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Zhang C, Guo J. Cell cycle disorders in podocytes: an emerging and increasingly recognized phenomenon. Cell Death Discov 2025; 11:182. [PMID: 40246828 PMCID: PMC12006314 DOI: 10.1038/s41420-025-02486-w] [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: 02/04/2025] [Revised: 04/01/2025] [Accepted: 04/08/2025] [Indexed: 04/19/2025] Open
Abