Durham, NC, USA
| | - Jennifer L Peek
- Department of Cell and Developmental Biology, Vanderbilt University, Nashville, TN, USA
| | - Alejandra Vargas
- Department of Surgery, Duke University School of Medicine, Durham, NC, USA
| | - Sophia Fergione
- Department of Surgery, Duke University School of Medicine, Durham, NC, USA
| | - Mingqing Song
- Department of Surgery, Duke University School of Medicine, Durham, NC, USA
| | - Matthew H Wilson
- Department of Cell and Developmental Biology, Vanderbilt University, Nashville, TN, USA
- Department of Pharmacology, Vanderbilt University, Nashville, TN, USA
- Department of Medicine, Division of Nephrology and Hypertension, Vanderbilt University Medical Center, Nashville, TN, USA
- Department of Veterans Affairs, Nashville, TN, USA
| | - Andrew S Barbas
- Department of Surgery, Duke University School of Medicine, Durham, NC, USA
| | - Aravind Asokan
- Department of Biomedical Engineering, Duke University, Durham, NC, USA.
- Department of Surgery, Duke University School of Medicine, Durham, NC, USA.
- Department of Molecular Genetics and Microbiology, Duke University School of Medicine, Durham, NC, USA.
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Huang S, Zhou Y, Zhang Y, Liu N, Liu J, Liu L, Fan C. Advances in MicroRNA Therapy for Heart Failure: Clinical Trials, Preclinical Studies, and Controversies. Cardiovasc Drugs Ther 2025; 39:221-232. [PMID: 37505309 DOI: 10.1007/s10557-023-07492-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 07/17/2023] [Indexed: 07/29/2023]
Abstract
Heart failure (HF) is a rapidly growing public health issue with more than 37.7 million patients worldwide and an annual healthcare cost of $108 billion. However, HF-related drugs have not changed significantly for decades, and it is essential to find biological drugs to provide better treatment for HF patients. MicroRNAs (miRNAs) are non-coding RNAs (ncRNAs) with a length of approximately 21 nucleotides and play an important role in the onset and progression of cardiovascular diseases. Increasing studies have shown that miRNAs are widely involved in the pathophysiology of HF, and the regulation of miRNAs has promising therapeutic effects. Among them, there is great interest in miRNA-132, since the encouraging success of anti-miRNA-132 therapy in a phase 1b clinical trial in 2020. However, it is worth noting that the multi-target effect of miRNA may produce side effects such as thrombocytopenia, revascularization dysfunction, severe immune response, and even death. Advances in drug delivery modalities, delivery vehicles, chemical modifications, and plant-derived miRNAs are expected to address safety concerns and further improve miRNA therapy. Here, we reviewed the preclinical studies and clinical trials of HF-related miRNAs (especially miRNA-132) in the past 5 years and summarized the controversies of miRNA therapy.
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Affiliation(s)
- Shengyuan Huang
- Department of Cardiovascular Surgery, The Second Xiangya Hospital, Central South University, Middle Renmin Road 139, Changsha, 410011, China
| | - Yong Zhou
- Department of Cardiovascular Medicine, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Yiru Zhang
- Department of Laboratory Medicine, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Ningyuan Liu
- Department of Radiology, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Jiachen Liu
- Xiangya Medical College of Central South University, Changsha, China
| | - Liming Liu
- Department of Cardiovascular Surgery, The Second Xiangya Hospital, Central South University, Middle Renmin Road 139, Changsha, 410011, China
| | - Chengming Fan
- Department of Cardiovascular Surgery, The Second Xiangya Hospital, Central South University, Middle Renmin Road 139, Changsha, 410011, China.
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21
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Hackl A, Weber LT. The Ca 2+-actin-cytoskeleton axis in podocytes is an important, non-immunologic target of immunosuppressive therapy in proteinuric kidney diseases. Pediatr Nephrol 2025:10.1007/s00467-025-06670-z. [PMID: 39856247 DOI: 10.1007/s00467-025-06670-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/10/2024] [Revised: 12/19/2024] [Accepted: 12/19/2024] [Indexed: 01/27/2025]
Abstract
The integrity of the filtration barrier of the kidney relies on the proper composition of podocyte interdigitating foot processes. Their architecture is supported by a complex actin-cytoskeleton. Following podocyte stress or injury, podocytes encounter structural changes, including rearrangement of the actin network and subsequent effacement of the foot processes. Immunosuppressive drugs, which are currently used as treatment in proteinuric kidney diseases, have been shown to exert not only immune-mediated effects. This review will focus on the direct effects of glucocorticoids, cyclosporine A, tacrolimus, mycophenolate mofetil, and rituximab on podocytes by regulation of Ca2+ ion channels and consecutive downstream signaling which prevent cytoskeletal rearrangements and ultimately proteinuria. In addition, the efficacy of these drugs in genetic nephrotic syndrome will be discussed.
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Affiliation(s)
- Agnes Hackl
- Department of Pediatrics, University of Cologne, Faculty of Medicine and University Hospital Cologne, Kerpener Street 62, 50937, Cologne, Germany.
| | - Lutz T Weber
- Department of Pediatrics, University of Cologne, Faculty of Medicine and University Hospital Cologne, Kerpener Street 62, 50937, Cologne, Germany
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Lv J, Yu H, Du S, Xu P, Zhao Y, Qi W, Wang X. Targeting endoplasmic reticulum stress: an innovative therapeutic strategy for podocyte-related kidney diseases. J Transl Med 2025; 23:95. [PMID: 39838496 PMCID: PMC11752968 DOI: 10.1186/s12967-025-06076-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2024] [Accepted: 01/03/2025] [Indexed: 01/23/2025] Open
Abstract
The endoplasmic reticulum (ER) is a vital organelle responsible for protein quality control, including the folding, modification, and transport of proteins. When misfolded or unfolded proteins accumulate in the ER, it triggers endoplasmic reticulum stress (ERS) and activates the unfolded protein response (UPR) to restore ER homeostasis. However, prolonged or excessive ERS can lead to apoptosis. The kidneys play a crucial role in maintaining physiological functions by excreting metabolic waste, regulating blood volume, balancing electrolytes and acid-base levels, and secreting various bioactive substances. Podocytes, epithelial cells situated outside the glomerular basement membrane, are essential for maintaining the structural integrity and permeability of the glomerular filtration barrier. Previous studies have shown that ERS in podocytes can contribute to the development of diseases such as glomerulonephritis, hereditary nephropathy, and diabetic kidney disease, potentially progressing to end-stage renal disease and causing patient mortality. As such, investigating ERS in podocytes has become a key area of focus in kidney disease research. This study examines recent advancements in understanding the effects of excessive ERS on podocytes across various kidney diseases, highlights the role of podocyte ERS in disease progression, and explores the potential therapeutic benefits of targeting the UPR to manage ERS in kidney diseases, thereby providing a scientific basis for clinical interventions.
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Affiliation(s)
- Jiao Lv
- College of Chinese Medicine, Changchun University of Chinese Medicine, Changchun, 130117, China
| | - Honghai Yu
- College of Chinese Medicine, Changchun University of Chinese Medicine, Changchun, 130117, China
| | - Sasa Du
- College of Chinese Medicine, Changchun University of Chinese Medicine, Changchun, 130117, China
| | - Pengyu Xu
- College of Acupuncture and Moxibustion, Changchun University of Traditional Chinese Medicine, Changchun, 130117, China
| | - Yunyun Zhao
- Endocrinology Department, First Affiliated Hospital, Changchun University of Chinese Medicine, Changchun, 130021, China
| | - Wenxiu Qi
- Key Laboratory of Active Substances and Biological Mechanisms of Ginseng Efficacy, Jilin Provincial Key Laboratory of Biomacromolecules of Chinese Medicine, Ministry of Education, Northeast Asia Research Institute of Traditional Chinese Medicine, Changchun University of Chinese Medicine, Changchun, 130117, China.
| | - Xiuge Wang
- Endocrinology Department, First Affiliated Hospital, Changchun University of Chinese Medicine, Changchun, 130021, China.
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23
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Wu X, Hu W, Xu J, Shen J, Lin L, Zhu J, Wei T, Lv L. Difference between estimated glomerular filtration rate based on cystatin C versus creatinine and cardiovascular-kidney-metabolic health. Front Med (Lausanne) 2025; 11:1477343. [PMID: 39882526 PMCID: PMC11774968 DOI: 10.3389/fmed.2024.1477343] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2024] [Accepted: 12/24/2024] [Indexed: 01/31/2025] Open
Abstract
Background The difference between the estimated glomerular filtration rate (eGFR) calculated from cystatin C and creatinine (eGFRdiff) serves as a biomarker of kidney function impairment. However, the role of eGFRdiff in cardiovascular-kidney-metabolic (CKM) health and its impact on mortality in CKM syndrome patients has not yet been studied. Methods This study included 3,622 participants from the National Health and Nutrition Examination Survey (NHANES) conducted between 1999 and 2004. Weighted ordinal logistic regression was used to explore the link between eGFRdiff and CKM health, while weighted Cox regression was used to examine the relationship between eGFRdiff and mortality in CKM syndrome patients. Restricted cubic splines (RCSs) were used to analyze the dose-response relationship. Results The common odds ratio (cOR) per 10 mL/min/1.73m2 increase in eGFRdiff was 0.86 [95% confidence interval (CI), 0.81 to 0.91]. Compared to the midrange eGFRdiff, the cOR values for the negative and positive eGFRdiff were 1.88 [95% CI, 1.23 to 2.88] and 0.69 [95% CI, 0.58 to 0.83], respectively. During a median follow-up of 201 months, 853 participants died from all causes, while 265 died due to cardiovascular causes. The hazard ratios (HRs) per 10 mL/min/1.73m2 increase in eGFRdiff were 0.88 [95% CI, 0.83 to 0.93] for all-cause mortality and 0.90 [95% CI, 0.81 to 1.00] for cardiovascular mortality cases. Compared to the participants with a midrange eGFRdiff, those with negative eGFRdiff had a 48% higher risk of all-cause mortality, while those with positive eGFRdiff had a 30% lower risk. No significant non-linear associations were found in these regression analyses. Conclusion Our study found that eGFRdiff is associated with CKM health and stratified mortality risk in CKM syndrome patients.
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Affiliation(s)
- Xiaoyan Wu
- Department of Cardiology, Lishui Central Hospital and the Fifth Affiliated Hospital of Wenzhou Medical University, Lishui, China
| | - Wuming Hu
- Department of Cardiology, Lishui Central Hospital and the Fifth Affiliated Hospital of Wenzhou Medical University, Lishui, China
| | - Jian Xu
- Department of Cardiology, Lishui Central Hospital and the Fifth Affiliated Hospital of Wenzhou Medical University, Lishui, China
| | - Jiayi Shen
- Department of Cardiology, Lishui Central Hospital and the Fifth Affiliated Hospital of Wenzhou Medical University, Lishui, China
| | - Li Lin
- Department of Cardiology, Lishui Central Hospital and the Fifth Affiliated Hospital of Wenzhou Medical University, Lishui, China
| | - Jingshuai Zhu
- Department of Cardiology, Lishui Central Hospital and the Fifth Affiliated Hospital of Wenzhou Medical University, Lishui, China
| | - Tiemin Wei
- Department of Cardiology, Lishui Central Hospital and the Fifth Affiliated Hospital of Wenzhou Medical University, Lishui, China
| | - Lingchun Lv
- Department of Cardiology, Lishui Central Hospital and the Fifth Affiliated Hospital of Wenzhou Medical University, Lishui, China
- Department of Cardiology, Lishui Hospital, Zhejiang University School of Medicine, Lishui, China
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Liu C, Cao Z, Li L, Li Q, Zhang C, Wang Y, Li L, Fu P. Self-Assembled Pt/Honokiol Nanomicelles for the Treatment of Sepsis-Associated Acute Kidney Injury. ACS Biomater Sci Eng 2025; 11:383-401. [PMID: 39681978 DOI: 10.1021/acsbiomaterials.4c01852] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2024]
Abstract
Sepsis is a severe and complex systemic infection that can result in multiple organ dysfunction. Sepsis-associated acute kidney injury (SAKI), caused by inflammatory response, oxidative stress, and cellular apoptosis, is a common complication that seriously impacts patient survival rates. Herein, a potent and novel metal-polyphenol nanomicelle can be efficiently self-assembled with Pt4+ and honokiol (HK) by the chelation, π-π conjugation, hydrophobic action, and the surfactant properties of Tween-80. These nanomicelles not only enhance drug bioavailability (encapsulation rates: Pt─49%, HK─70%) and reduce drug toxicity (safety dose: <20 μg/g) but also improve targeting toward damaged renal tissues. Furthermore, Pt4+ and HK in the nanomicelles exert a synergistic physiological effect by scavenging free radicals to alleviate oxidative damage, inhibiting macrophage activation and the release of inflammatory factors to regulate inflammation, and displaying broad-spectrum antimicrobial activity to control infection. These actions collectively protect renal tissue and restore its functionality. Here, we constructed metal-polyphenol nanomicelles (Pt/HK-NMs) via ingenious and efficient self-assembly, providing a new strategy to compensate for deficiencies in the hemodialysis and antibiotic treatment of SAKI.
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Affiliation(s)
- Chang Liu
- Department of Nephrology, Institute of Kidney Diseases, West China Hospital of Sichuan University, Chengdu 610041, Sichuan, China
| | - Zhengjiang Cao
- Department of Nephrology, Institute of Kidney Diseases, West China Hospital of Sichuan University, Chengdu 610041, Sichuan, China
| | - Li Li
- Institute of Clinical Pathology, West China Hospital of Sichuan University, Chengdu 610041, Sichuan, China
| | - Qingyin Li
- Department of Nephrology, Institute of Kidney Diseases, Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University, Chengdu 610041, Sichuan, China
| | - Chunle Zhang
- Department of Nephrology, Institute of Kidney Diseases, West China Hospital of Sichuan University, Chengdu 610041, Sichuan, China
| | - Yunbing Wang
- National Engineering Research Center for Biomaterials, Sichuan University, Chengdu 610064, China
| | - Linhua Li
- Department of Nephrology, Institute of Kidney Diseases, West China Hospital of Sichuan University, Chengdu 610041, Sichuan, China
| | - Ping Fu
- Department of Nephrology, Institute of Kidney Diseases, West China Hospital of Sichuan University, Chengdu 610041, Sichuan, China
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Fan X, Wu L, Wang F, Liu D, Cen X, Xia H. Mitophagy Regulates Kidney Diseases. KIDNEY DISEASES (BASEL, SWITZERLAND) 2024; 10:573-587. [PMID: 39664332 PMCID: PMC11631111 DOI: 10.1159/000541486] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/12/2024] [Accepted: 08/31/2024] [Indexed: 12/13/2024]
Abstract
Background Mitophagy is a crucial process involved in maintaining cellular homeostasis by selectively eliminating damaged or surplus mitochondria. As the kidney is an organ with a high dynamic metabolic rate and abundant mitochondria, it is particularly crucial to control mitochondrial quality through mitophagy. Dysregulation of mitophagy has been associated with various renal diseases, including acute and chronic kidney diseases, and therefore a better understanding of the links between mitophagy and these diseases may present new opportunities for therapeutic interventions. Summary Mitophagy plays a pivotal role in the development of kidney diseases. Upregulation and downregulation of mitophagy have been observed in various kidney diseases, such as renal ischemia-reperfusion injury, contrast-induced acute kidney injury, diabetic nephropathy, kidney fibrosis, and several inherited renal diseases. A growing body of research has suggested that PINK1 and Parkin, the main mitophagy regulatory proteins, represent promising potential therapeutic targets for kidney diseases. In this review, we summarize the latest insights into how the progression of renal diseases can be mitigated through the regulation of mitophagy, while highlighting their performance in clinical trials. Key Message This review comprehensively outlines the mechanisms of mitophagy and its role in numerous kidney diseases. While early research holds promise, most mitophagy-centered therapeutic approaches have yet to reach the clinical application stage.
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Affiliation(s)
- Xiaolu Fan
- Research Center of Clinical Pharmacy of The First Affiliated Hospital and Liangzhu Laboratory, Zhejiang University School of Medicine, Hangzhou, China
| | - Linlin Wu
- Hangzhou PhecdaMed Co., Ltd, Hangzhou, China
| | - Fengqi Wang
- Research Center of Clinical Pharmacy of The First Affiliated Hospital and Liangzhu Laboratory, Zhejiang University School of Medicine, Hangzhou, China
- Department of Biochemistry and Research Center of Clinical Pharmacy of The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Dong Liu
- Hangzhou PhecdaMed Co., Ltd, Hangzhou, China
| | - Xufeng Cen
- Research Center of Clinical Pharmacy of The First Affiliated Hospital and Liangzhu Laboratory, Zhejiang University School of Medicine, Hangzhou, China
| | - Hongguang Xia
- Research Center of Clinical Pharmacy of The First Affiliated Hospital and Liangzhu Laboratory, Zhejiang University School of Medicine, Hangzhou, China
- Department of Biochemistry and Research Center of Clinical Pharmacy of The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
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Yadav S, Maity P, Kapat K. The Opportunities and Challenges of Mesenchymal Stem Cells-Derived Exosomes in Theranostics and Regenerative Medicine. Cells 2024; 13:1956. [PMID: 39682706 PMCID: PMC11640604 DOI: 10.3390/cells13231956] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2024] [Revised: 11/19/2024] [Accepted: 11/22/2024] [Indexed: 12/18/2024] Open
Abstract
Cell-secreted nanovesicles of endosomal origin, called exosomes, are vital for mediating intracellular communication. As local or distal transporters of intracellular cargo, they reflect the unique characteristics of secretory cells and establish cell-specific interactions via characteristic surface proteins and receptors. With the advent of rapid isolation, purification, and identification techniques, exosomes have become an attractive choice for disease diagnosis (exosomal content as biomarkers), cell-free therapy, and tissue regeneration. Mesenchymal stem cell (MSC)-derived exosomes (MSC-exosomes) display angiogenic, immune-modulatory, and other therapeutic effects crucial for cytoprotection, ischemic wound repair, myocardial regeneration, etc. The primary focus of this review is to highlight the widespread application of MSC-exosomes in therapeutics, theranostics, and tissue regeneration. After a brief introduction of exosome properties, biogenesis, isolation, and functions, recent studies on therapeutic and regenerative applications of MSC-exosomes are described, focusing on bone, cartilage, periodontal, cardiovascular, skin, and nerve regeneration. Finally, the review highlights the theranostic potential of exosomes followed by challenges, summary, and outlook.
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Affiliation(s)
- Sachin Yadav
- Department of Medical Devices, National Institute of Pharmaceutical Education and Research Kolkata, 168, Maniktala Main Road, Kankurgachi, Kolkata 700054, West Bengal, India;
| | - Pritiprasanna Maity
- School of Medicine, University of California Riverside, Riverside, CA 92525, USA
| | - Kausik Kapat
- Department of Medical Devices, National Institute of Pharmaceutical Education and Research Kolkata, 168, Maniktala Main Road, Kankurgachi, Kolkata 700054, West Bengal, India;
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Yao S, Wang Y, Mou X, Yang X, Cai Y. Recent advances of photoresponsive nanomaterials for diagnosis and treatment of acute kidney injury. J Nanobiotechnology 2024; 22:676. [PMID: 39501286 PMCID: PMC11536863 DOI: 10.1186/s12951-024-02906-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2024] [Accepted: 10/04/2024] [Indexed: 11/09/2024] Open
Abstract
Non-invasive imaging in the near-infrared region (NIR) offers enhanced tissue penetration, reduced spontaneous fluorescence of biological tissues, and improved signal-to-noise ratio (SNR), rendering it more suitable for in vivo deep tissue imaging. In recent years, a plethora of NIR photoresponsive materials have been employed for disease diagnosis, particularly acute kidney injury (AKI). These encompass inorganic nonmetallic materials such as carbon (C), silicon (Si), phosphorus (P), and upconversion nanoparticles (UCNPs); precious metal nanoparticles like gold and silver; as well as small molecule and organic semiconductor polymer nanoparticles with near infrared responsiveness. These materials enable effective therapy triggered by NIR light and serve as valuable tools for monitoring AKI in living systems. The review provides a concise overview of the current state and pathological characteristics of AKI, followed by an exploration of the application of nanomaterials and photoresponsive nanomaterials in AKI. Finally, it presents the design challenges and prospects associated with NIR photoresponsive materials in AKI.
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Affiliation(s)
- Shijie Yao
- Emergency and Critical Care Center, Intensive Care Unit, Zhejiang Provincial People's Hospital (Affiliated People's Hospital), Hangzhou Medical College, Hangzhou, 310014, Zhejiang, China
| | - Yinan Wang
- The Second School of Clinical Medicine, Zhejiang Chinese Medical University, Hangzhou, 310053, Zhejiang, China
| | - Xiaozhou Mou
- Clinical Research Institute, Zhejiang Provincial People's Hospital, (Affiliated People's Hospital), Hangzhou Medical College, Hangzhou, 310014, Zhejiang, China.
| | - Xianghong Yang
- Emergency and Critical Care Center, Intensive Care Unit, Zhejiang Provincial People's Hospital (Affiliated People's Hospital), Hangzhou Medical College, Hangzhou, 310014, Zhejiang, China.
| | - Yu Cai
- Center for Rehabilitation Medicine, Rehabilitation & Sports Medicine Research Institute of Zhejiang Province, Department of Rehabilitation Medicine, Zhejiang Provincial People's Hospital, (Affiliated People's Hospital), Hangzhou Medical College, Hangzhou, 310014, Zhejiang, China.
- Clinical Research Institute, Zhejiang Provincial People's Hospital, (Affiliated People's Hospital), Hangzhou Medical College, Hangzhou, 310014, Zhejiang, China.
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Meng F, Fu Y, Xie H, Wang H. Nanoparticle-assisted Targeting Delivery Technologies for Preventing Organ Rejection. Transplantation 2024; 108:2174-2185. [PMID: 38597913 DOI: 10.1097/tp.0000000000005025] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/11/2024]
Abstract
Although organ transplantation is a life-saving medical procedure, the challenge of posttransplant rejection necessitates safe and effective immune modulation strategies. Nanodelivery approaches may have the potential to overcome the limitations of small-molecule immunosuppressive drugs, achieving efficacious treatment options for transplant tolerance without compromising overall host immunity. This review highlights recent advances in biomaterial-assisted formulations and technologies for targeted nanodrug delivery with transplant organ- or immune cell-level precision for treating graft rejection after transplantation. We provide an overview of the mechanism of transplantation rejection, current clinically approved immunosuppressive drugs, and their relevant limitations. Finally, we discuss the targeting principles and advantages of organ- and immune cell-specific delivery technologies. The development of biomaterial-assisted novel therapeutic strategies holds considerable promise for treating organ rejection and clinical translation.
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Affiliation(s)
- Fanchao Meng
- Jinan Microecological Biomedicine Shandong Laboratory, Jinan, Shandong Province, People's Republic of China
- The First Affiliated Hospital, NHC Key Laboratory of Combined Multi-Organ Transplantation, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, People's Republic of China
| | - Yang Fu
- Department of Medical Oncology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, People's Republic of China
| | - Haiyang Xie
- The First Affiliated Hospital, NHC Key Laboratory of Combined Multi-Organ Transplantation, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, People's Republic of China
| | - Hangxiang Wang
- Jinan Microecological Biomedicine Shandong Laboratory, Jinan, Shandong Province, People's Republic of China
- The First Affiliated Hospital, NHC Key Laboratory of Combined Multi-Organ Transplantation, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, People's Republic of China
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Shahzad A, Teng Z, Yameen M, Liu W, Cui K, Liu X, Sun Y, Duan Q, Xia J, Dong Y, Bai Z, Peng D, Zhang J, Xu Z, Pi J, Yang Z, Zhang Q. Innovative lipid nanoparticles: A cutting-edge approach for potential renal cell carcinoma therapeutics. Biomed Pharmacother 2024; 180:117465. [PMID: 39321512 DOI: 10.1016/j.biopha.2024.117465] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2024] [Revised: 09/09/2024] [Accepted: 09/19/2024] [Indexed: 09/27/2024] Open
Abstract
The kidney plays a crucial role in regulating homeostasis within the human body. Renal cell carcinoma (RCC) is the most common form of kidney cancer, accounting for nearly 90 % of all renal malignancies. Despite the availability of various therapeutic strategies, RCC remains a challenging disease due to its resistance to conventional treatments. Nanotechnology has emerged as a promising field, offering new opportunities in cancer therapeutics. It presents several advantages over traditional methods, enabling diverse biomedical applications, including drug delivery, prevention, diagnosis, and treatment. Lipid nanoparticles (LNPs), approximately 100 nm in size, are derived from a range of lipids and other biochemical compounds. these particulates are designed to overcome biological barriers, allowing them to selectively accumulate at diseased target sites for effective therapeutic action. Many pharmaceutically important compounds face challenges such as poor solubility in aqueous solutions, chemical and physiological instability, or toxicity. LNP technology stands out as a promising drug delivery system for bioactive organic compounds. This article reviews the applications of LNPs in RCC treatment and explores their potential clinical translation, identifying the most viable LNPs for medical use. With ongoing advancement in LNP-based anticancer strategies, there is a growing potential to improve the management and treatment of renal cancer.
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Affiliation(s)
- Asif Shahzad
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Kunming Medical University, Kunming, Yunnan 650500, China
| | - Zhuoran Teng
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Kunming Medical University, Kunming, Yunnan 650500, China
| | - Muhammad Yameen
- Department of Biochemistry, Government College University Faisalabad, Punjab 38000, Pakistan
| | - Wenjing Liu
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Kunming Medical University, Kunming, Yunnan 650500, China
| | - Kun Cui
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Kunming Medical University, Kunming, Yunnan 650500, China
| | - Xiangjie Liu
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Kunming Medical University, Kunming, Yunnan 650500, China
| | - Yijian Sun
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Kunming Medical University, Kunming, Yunnan 650500, China
| | - Qiuxin Duan
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Kunming Medical University, Kunming, Yunnan 650500, China
| | - JiaoJiao Xia
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Kunming Medical University, Kunming, Yunnan 650500, China
| | - Yurong Dong
- Department of Pathology, The First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan 650032, China
| | - Ziyuan Bai
- Department of Pathology, The First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan 650032, China
| | - Dongmei Peng
- Department of Pathology, The First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan 650032, China
| | - Jinshan Zhang
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Kunming Medical University, Kunming, Yunnan 650500, China
| | - Zhe Xu
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Kunming Medical University, Kunming, Yunnan 650500, China
| | - Jiang Pi
- Guangdong Provincial Key Laboratory of Medical Immunology and Molecular Diagnostics, The First Dongguan Affiliated Hospital, School of Medical Technology, Guangdong Medical University, Dongguan, Guangdong, China.
| | - Zhe Yang
- Department of Pathology, The First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan 650032, China.
| | - Qiao Zhang
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Kunming Medical University, Kunming, Yunnan 650500, China.
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Chow MBCY, Yildiz V, Biederman L, Dasgupta A, Satoskar AA, Chow A, Nadasdy T, Brodsky SV. Proteinuria and proximal tubular epithelial cells: correlation between immunofluorescence, histology, and degree of proteinuria. FRONTIERS IN NEPHROLOGY 2024; 4:1469388. [PMID: 39544696 PMCID: PMC11560906 DOI: 10.3389/fneph.2024.1469388] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/23/2024] [Accepted: 10/08/2024] [Indexed: 11/17/2024]
Abstract
Proteins are filtered from the blood through the glomerular filtration barrier. Filtered proteins are reabsorbed by proximal tubular epithelial cells (PTECs), which have been shown to possess the ability to regulate protein reabsorption. Histologically, these reabsorbed proteins are seen as tubular protein reabsorption droplets (TPRDs). Experimental studies indicate that PTECs play an important role in regulating proteinuria but the correlations between TPRD and the degree of proteinuria in human kidney biopsies have not been investigated in detail. Consecutive native kidney biopsies with non-proliferative glomerular disease performed at the OSUWMC for a 1-year period were analyzed. Cases with acute glomerular diseases and inadequate biopsies were excluded. The staining intensity and the percentage of TPRDs, as well as other morphologic parameters, were assessed. A total of 109 kidney biopsies were included in the study. A reverse correlation was identified between the percentage of albumin TPRDs and proteinuria (p = 0.047). There were positive correlations between proteinuria and the staining intensity for IgG TPRDs (p = 0.05) and the degree of acute tubular necrosis (ATN) (p = 0.015). In patients with no ATN, positive correlations between proteinuria and albumin and IgG TPRDs were seen, whereas in patients with ATN, these correlations were lost. A positive correlation was seen between proteinuria and chronic kidney injury. A strong correlation was noted between the degree of proteinuria and podocyte foot process effacement. Our data indicate that PTECs regulate proteinuria by absorbing proteins from the urine filtrate. Therefore, based on the human renal biopsy material, our study confirms that well-functioning renal PTECs play an important role in the regulation of proteinuria.
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Affiliation(s)
- Maria Bernadette CY Chow
- Department of Pathology, The Ohio State University Wexner Medical Center, Columbus, OH, United States
- Deparment of Pathology, North District Hospital, Hong Kong, Hong Kong SAR, China
| | - Vedat Yildiz
- Center for Biostatistics, The Ohio State University Wexner Medical Center, Columbus, OH, United States
| | - Laura Biederman
- Department of Pathology, The Ohio State University Wexner Medical Center, Columbus, OH, United States
- Department of Pathology, Nationwide Children Hospital, Columbus, OH, United States
| | - Alana Dasgupta
- Department of Pathology, The Ohio State University Wexner Medical Center, Columbus, OH, United States
| | - Anjali A. Satoskar
- Department of Pathology, The Ohio State University Wexner Medical Center, Columbus, OH, United States
| | - Aaron Chow
- Department of Pathology, The Ohio State University Wexner Medical Center, Columbus, OH, United States
| | - Tibor Nadasdy
- Department of Pathology, The Ohio State University Wexner Medical Center, Columbus, OH, United States
| | - Sergey V. Brodsky
- Department of Pathology, The Ohio State University Wexner Medical Center, Columbus, OH, United States
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Sun Y, Kronenberg NM, Sethi SK, Dash SN, Kovalik ME, Sempowski B, Strickland S, Raina R, Sperati CJ, Tian X, Ishibe S, Hall G, Gather MC. CRB2 Depletion Induces YAP Signaling and Disrupts Mechanosensing in Podocytes. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.10.22.619513. [PMID: 39484460 PMCID: PMC11527017 DOI: 10.1101/2024.10.22.619513] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 11/03/2024]
Abstract
Focal Segmental Glomerulosclerosis (FSGS) is a histologic lesion caused by a variety of injurious stimuli that lead to dysfunction/loss of glomerular visceral epithelial cells (i.e. podocytes). Pathogenic mutations in CRB2, encoding the type 1 transmembrane protein Crumb 2 Homolog Protein, have been shown to cause early-onset corticosteroid-resistant nephrotic syndrome (SRNS)/FSGS. Here, we identified a 2-generation East Asian kindred (DUK40595) with biopsy-proven SRNS/FSGS caused by a compound heterozygous mutation in CRB2 comprised of the previously described truncating mutation p.Gly1036_Alafs*43 and a rare 9-bp deletion mutation p.Leu1074_Asp1076del. Because compound heterozygous mutations involving the truncating p.Gly1036_Alafs*43 variant have been associated with reduced CRB2 expression in podocytes and autosomal recessive SRNS/FSGS, we sought to define the pathogenic effects of CRB2 deficiency in podocytes. We show that CRB2 knockdown induces YAP activity and target gene expression in podocytes. It upregulates YAP-mediated mechanosignaling and increases the density of focal adhesion and F-actin. Using Elastic Resonator Interference Stress Microscopy (ERISM), we demonstrate that CRB2 knockdown also enhances podocyte contractility in a substrate stiffness-dependent manner. The knockdown effect decreases with increasing substrate stiffness, indicating impaired mechanosensing in CRB2 knockdown cells at low substrate stiffness. While the mechanical activation of CRB2 knockdown cells is associated with increased YAP activity, the enhanced cell contractility is not significantly reduced by the selective YAP inhibitors K-975 and verteporfin, suggesting that multiple pathways may be involved in mechanosignaling downstream of CRB2. Taken together, these studies provide the first evidence that CRB2 deficiency may impair podocyte mechanotransduction via disruption of YAP signaling in podocytes.
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Affiliation(s)
- Yingyu Sun
- Humboldt Centre for Nano- and Biophotonics, Department of Chemistry, University of Cologne, Cologne, Germany
| | - Nils M. Kronenberg
- Humboldt Centre for Nano- and Biophotonics, Department of Chemistry, University of Cologne, Cologne, Germany
| | - Sidharth K. Sethi
- Pediatric Nephrology and Pediatric Kidney Transplantation, Medanta Kidney and Urology Institute, The Medicity Hospital, Gurgaon, Haryana, India
| | - Surjya N. Dash
- Division of Nephrology, Department of Medicine, Duke University, Durham, North Carolina, U.S.A
- Duke Molecular Physiology Institute, Duke University, Durham, North Carolina, U.S.A
| | - Maria E. Kovalik
- Duke Molecular Physiology Institute, Duke University, Durham, North Carolina, U.S.A
| | - Benjamin Sempowski
- Duke Molecular Physiology Institute, Duke University, Durham, North Carolina, U.S.A
| | - Shelby Strickland
- Duke Molecular Physiology Institute, Duke University, Durham, North Carolina, U.S.A
| | - Rupresh Raina
- Division of Nephrology, Department of Medicine, Yale University, New Haven, Connecticut, U.S.A
- Cleveland Clinic Akron General Medical Center, Akron Nephrology Associates, Akron, Ohio, USA
| | - C. John Sperati
- Division of Nephrology, Department of Medicine, Johns Hopkins University, Baltimore, Maryland, U.S.A
| | - Xuefei Tian
- Cleveland Clinic Akron General Medical Center, Akron Nephrology Associates, Akron, Ohio, USA
| | - Shuta Ishibe
- Cleveland Clinic Akron General Medical Center, Akron Nephrology Associates, Akron, Ohio, USA
| | - Gentzon Hall
- Division of Nephrology, Department of Medicine, Duke University, Durham, North Carolina, U.S.A
- Duke Molecular Physiology Institute, Duke University, Durham, North Carolina, U.S.A
| | - Malte C. Gather
- Humboldt Centre for Nano- and Biophotonics, Department of Chemistry, University of Cologne, Cologne, Germany
- Centre of Biophotonics, SUPA, School of Physics and Astronomy, University of St Andrews, St Andrews, U.K
- Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Disease (CECAD), University of Cologne, Cologne, Germany
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Zhou Z, Wang Y, Xing Y, Pan S, Wang W, Yang J, Wu W, Zhou J, Huang L, Liang Q, Zhang D, Kong L. Magnolol Inhibits High Fructose-Induced Podocyte Inflammation via Downregulation of TKFC/Sp1/HDAC4/Notch1 Activation. Pharmaceuticals (Basel) 2024; 17:1416. [PMID: 39598328 PMCID: PMC11597211 DOI: 10.3390/ph17111416] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2024] [Revised: 10/06/2024] [Accepted: 10/19/2024] [Indexed: 11/29/2024] Open
Abstract
BACKGROUND/OBJECTIVES High fructose has been implicated as an important trigger of kidney inflammation in patients and experimental models. Magnolol, isolated from Magnolia officinalis, has an anti-inflammatory effect, but its protective role in podocytes remains underexplored. This study explored the protective effects and underlying mechanism of magnolol against high fructose-induced podocyte inflammation. METHODS The effects of magnolol on high fructose-induced podocyte inflammation were assessed in male Sprague Dawley rats administered 10% (w/v) fructose water for 12 weeks and heat-sensitive human podocyte cell lines (HPCs) exposed to 5 mM fructose. Podocyte foot processes were examined using transmission electron microscopy. The expression levels of nephrin, podocin, tumor necrosis factor-α (TNF-α), Notch1 intracellular domain (NICD1), triokinase/FMN cyclase (TKFC), specificity protein 1 (Sp1) and histone deacetylase 4 (HDAC4) were determined by Western blot, immunofluorescence and real-time quantitative polymerase chain reaction (qRT-PCR). The chromatin immunoprecipitation (ChIP) assay was performed to evaluate the interaction between Sp1 and the promoter region of HDAC4. RESULTS Magnolol mitigated the impairment of glomerular filtration function in high fructose-fed rats. Besides, it significantly alleviated the inflammatory responses in glomeruli and HPCs, evidenced by decreased protein levels of TNF-α and NICD1. Increased protein levels of TKFC, Sp1 and HDAC4 were observed in high fructose-stimulated HPCs and rat glomeruli. TMP195, an HDAC4 inhibitor, reduced TNF-α and NICD1 protein levels in high fructose-exposed HPCs. The increased Sp1 was shown to associate with the promoter region of HDAC4, promoting HDAC4 protein expression in high fructose-exposed HPCs. The knockdown of TKFC in HPCs by TKFC siRNA decreased Sp1, HDAC4 and NICD1 protein levels, alleviating podocyte inflammatory response. Furthermore, magnolol inhibited TKFC/Sp1/HDAC4/Notch1 activation in vivo and in vitro. CONCLUSIONS Magnolol attenuated high fructose-induced podocyte inflammation possibly through the suppression of TKFC/Sp1/HDAC4/Notch1 activation, providing new evidence for its potential role in podocyte protection.
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Affiliation(s)
| | | | | | | | | | | | | | | | | | | | - Dongmei Zhang
- State Key Laboratory of Pharmaceutical Biotechnology, Institute of Chinese Medicine, Nanjing Drum Tower Hospital, School of Life Sciences, Nanjing University, Nanjing 210023, China; (Z.Z.); (Y.W.); (Y.X.); (S.P.); (W.W.); (J.Y.); (W.W.); (J.Z.); (L.H.); (Q.L.)
| | - Lingdong Kong
- State Key Laboratory of Pharmaceutical Biotechnology, Institute of Chinese Medicine, Nanjing Drum Tower Hospital, School of Life Sciences, Nanjing University, Nanjing 210023, China; (Z.Z.); (Y.W.); (Y.X.); (S.P.); (W.W.); (J.Y.); (W.W.); (J.Z.); (L.H.); (Q.L.)
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Zeng D, Wang B, Xiao Z, Wang X, Tang X, Yao X, Wang P, Li M, Dai Y, Yu X. Early Diagnosis and Treatment of Kidney Injury: A Focus on Urine Protein. Int J Mol Sci 2024; 25:11171. [PMID: 39456955 PMCID: PMC11508809 DOI: 10.3390/ijms252011171] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2024] [Revised: 10/14/2024] [Accepted: 10/14/2024] [Indexed: 10/28/2024] Open
Abstract
The kidney, an essential excretory organ of the body, performs a series of crucial physiological functions such as waste removal, maintenance of electrolyte and acid-base balance, and endocrine regulation. Due to its rich blood flow and high metabolic activity, the kidney is susceptible to damage. Currently, kidney injury is classified into acute kidney injury (AKI) and chronic kidney disease (CKD), both of which are associated with high rates of morbidity and mortality on a global scale. The current clinical diagnosis of renal injury relies on the assessment of renal filtration function using creatinine and urea nitrogen as "gold-standard" markers. However, the delayed response time, limited specificity, and reduced accuracy of creatinine and urea nitrogen in evaluating kidney injury have significantly hindered advancements in diagnostic methods for kidney injury. Urinary protein is widely utilized as a biomarker for the early diagnosis of kidney injury due to the selectivity of the glomerular filtration system determining whether proteins can pass through the filtration barrier based on their size and charge. Therefore, as a complex biological sample with varying charges and particle sizes, urinary protein is considered an ideal indicator for monitoring the progression of kidney disease. Exploring the relationship between urinary protein and the advancement of kidney injury based on differences in particle size and charge offers a new perspective for assessing and treating such injuries. Hence, we conducted a comprehensive review of 74 relevant studies to gain a thorough understanding of the physiological mechanism and significance of proteinuria production. The aim was to explore the challenges and opportunities in clinical urine protein detection, as well as to discuss strategies targeting glomerular filtration barriers in order to effectively reduce urine protein levels and treat kidney injury, which could provide a new perspective for identifying the progression of kidney injury.
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Affiliation(s)
- Duanna Zeng
- College of Pharmacy and International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development of Chinese Ministry of Education, Jinan University, Guangzhou 510632, China; (D.Z.); (Z.X.); (X.T.); (X.Y.)
- NMPA Key Laboratory for Bioequivalence Research of Generic Drug Evaluation, Shenzhen Institute for Drug Control, Shenzhen 518057, China; (B.W.); (X.W.); (P.W.); (M.L.)
| | - Bing Wang
- NMPA Key Laboratory for Bioequivalence Research of Generic Drug Evaluation, Shenzhen Institute for Drug Control, Shenzhen 518057, China; (B.W.); (X.W.); (P.W.); (M.L.)
| | - Zheng Xiao
- College of Pharmacy and International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development of Chinese Ministry of Education, Jinan University, Guangzhou 510632, China; (D.Z.); (Z.X.); (X.T.); (X.Y.)
- NMPA Key Laboratory for Bioequivalence Research of Generic Drug Evaluation, Shenzhen Institute for Drug Control, Shenzhen 518057, China; (B.W.); (X.W.); (P.W.); (M.L.)
| | - Xiongqin Wang
- NMPA Key Laboratory for Bioequivalence Research of Generic Drug Evaluation, Shenzhen Institute for Drug Control, Shenzhen 518057, China; (B.W.); (X.W.); (P.W.); (M.L.)
| | - Xiyang Tang
- College of Pharmacy and International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development of Chinese Ministry of Education, Jinan University, Guangzhou 510632, China; (D.Z.); (Z.X.); (X.T.); (X.Y.)
| | - Xinsheng Yao
- College of Pharmacy and International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development of Chinese Ministry of Education, Jinan University, Guangzhou 510632, China; (D.Z.); (Z.X.); (X.T.); (X.Y.)
| | - Ping Wang
- NMPA Key Laboratory for Bioequivalence Research of Generic Drug Evaluation, Shenzhen Institute for Drug Control, Shenzhen 518057, China; (B.W.); (X.W.); (P.W.); (M.L.)
| | - Meifang Li
- NMPA Key Laboratory for Bioequivalence Research of Generic Drug Evaluation, Shenzhen Institute for Drug Control, Shenzhen 518057, China; (B.W.); (X.W.); (P.W.); (M.L.)
| | - Yi Dai
- College of Pharmacy and International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development of Chinese Ministry of Education, Jinan University, Guangzhou 510632, China; (D.Z.); (Z.X.); (X.T.); (X.Y.)
| | - Xiean Yu
- NMPA Key Laboratory for Bioequivalence Research of Generic Drug Evaluation, Shenzhen Institute for Drug Control, Shenzhen 518057, China; (B.W.); (X.W.); (P.W.); (M.L.)
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Qin W, Huang J, Zhang M, Xu M, He J, Liu Q. Nanotechnology-Based Drug Delivery Systems for Treating Acute Kidney Injury. ACS Biomater Sci Eng 2024; 10:6078-6096. [PMID: 39226188 PMCID: PMC11480945 DOI: 10.1021/acsbiomaterials.4c01385] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2024] [Revised: 08/25/2024] [Accepted: 08/28/2024] [Indexed: 09/05/2024]
Abstract
Acute kidney injury (AKI) is a disease that is characterized by a rapid decline in renal function and has a relatively high incidence in hospitalized patients. Sepsis, renal hypoperfusion, and nephrotoxic drug exposure are the main causes of AKI. The major therapy measures currently include supportive treatment, symptomatic treatment, and kidney transplantation. These methods are supportive treatments, and their results are not satisfactory. Fortunately, many new treatments that markedly improve the AKI therapy efficiency are emerging. These include antioxidant therapy, ferroptosis therapy, anti-inflammatory therapy, autophagy therapy, and antiapoptotic therapy. In addition, the development of nanotechnology has further promoted therapeutic effects on AKI. In this review, we highlight recent advances in the development of nanocarriers for AKI drug delivery. Emphasis has been placed on the latest developments in nanocarrier modification and design. We also summarize the applications of different nanocarriers in AKI treatment. Finally, the advantages and challenges of nanocarrier applications in AKI are summarized, and several nanomedicines that have been approved for clinical trials to treat diverse kidney diseases are listed.
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Affiliation(s)
- Wanbing Qin
- Jieyang Medical
Research Center, Jieyang People’s
Hospital, Jieyang, 522000 Guangdong, China
| | - Jiaqi Huang
- Jieyang Medical
Research Center, Jieyang People’s
Hospital, Jieyang, 522000 Guangdong, China
| | - Manting Zhang
- Jieyang Medical
Research Center, Jieyang People’s
Hospital, Jieyang, 522000 Guangdong, China
| | - Mingwei Xu
- Jieyang Medical
Research Center, Jieyang People’s
Hospital, Jieyang, 522000 Guangdong, China
| | - Junbing He
- Jieyang Medical
Research Center, Jieyang People’s
Hospital, Jieyang, 522000 Guangdong, China
| | - Qinghua Liu
- Jieyang Medical
Research Center, Jieyang People’s
Hospital, Jieyang, 522000 Guangdong, China
- Department
of Nephrology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080 Guangdong, China
- NHC Key
Laboratory of Clinical Nephrology (Sun Yat-sen University) and Guangdong
Provincial Key Laboratory of Nephrology, Guangzhou, 510080 Guangdong, China
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Boshart A, Petrovic S, Abovsky M, Pastrello C, Farkona S, Manion K, Neupane S, Allen M, Jurisica I, Konvalinka A. Molecular landscape of kidney allograft tissues data integration portal (NephroDIP): a curated database to improve integration of high-throughput kidney transplant datasets. Front Immunol 2024; 15:1469500. [PMID: 39399491 PMCID: PMC11466753 DOI: 10.3389/fimmu.2024.1469500] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2024] [Accepted: 09/03/2024] [Indexed: 10/15/2024] Open
Abstract
Introduction Kidney transplantation is the optimal treatment for end-stage kidney disease; however, premature allograft loss remains a serious issue. While many high-throughput omics studies have analyzed patient allograft biospecimens, integration of these datasets is challenging, which represents a considerable barrier to advancing our understanding of the mechanisms of allograft loss. Methods To facilitate integration, we have created a curated database containing all open-access high-throughput datasets from human kidney transplant studies, termed NephroDIP (Nephrology Data Integration Portal). PubMed was searched for high-throughput transcriptomic, proteomic, single nucleotide variant, metabolomic, and epigenomic studies in kidney transplantation, which yielded 9,964 studies. Results From these, 134 studies with available data detailing 260 comparisons and 83,262 molecules were included in NephroDIP v1.0. To illustrate the capabilities of NephroDIP, we have used the database to identify common gene, protein, and microRNA networks that are disrupted in patients with chronic antibody-mediated rejection, the most important cause of late allograft loss. We have also explored the role of an immunomodulatory protein galectin-1 (LGALS1), along with its interactors and transcriptional regulators, in kidney allograft injury. We highlight the pathways enriched among LGALS1 interactors and transcriptional regulators in kidney fibrosis and during immunosuppression. Discussion NephroDIP is an open access data portal that facilitates data visualization and will help provide new insights into existing kidney transplant data through integration of distinct studies and modules (https://ophid.utoronto.ca/NephroDIP).
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Affiliation(s)
- Alex Boshart
- Toronto General Hospital Research Institute, University Health Network, Toronto, ON, Canada
- Ajmera Transplant Centre, University Health Network, Toronto, ON, Canada
- Institute of Medical Science, University of Toronto, Toronto, ON, Canada
| | - Stefan Petrovic
- Toronto General Hospital Research Institute, University Health Network, Toronto, ON, Canada
- Ajmera Transplant Centre, University Health Network, Toronto, ON, Canada
| | - Mark Abovsky
- Osteoarthritis Research Program, Division of Orthopedic Surgery, Schroeder Arthritis Institute, University Health Network, Toronto, ON, Canada
- Data Science Discovery Centre for Chronic Diseases, Krembil Research Institute, University Health Network, Toronto, ON, Canada
| | - Chiara Pastrello
- Osteoarthritis Research Program, Division of Orthopedic Surgery, Schroeder Arthritis Institute, University Health Network, Toronto, ON, Canada
- Data Science Discovery Centre for Chronic Diseases, Krembil Research Institute, University Health Network, Toronto, ON, Canada
| | - Sofia Farkona
- Toronto General Hospital Research Institute, University Health Network, Toronto, ON, Canada
- Ajmera Transplant Centre, University Health Network, Toronto, ON, Canada
| | - Kieran Manion
- Toronto General Hospital Research Institute, University Health Network, Toronto, ON, Canada
- Ajmera Transplant Centre, University Health Network, Toronto, ON, Canada
| | - Slaghaniya Neupane
- Toronto General Hospital Research Institute, University Health Network, Toronto, ON, Canada
- Ajmera Transplant Centre, University Health Network, Toronto, ON, Canada
- Institute of Medical Science, University of Toronto, Toronto, ON, Canada
| | - Maya Allen
- Toronto General Hospital Research Institute, University Health Network, Toronto, ON, Canada
- Ajmera Transplant Centre, University Health Network, Toronto, ON, Canada
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada
| | - Igor Jurisica
- Osteoarthritis Research Program, Division of Orthopedic Surgery, Schroeder Arthritis Institute, University Health Network, Toronto, ON, Canada
- Data Science Discovery Centre for Chronic Diseases, Krembil Research Institute, University Health Network, Toronto, ON, Canada
- Departments of Medical Biophysics and Computer Science, and Faculty of Dentistry, University of Toronto, Toronto, ON, Canada
- Institute of Neuroimmunology, Slovak Academy of Sciences, Bratislava, Slovakia
| | - Ana Konvalinka
- Toronto General Hospital Research Institute, University Health Network, Toronto, ON, Canada
- Ajmera Transplant Centre, University Health Network, Toronto, ON, Canada
- Institute of Medical Science, University of Toronto, Toronto, ON, Canada
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada
- Department of Medicine, Division of Nephrology, University Health Network, Toronto, ON, Canada
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Nan S, Che Y, Gong T, Zhang Z, Fu Y. Renal-Targeted Drug Delivery by Chitosan Oligosaccharide Micelles with HSA-Enriched Protein Corona for the Treatment of Ischemia/Reperfusion-Induced Acute Kidney Injury. ACS APPLIED MATERIALS & INTERFACES 2024; 16:49913-49925. [PMID: 39240782 DOI: 10.1021/acsami.4c09665] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/08/2024]
Abstract
Renal-specific nanoparticulate drug delivery systems have shown great potential in reducing systemic side effects and improving the safety and efficacy of treatments for renal diseases. Here, stearic acid-grafted chitosan oligosaccharide (COS-SA) was synthesized as a renal-targeted carrier due to the high affinity of the 2-glucosamine moiety on COS to the megalin receptor expressed on renal proximal tubular epithelial cells. Specifically, COS-SA/CLT micelles were prepared by encapsulating celastrol (CLT) with COS-SA, and different proportions of human serum albumin (HSA) were then adsorbed onto its surface to explore the interaction between the protein corona and cationic polymeric micelles. Our results showed that a multilayered protein corona, consisting of an inner "hard" corona and an outer "soft" corona, was formed on the surface of COS-SA/CLT@HSA8, which was beneficial in preventing its recognition and phagocytosis by macrophages. The formation of HSA protein corona on COS-SA/CLT micelles also increased its accumulation in the renal tubules. Furthermore, the electropositivity of COS-SA/CLT micelles affected the conformation of adsorbed proteins to various degrees. During the adsorption process, the protein corona on the surface of COS-SA/CLT@HSA1 was partially denatured. Overall, COS-SA/CLT and COS-SA/CLT@HSA micelles demonstrated sufficient safety with renal targeting potential, providing a viable strategy for the management of ischemia/reperfusion-induced acute kidney injury.
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Affiliation(s)
- Simin Nan
- Key Laboratory of Drug Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu 610041, China
| | - Yujie Che
- Key Laboratory of Drug Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu 610041, China
| | - Tao Gong
- Key Laboratory of Drug Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu 610041, China
| | - Zhirong Zhang
- Key Laboratory of Drug Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu 610041, China
| | - Yao Fu
- Key Laboratory of Drug Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu 610041, China
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Matsumoto T, Nagano T, Taguchi K, Kobayashi T, Tanaka-Totoribe N. Toll-like receptor 3 involvement in vascular function. Eur J Pharmacol 2024; 979:176842. [PMID: 39033837 DOI: 10.1016/j.ejphar.2024.176842] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2024] [Revised: 06/24/2024] [Accepted: 07/19/2024] [Indexed: 07/23/2024]
Abstract
Maintaining endothelial cell (EC) and vascular smooth muscle cell (VSMC) integrity is an important component of human health and disease because both EC and VSMC regulate various functions, including vascular tone control, cellular adhesion, homeostasis and thrombosis regulation, proliferation, and vascular inflammation. Diverse stressors affect functions in both ECs and VSMCs and abnormalities of functions in these cells play a crucial role in cardiovascular disease initiation and progression. Toll-like receptors (TLRs) are important detectors of pathogen-associated molecular patterns derived from various microbes and viruses as well as damage-associated molecular patterns derived from damaged cells and perform innate immune responses. Among TLRs, several studies reveal that TLR3 plays a key role in initiation, development and/or protection of diseases, and an emerging body of evidence indicates that TLR3 presents components of the vasculature, including ECs and VSMCs, and plays a functional role. An agonist of TLR3, polyinosinic-polycytidylic acid [poly (I:C)], affects ECs, including cell death, inflammation, chemoattractant, adhesion, permeability, and hemostasis. Poly (I:C) also affects VSMCs including inflammation, proliferation, and modulation of vascular tone. Moreover, alterations of vascular function induced by certain molecules and/or interventions are exerted through TLR3 signaling. Hence, we present the association between TLR3 and vascular function according to the latest studies.
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Affiliation(s)
- Takayuki Matsumoto
- Second Department of Pharmacology, School of Pharmaceutical Sciences, Kyushu University of Medical Science, Nobeoka, Miyazaki, 882-8508, Japan.
| | - Takayuki Nagano
- Second Department of Pharmacology, School of Pharmaceutical Sciences, Kyushu University of Medical Science, Nobeoka, Miyazaki, 882-8508, Japan
| | - Kumiko Taguchi
- Department of Physiology and Morphology, Institute of Medicinal Chemistry, Hoshi University, Shinagawa-ku, Tokyo, 142-8501, Japan
| | - Tsuneo Kobayashi
- Department of Physiology and Morphology, Institute of Medicinal Chemistry, Hoshi University, Shinagawa-ku, Tokyo, 142-8501, Japan
| | - Naoko Tanaka-Totoribe
- First Department of Pharmacology, School of Pharmaceutical Sciences, Kyushu University of Medical Science, Nobeoka, Miyazaki, 882-8508, Japan
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Königshausen E, Zierhut UM, Ruetze M, Rump LC, Sellin L. A molecular mechanism for angiotensin II receptor blocker-mediated slit membrane protection: Angiotensin II increases nephrin endocytosis via AT1-receptor-dependent ERK 1/2 activation. FASEB J 2024; 38:e70018. [PMID: 39212304 DOI: 10.1096/fj.202400369r] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2024] [Revised: 07/31/2024] [Accepted: 08/19/2024] [Indexed: 09/04/2024]
Abstract
Albuminuria is characterized by a disruption of the glomerular filtration barrier, which is composed of the fenestrated endothelium, the glomerular basement membrane, and the slit diaphragm. Nephrin is a major component of the slit diaphragm. Apart from hemodynamic effects, Ang II enhances albuminuria by β-Arrestin2-mediated nephrin endocytosis. Blocking the AT1 receptor with candesartan and irbesartan reduces the Ang II-mediated nephrin-β-Arrestin2 interaction. The inhibition of MAPK ERK 1/2 blocks Ang II-enhanced nephrin-β-Arrestin2 binding. ERK 1/2 signaling, which follows AT1 receptor activation, is mediated by G-protein signaling, EGFR transactivation, and β-Arrestin2 recruitment. A mutant AT1 receptor defective in EGFR transactivation and β-Arrestin2 recruitment reduces the Ang II-mediated increase in nephrin β-Arrestin2 binding. The mutation of β-Arrestin2K11,K12, critical for AT1 receptor binding, completely abrogates the interaction with nephrin, independent of Ang II stimulation. β-Arrestin2K11R,K12R does not influence nephrin cell surface expression. The data presented here deepen our molecular understanding of a blood-pressure-independent molecular mechanism of AT-1 receptor blockers (ARBs) in reducing albuminuria.
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Affiliation(s)
- Eva Königshausen
- Department of Nephrology, Medical School Duesseldorf, Heinrich Heine University, Duesseldorf, Germany
| | - Ulf M Zierhut
- Department of Nephrology, Medical School Duesseldorf, Heinrich Heine University, Duesseldorf, Germany
| | - Martin Ruetze
- Department of Nephrology, Medical School Duesseldorf, Heinrich Heine University, Duesseldorf, Germany
| | - Lars C Rump
- Department of Nephrology, Medical School Duesseldorf, Heinrich Heine University, Duesseldorf, Germany
| | - Lorenz Sellin
- Department of Nephrology, Medical School Duesseldorf, Heinrich Heine University, Duesseldorf, Germany
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Jiang Q, Song G, He L, Li X, Jiang B, Wang Q, Wang S, Kim C, Barkestani MN, Lopez R, Fan M, Wanniarachchi K, Quaranta M, Tian X, Mani A, Gonzalez A, Goodwin JE, Sessa WC, Ishibe S, Jane-Wit D. ZFYVE21 promotes endothelial nitric oxide signaling and vascular barrier function in the kidney during aging. Kidney Int 2024; 106:419-432. [PMID: 38797325 PMCID: PMC11343665 DOI: 10.1016/j.kint.2024.05.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2023] [Revised: 04/26/2024] [Accepted: 05/08/2024] [Indexed: 05/29/2024]
Abstract
ZFYVE21 is an ancient, endosome-associated protein that is highly expressed in endothelial cells (ECs) but whose function(s) in vivo are undefined. Here, we identified ZFYVE21 as an essential regulator of vascular barrier function in the aging kidney. ZFYVE21 levels significantly decline in ECs in aged human and mouse kidneys. To investigate attendant effects, we generated EC-specific Zfyve21-/- reporter mice. These knockout mice developed accelerated aging phenotypes including reduced endothelial nitric oxide (ENOS) activity, failure to thrive, and kidney insufficiency. Kidneys from Zfyve21 EC-/- mice showed interstitial edema and glomerular EC injury. ZFYVE21-mediated phenotypes were not programmed developmentally as loss of ZFYVE21 in ECs during adulthood phenocopied its loss prenatally, and a nitric oxide donor normalized kidney function in adult hosts. Using live cell imaging and human kidney organ cultures, we found that in a GTPase Rab5- and protein kinase Akt-dependent manner, ZFYVE21 reduced vesicular levels of inhibitory caveolin-1 and promoted transfer of Golgi-derived ENOS to a perinuclear Rab5+ vesicular population to functionally sustain ENOS activity. Thus, our work defines a ZFYVE21- mediated trafficking mechanism sustaining ENOS activity and demonstrates the relevance of this pathway for maintaining kidney function with aging.
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Affiliation(s)
- Quan Jiang
- Section of Cardiovascular Medicine, Yale University School of Medicine, New Haven, Connecticut, USA; Department of Cardiology, West Haven VA Medical Center, West Haven, Connecticut, USA.
| | - Guiyu Song
- Section of Cardiovascular Medicine, Yale University School of Medicine, New Haven, Connecticut, USA; Department of Cardiology, West Haven VA Medical Center, West Haven, Connecticut, USA; Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, Shenyang, China.
| | - Liying He
- Section of Cardiovascular Medicine, Yale University School of Medicine, New Haven, Connecticut, USA.
| | - Xue Li
- Department of Nephrology, Shengjing Hospital of China Medical University, Shenyang, China.
| | - Bo Jiang
- Department of Vascular Surgery, The First Hospital of China Medical University, Shenyang, China.
| | - Qianxun Wang
- Section of Cardiovascular Medicine, Yale University School of Medicine, New Haven, Connecticut, USA; Department of Cardiology, West Haven VA Medical Center, West Haven, Connecticut, USA
| | - Shaoxun Wang
- Section of Cardiovascular Medicine, Yale University School of Medicine, New Haven, Connecticut, USA; Department of Cardiology, West Haven VA Medical Center, West Haven, Connecticut, USA; Department of Surgery, Yale University School of Medicine, New Haven, Connecticut, USA
| | - Catherine Kim
- Department of Biomedical Engineering, Yale University School of Medicine, New Haven, Connecticut, USA
| | - Mahsa Nouri Barkestani
- Section of Cardiovascular Medicine, Yale University School of Medicine, New Haven, Connecticut, USA; Department of Cardiology, West Haven VA Medical Center, West Haven, Connecticut, USA
| | - Roberto Lopez
- Section of Cardiovascular Medicine, Yale University School of Medicine, New Haven, Connecticut, USA
| | - Matthew Fan
- Section of Cardiovascular Medicine, Yale University School of Medicine, New Haven, Connecticut, USA
| | - Kujani Wanniarachchi
- Section of Cardiovascular Medicine, Yale University School of Medicine, New Haven, Connecticut, USA; University of Cambridge, School of Clinical Medicine, Cambridge, UK
| | - Maya Quaranta
- Section of Cardiovascular Medicine, Yale University School of Medicine, New Haven, Connecticut, USA
| | - Xuefei Tian
- Section of Nephrology, Department of Internal Medicine, Yale School of Medicine, New Haven, Connecticut, USA
| | - Arya Mani
- Section of Cardiovascular Medicine, Yale University School of Medicine, New Haven, Connecticut, USA
| | - Anjelica Gonzalez
- Department of Biomedical Engineering, Yale University School of Medicine, New Haven, Connecticut, USA
| | - Julie E Goodwin
- Department of Pediatrics, Yale University School of Medicine, New Haven, Connecticut, USA
| | - William C Sessa
- Internal Medicine Research Unit, Pfizer, Cambridge, Massachussetts, USA
| | - Shuta Ishibe
- Section of Nephrology, Department of Internal Medicine, Yale School of Medicine, New Haven, Connecticut, USA
| | - Dan Jane-Wit
- Section of Cardiovascular Medicine, Yale University School of Medicine, New Haven, Connecticut, USA; Department of Cardiology, West Haven VA Medical Center, West Haven, Connecticut, USA.
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Boruah D, Kashif AW, Chakrabarty BK, Harikrishnan S, Sen A. Correlation of light and electron microscopic morphometric parameters of glomerular capillaries with serum creatinine and proteinuria. J Histotechnol 2024; 47:97-108. [PMID: 38465441 DOI: 10.1080/01478885.2024.2326274] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2023] [Accepted: 02/27/2024] [Indexed: 03/12/2024]
Abstract
Waste products in the bloodstream are filtered by the glomerular capillaries in the kidneys and excreted into the urine. When making a differential diagnosis of kidney diseases, structural assessment of glomeruli using histological, ultrastructural, and immunological studies is crucial. This study assessed the microscopic and ultrastructural morphometric parameters of glomerular capillaries and examined their correlation with serum creatinine and proteinuria. A total of 60 kidney biopsy cases received by the transmission electron microscope (TEM) laboratory for diagnosis were included in the study. Toluidine blue stained 300 nm thick sections of TEM tissue blocks were scanned for glomerular morphometry by a whole slide imaging system, and the estimation of Bowman's capsule (BC) area, glomerular capillary lumen diameter (GCLD), glomerular capillary density (GCD), glomerular capillary surface area density (GCSA), and percentage of glomerular capillary lumen space (%GCLS) was performed with QuPath software. TEM images of 70 nm thick sections were used for the evaluation of endothelial fenestration diameter (EFD), glomerular basement membrane (GBM) thickness, and podocyte foot process (PFP) effacement. Proteinuria and serum creatinine showed positive correlations with GBM thickness and PFP effacement. Negative correlations of serum creatinine were observed with EFD, %GCLS, and GCSA. Hence, glomerular filtration is greatly affected by the total area of the glomerular capillary surface and structural changes of GBM. Reduction of glomerulus filtration due to foot process effacement and thickening of GBM results in damage to the filtration barrier leading to the leakage of plasma protein into urine.
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Affiliation(s)
| | - A W Kashif
- Department of Pathology, Armed Forces Medical College, Pune, India
| | | | | | - Arijit Sen
- Department of Pathology, Armed Forces Medical College, Pune, India
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41
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Mathur M, Sahay M, Pereira BJG, Rizk DV. State-of-Art Therapeutics in IgA Nephropathy. Indian J Nephrol 2024; 34:417-430. [PMID: 39372635 PMCID: PMC11450772 DOI: 10.25259/ijn_319_23] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2023] [Accepted: 10/12/2023] [Indexed: 10/08/2024] Open
Abstract
Immunoglobulin-A nephropathy (IgAN) is the most common primary glomerulonephritis in the world, with up to 40% of patients progressing to end-stage kidney disease (ESKD) within 30 years of diagnosis. IgAN is characterized by elevated serum levels of galactose-deficient IgA1 (Gd-IgA1), which leads to immune complex formation and deposition in the glomerular mesangium, causing kidney injury. A diverse disease course and the long-term follow-up required for clinically relevant endpoints (e.g., ESKD) have been barriers to the development of novel therapies in IgAN. Disease management has focused on supportive care with inhibitors of the renin-angiotensin system and, more recently, sodium-glucose transporter inhibitors to control proteinuria. The recent acceptance of proteinuria as a surrogate endpoint by regulatory bodies and a better understanding of disease pathology have helped to initiate the development of several novel treatments. Subsequently, a targeted-release formulation of budesonide and a dual endothelin/angiotensin inhibitor (sparsentan) have received accelerated approval for patients with IgAN. However, additional therapies are needed to target the different pathogenic mechanisms and individualize patient care. Several compounds currently under investigation target various effectors of pathology. There are promising clinical results from emerging compounds that target the generation of Gd-IgA1 by B cells, including inhibitors of A PRoliferation-Inducing Ligand (APRIL) and dual inhibitors of APRIL and B-cell activating factor (BAFF). Other investigational therapies target the complement cascade by inhibiting proteins of the lectin or alternative pathways. As the therapeutic landscape evolves, it will be important to revise treatment guidelines and develop updated standards of care.
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Affiliation(s)
| | - Manisha Sahay
- Department of Nephrology, Osmania General Hospital and Osmania Medical College, Hyderabad, India
| | | | - Dana V. Rizk
- Department of Medicine, Division of Nephrology, University of Alabama, Birmingham, USA
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Solovev I, Sergeeva A, Geraskina A, Shaposhnikov M, Vedunova M, Borysova O, Moskalev A. Aging and physiological barriers: mechanisms of barrier integrity changes and implications for age-related diseases. Mol Biol Rep 2024; 51:917. [PMID: 39158744 DOI: 10.1007/s11033-024-09833-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2024] [Accepted: 07/30/2024] [Indexed: 08/20/2024]
Abstract
The phenomenon of compartmentalization is one of the key traits of life. Biological membranes and histohematic barriers protect the internal environment of the cell and organism from endogenous and exogenous impacts. It is known that the integrity of these barriers decreases with age due to the loss of homeostasis, including age-related gene expression profile changes and the abnormal folding/assembly, crosslinking, and cleavage of barrier-forming macromolecules in addition to morphological changes in cells and tissues. The critical molecular and cellular mechanisms involved in physiological barrier integrity maintenance and aging-associated changes in their functioning are reviewed on different levels: molecular, organelle, cellular, tissue (histohematic, epithelial, and endothelial barriers), and organ one (skin). Biogerontology, which studies physiological barriers in the aspect of age, is still in its infancy; data are being accumulated, but there is no talk of the synthesis of complex theories yet. This paper mainly presents the mechanisms that will become targets of anti-aging therapy only in the future, possibly: pharmacological, cellular, and gene therapies, including potential geroprotectors, hormetins, senomorphic drugs, and senolytics.
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Affiliation(s)
- Ilya Solovev
- Laboratory of Geroprotective and Radioprotective Technologies, Institute of Biology, Komi Science Center, Ural Branch, Russian Academy of Sciences, 28 Kommunisticheskaya st, Syktyvkar, 167982, Russian Federation
- Pitirim Sorokin Syktyvkar State University, 55 Oktyabrsky prosp, Syktyvkar, 167001, Russian Federation
| | - Alena Sergeeva
- Lobachevsky State University, Nizhny Novgorod, 603022, Russian Federation
| | | | - Mikhail Shaposhnikov
- Laboratory of Geroprotective and Radioprotective Technologies, Institute of Biology, Komi Science Center, Ural Branch, Russian Academy of Sciences, 28 Kommunisticheskaya st, Syktyvkar, 167982, Russian Federation
| | - Maria Vedunova
- Laboratory of genetics and epigenetics of aging, Russian Clinical Research Center for Gerontology, Pirogov Russian National Research Medical University, Moscow, 129226, Russian Federation
| | | | - Alexey Moskalev
- Laboratory of Geroprotective and Radioprotective Technologies, Institute of Biology, Komi Science Center, Ural Branch, Russian Academy of Sciences, 28 Kommunisticheskaya st, Syktyvkar, 167982, Russian Federation.
- Lobachevsky State University, Nizhny Novgorod, 603022, Russian Federation.
- Laboratory of genetics and epigenetics of aging, Russian Clinical Research Center for Gerontology, Pirogov Russian National Research Medical University, Moscow, 129226, Russian Federation.
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Wu G, Liu S, Hagenstein J, Alawi M, Hengel FE, Schaper M, Akyüz N, Liao Z, Wanner N, Tomas NM, Failla AV, Dierlamm J, Körbelin J, Lu S, Huber TB. Adeno-associated virus-based gene therapy treats inflammatory kidney disease in mice. J Clin Invest 2024; 134:e174722. [PMID: 39225099 PMCID: PMC11364381 DOI: 10.1172/jci174722] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2023] [Accepted: 07/10/2024] [Indexed: 09/04/2024] Open
Abstract
Adeno-associated virus (AAV) is a promising in vivo gene delivery platform showing advantages in delivering therapeutic molecules to difficult or undruggable cells. However, natural AAV serotypes have insufficient transduction specificity and efficiency in kidney cells. Here, we developed an evolution-directed selection protocol for renal glomeruli and identified what we believe to be a new vector termed AAV2-GEC that specifically and efficiently targets the glomerular endothelial cells (GEC) after systemic administration and maintains robust GEC tropism in healthy and diseased rodents. AAV2-GEC-mediated delivery of IdeS, a bacterial antibody-cleaving proteinase, provided sustained clearance of kidney-bound antibodies and successfully treated antiglomerular basement membrane glomerulonephritis in mice. Taken together, this study showcases the potential of AAV as a gene delivery platform for challenging cell types. The development of AAV2-GEC and its successful application in the treatment of antibody-mediated kidney disease represents a significant step forward and opens up promising avenues for kidney medicine.
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Affiliation(s)
- Guochao Wu
- III. Department of Medicine
- Hamburg Center for Kidney Health (HCKH)
| | - Shuya Liu
- III. Department of Medicine
- Hamburg Center for Kidney Health (HCKH)
| | - Julia Hagenstein
- III. Department of Medicine
- Hamburg Center for Kidney Health (HCKH)
| | | | | | - Melanie Schaper
- III. Department of Medicine
- Hamburg Center for Kidney Health (HCKH)
| | - Nuray Akyüz
- Department of Oncology, Hematology and Bone Marrow Transplantation with Section Pneumology, and
| | - Zhouning Liao
- III. Department of Medicine
- Hamburg Center for Kidney Health (HCKH)
| | - Nicola Wanner
- III. Department of Medicine
- Hamburg Center for Kidney Health (HCKH)
| | - Nicola M. Tomas
- III. Department of Medicine
- Hamburg Center for Kidney Health (HCKH)
| | | | - Judith Dierlamm
- Department of Oncology, Hematology and Bone Marrow Transplantation with Section Pneumology, and
| | - Jakob Körbelin
- Department of Oncology, Hematology and Bone Marrow Transplantation with Section Pneumology, and
| | - Shun Lu
- III. Department of Medicine
- Hamburg Center for Kidney Health (HCKH)
| | - Tobias B. Huber
- III. Department of Medicine
- Hamburg Center for Kidney Health (HCKH)
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Xu J, Hu H, Sun Y, Zhao Z, Zhang D, Yang L, Lu Q. The fate of immune complexes in membranous nephropathy. Front Immunol 2024; 15:1441017. [PMID: 39185424 PMCID: PMC11342396 DOI: 10.3389/fimmu.2024.1441017] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2024] [Accepted: 07/24/2024] [Indexed: 08/27/2024] Open
Abstract
The most characteristic feature of membranous nephropathy (MN) is the presence of subepithelial electron dense deposits and the consequential thickening of the glomerular basement membrane. There have been great advances in the understanding of the destiny of immune complexes in MN by the benefit of experimental models represented by Heymann nephritis. Subepithelial immune complexes are formed in situ by autoantibodies targeting native autoantigens or exogenous planted antigens such as the phospholipase A2 receptor (PLA2R) and cationic BSA respectively. The nascent immune complexes would not be pathogenic until they develop into immune deposits. Podocytes are the major source of autoantigens in idiopathic membranous nephropathy. They also participate in the modulation and removal of the immune complexes to a large extent. The balance between deposition and clearance is regulated by a wide range of factors such as the composition and physicochemical properties of the immune complexes and the complement system. Complement components such as C3 and C1q have been reported to be precipitated with the deposits whereas a complement regulatory protein CR1 expressed by podocytes is involved in the phagocytosis of immune complexes by podocytes. Podocytes regulate the dynamic change of immune complexes which is disturbed in membranous nephropathy. To elucidate the precise fate of the immune complexes is essential for developing more rational and novel therapies for membranous nephropathy.
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Affiliation(s)
- Jie Xu
- School of Life Sciences, Beijing University of Chinese Medicine, Beijing, China
| | - Haikun Hu
- School of Life Sciences, Beijing University of Chinese Medicine, Beijing, China
| | - Yuhe Sun
- School of Life Sciences, Beijing University of Chinese Medicine, Beijing, China
| | - Zihan Zhao
- School of Life Sciences, Beijing University of Chinese Medicine, Beijing, China
| | - Danyuan Zhang
- Qi Huang of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, China
| | - Lei Yang
- Department of Nephropathy, The Third Affiliated Hospital of Beijing University of Chinese Medicine, Beijing, China
| | - Qingyi Lu
- School of Life Sciences, Beijing University of Chinese Medicine, Beijing, China
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Chen G, Wang Y, Zhang L, Yang K, Wang X, Chen X. Research progress on miR-124-3p in the field of kidney disease. BMC Nephrol 2024; 25:252. [PMID: 39112935 PMCID: PMC11308398 DOI: 10.1186/s12882-024-03688-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2024] [Accepted: 07/26/2024] [Indexed: 08/10/2024] Open
Abstract
MicroRNAs (miRNAs) are 18-25 nucleotides long, single-stranded, non-coding RNA molecules that regulate gene expression. They play a crucial role in maintaining normal cellular functions and homeostasis in organisms. Studies have shown that miR-124-3p is highly expressed in brain tissue and plays a significant role in nervous system development. It is also described as a tumor suppressor, regulating biological processes like cancer cell proliferation, apoptosis, migration, and invasion by controlling multiple downstream target genes. miR-124-3p has been found to be involved in the progression of various kidney diseases, including diabetic kidney disease, calcium oxalate kidney stones, acute kidney injury, lupus nephritis, and renal interstitial fibrosis. It mediates these processes through mechanisms like oxidative stress, inflammation, autophagy, and ferroptosis. To lay the foundation for future therapeutic strategies, this research group reviewed recent studies on the functional roles of miR-124-3p in renal diseases and the regulation of its downstream target genes. Additionally, the feasibility, limitations, and potential application of miR-124-3p as a diagnostic biomarker and therapeutic target were thoroughly investigated.
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Affiliation(s)
- Guanting Chen
- Department of Nephrology, First Affiliated Hospital of Henan University of Chinese Medicine, Zhengzhou, Henan Province, 450003, China
- Collaborative Innovation Center of Prevention and Treatment of Major Diseases by Chinese and Western Medicine, Zhengzhou, Henan Province, 450003, China
| | - Yaoxian Wang
- Henan University of Chinese Medicine, Zhengzhou, Henan Province, 450003, China.
- Collaborative Innovation Center of Prevention and Treatment of Major Diseases by Chinese and Western Medicine, Zhengzhou, Henan Province, 450003, China.
| | - Linqi Zhang
- Department of Nephrology, First Affiliated Hospital of Henan University of Chinese Medicine, Zhengzhou, Henan Province, 450003, China.
- Collaborative Innovation Center of Prevention and Treatment of Major Diseases by Chinese and Western Medicine, Zhengzhou, Henan Province, 450003, China.
| | - Kang Yang
- Department of Nephrology, First Affiliated Hospital of Henan University of Chinese Medicine, Zhengzhou, Henan Province, 450003, China
- Collaborative Innovation Center of Prevention and Treatment of Major Diseases by Chinese and Western Medicine, Zhengzhou, Henan Province, 450003, China
| | - Xixi Wang
- Department of Nephrology, First Affiliated Hospital of Henan University of Chinese Medicine, Zhengzhou, Henan Province, 450003, China
- Collaborative Innovation Center of Prevention and Treatment of Major Diseases by Chinese and Western Medicine, Zhengzhou, Henan Province, 450003, China
| | - Xu Chen
- Department of Nephrology, First Affiliated Hospital of Henan University of Chinese Medicine, Zhengzhou, Henan Province, 450003, China
- Collaborative Innovation Center of Prevention and Treatment of Major Diseases by Chinese and Western Medicine, Zhengzhou, Henan Province, 450003, China
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Yang H, Sun J, Sun A, Wei Y, Xie W, Xie P, Zhang L, Zhao L, Huang Y. Podocyte programmed cell death in diabetic kidney disease: Molecular mechanisms and therapeutic prospects. Biomed Pharmacother 2024; 177:117140. [PMID: 39018872 DOI: 10.1016/j.biopha.2024.117140] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2024] [Revised: 06/28/2024] [Accepted: 07/10/2024] [Indexed: 07/19/2024] Open
Abstract
Diabetic kidney disease (DKD) is the primary cause of chronic kidney and end-stage renal disease. Glomerular podocyte loss and death are pathological hallmarks of DKD, and programmed cell death (PCD) in podocytes is crucial in DKD progression. PCD involves apoptosis, autophagy, ferroptosis, pyroptosis, and necroptosis. During DKD, PCD in podocytes is severely impacted and primarily characterized by accelerated podocyte apoptosis and suppressed autophagy. These changes lead to a gradual decrease in podocyte numbers, impairing the glomerular filtration barrier function and accelerating DKD progression. However, research on the interactions between the different types of PCD in podocytes is lacking. This review focuses on the novel roles and mechanisms of PCD in the podocytes of patients with DKD. Additionally, we summarize clinical drugs capable of regulating podocyte PCD, present challenges and prospects faced in developing drugs related to podocyte PCD and suggest that future research should further explore the detailed mechanisms of podocyte PCD and interactions among different types of PCD.
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Affiliation(s)
- Haoyu Yang
- Institute of Metabolic Diseases, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing 100053, China
| | - Jun Sun
- Changchun University of Chinese Medicine, Changchun 130117, China
| | - Aru Sun
- Changchun University of Chinese Medicine, Changchun 130117, China
| | - Yu Wei
- Institute of Metabolic Diseases, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing 100053, China
| | - Weinan Xie
- Institute of Metabolic Diseases, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing 100053, China
| | - Pengfei Xie
- Institute of Metabolic Diseases, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing 100053, China
| | - Lili Zhang
- Institute of Metabolic Diseases, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing 100053, China.
| | - Linhua Zhao
- Institute of Metabolic Diseases, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing 100053, China.
| | - Yishan Huang
- Institute of Metabolic Diseases, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing 100053, China; China-Japan Friendship Hospital, Beijing 100029, China.
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Mokhtar WA, Elsaid AM, Elrefaey AM, Saleh MM, Youssef MM. Association of PLCE1 (rs7922612) and COL4A3 (rs375290088) Genetic Variants with the Risk of Nephrotic Syndrome in Egyptian Pediatric Patients. Biochem Genet 2024:10.1007/s10528-024-10883-6. [PMID: 39028381 DOI: 10.1007/s10528-024-10883-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2023] [Accepted: 07/04/2024] [Indexed: 07/20/2024]
Abstract
Nephrotic syndrome is one of the most prevalent pediatric kidney illnesses seen in pediatric nephrology clinics. Steroid resistance in children with nephrotic syndrome is a primary cause of renal failure and is characterized by nephrotic range proteinuria that does not respond to conventional steroid therapy. The current work was intended to investigate the possible role of the Phospholipase C epsilon 1 (rs7922612) and collagen4 alpha 3 (rs375290088) single nucleotide polymorphisms as risk factors for developing nephrotic syndrome among Egyptian children. The study was conducted on 100 children with nephrotic syndrome and 100 age- and sex-matched healthy individuals. Geno typing was performed by two methods of polymerase chain reaction for the analysis of PLCE1 (rs7922612) and COL4A3 (rs375290088) variants. We observed a higher percentage of the heterozygous and homozygous variant genotypes of PLCE1 (rs7922612) SNP in NS patients in comparison with the controls (P < 0.001 for both). The frequencies of the PLCE1 (rs7922612) variant showed a statistically significant elevated risk of NS using several genetic models, including the dominant (OR = 9.12), recessive (OR = 2.31), and allelic (OR = 1.62) models (P < 0.001 for each). In addition, the PLCE1 (rs7922612) genotypes and alleles frequencies did not differ significantly between SRNS compared to SSNS cases. Furthermore, there was no significant difference regarding COL4A3 (rs375290088) polymorphism, neither between the NS and control groups nor between SDNS and SRNS. PLCE1 (rs7922612) is considered an independent risk factor for nephrotic syndrome in Egyptian pediatrics.COL4A3 (rs375290088) polymorphism is not correlated to Egyptian NS patients.
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Affiliation(s)
- Wafaa A Mokhtar
- Division of Biochemistry, Department of Chemistry, Faculty of Science, University of Mansoura, Mansoura, Egypt.
| | - Afaf M Elsaid
- Consultant of Biochemistry, Faculty of Medicine, University of Mansoura, Mansoura, Egypt
| | - Ahmed M Elrefaey
- Department of Paediatrics, Faculty of Medicine, University of Mansoura, Mansoura, Egypt
| | - Marwan Mahmood Saleh
- Department of Medical Physics, College of Applied Sciences, University of Anbar, Ramadi, Iraq
| | - Magdy M Youssef
- Division of Biochemistry, Department of Chemistry, Faculty of Science, University of Mansoura, Mansoura, Egypt
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Musah S, Bhattacharya R, Himmelfarb J. Kidney Disease Modeling with Organoids and Organs-on-Chips. Annu Rev Biomed Eng 2024; 26:383-414. [PMID: 38424088 PMCID: PMC11479997 DOI: 10.1146/annurev-bioeng-072623-044010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/02/2024]
Abstract
Kidney disease is a global health crisis affecting more than 850 million people worldwide. In the United States, annual Medicare expenditures for kidney disease and organ failure exceed $81 billion. Efforts to develop targeted therapeutics are limited by a poor understanding of the molecular mechanisms underlying human kidney disease onset and progression. Additionally, 90% of drug candidates fail in human clinical trials, often due to toxicity and efficacy not accurately predicted in animal models. The advent of ex vivo kidney models, such as those engineered from induced pluripotent stem (iPS) cells and organ-on-a-chip (organ-chip) systems, has garnered considerable interest owing to their ability to more accurately model tissue development and patient-specific responses and drug toxicity. This review describes recent advances in developing kidney organoids and organ-chips by harnessing iPS cell biology to model human-specific kidney functions and disease states. We also discuss challenges that must be overcome to realize the potential of organoids and organ-chips as dynamic and functional conduits of the human kidney. Achieving these technological advances could revolutionize personalized medicine applications and therapeutic discovery for kidney disease.
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Affiliation(s)
- Samira Musah
- Department of Biomedical Engineering, Pratt School of Engineering, Duke University, Durham, North Carolina, USA;
- Division of Nephrology, Department of Medicine, Duke University School of Medicine, Durham, North Carolina, USA
- Center for Biomolecular and Tissue Engineering, Duke University, Durham, North Carolina, USA
- Developmental and Stem Cell Biology Program and Department of Cell Biology, Duke University, Durham, North Carolina, USA
| | - Rohan Bhattacharya
- Department of Biomedical Engineering, Pratt School of Engineering, Duke University, Durham, North Carolina, USA;
- Center for Biomolecular and Tissue Engineering, Duke University, Durham, North Carolina, USA
| | - Jonathan Himmelfarb
- Department of Medicine, Kidney Research Institute, and Division of Nephrology, University of Washington School of Medicine, Seattle, Washington, USA;
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Monte Neto JTD, Kirsztajn GM. The role of podocyte injury in the pathogenesis of Fabry disease nephropathy. J Bras Nefrol 2024; 46:e20240035. [PMID: 39058283 PMCID: PMC11287863 DOI: 10.1590/2175-8239-jbn-2024-0035en] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2024] [Accepted: 05/02/2024] [Indexed: 07/28/2024] Open
Abstract
Renal involvement is one of the most severe morbidities of Fabry disease (FD), a multisystemic lysosomal storage disease with an X-linked inheritance pattern. It results from pathogenic variants in the GLA gene (Xq22.2), which encodes the production of alpha-galactosidase A (α-Gal), responsible for glycosphingolipid metabolism. Insufficient activity of this lysosomal enzyme generates deposits of unprocessed intermediate substrates, especially globotriaosylceramide (Gb3) and derivatives, triggering cellular injury and subsequently, multiple organ dysfunction, including chronic nephropathy. Kidney injury in FD is classically attributed to Gb3 deposits in renal cells, with podocytes being the main target of the pathological process, in which structural and functional alterations are established early and severely. This configures a typical hereditary metabolic podocytopathy, whose clinical manifestations are proteinuria and progressive renal failure. Although late clinical outcomes and morphological changes are well established in this nephropathy, the molecular mechanisms that trigger and accelerate podocyte injury have not yet been fully elucidated. Podocytes are highly specialized and differentiated cells that cover the outer surface of glomerular capillaries, playing a crucial role in preserving the structure and function of the glomerular filtration barrier. They are frequent targets of injury in many nephropathies. Furthermore, dysfunction and depletion of glomerular podocytes are essential events implicated in the pathogenesis of chronic kidney disease progression. We will review the biology of podocytes and their crucial role in regulating the glomerular filtration barrier, analyzing the main pathogenic pathways involved in podocyte injury, especially related to FD nephropathy.
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Korsmo HW, Ekperikpe US, Daehn IS. Emerging Roles of Xanthine Oxidoreductase in Chronic Kidney Disease. Antioxidants (Basel) 2024; 13:712. [PMID: 38929151 PMCID: PMC11200862 DOI: 10.3390/antiox13060712] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2024] [Revised: 06/09/2024] [Accepted: 06/10/2024] [Indexed: 06/28/2024] Open
Abstract
Xanthine Oxidoreductase (XOR) is a ubiquitous, essential enzyme responsible for the terminal steps of purine catabolism, ultimately producing uric acid that is eliminated by the kidneys. XOR is also a physiological source of superoxide ion, hydrogen peroxide, and nitric oxide, which can function as second messengers in the activation of various physiological pathways, as well as contribute to the development and the progression of chronic conditions including kidney diseases, which are increasing in prevalence worldwide. XOR activity can promote oxidative distress, endothelial dysfunction, and inflammation through the biological effects of reactive oxygen species; nitric oxide and uric acid are the major products of XOR activity. However, the complex relationship of these reactions in disease settings has long been debated, and the environmental influences and genetics remain largely unknown. In this review, we give an overview of the biochemistry, biology, environmental, and current clinical impact of XOR in the kidney. Finally, we highlight recent genetic studies linking XOR and risk for kidney disease, igniting enthusiasm for future biomarker development and novel therapeutic approaches targeting XOR.
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Affiliation(s)
| | | | - Ilse S. Daehn
- Department of Medicine, Division of Nephrology, The Icahn School of Medicine at Mount Sinai, One Gustave Levy Place, Box 1243, New York, NY 10029, USA
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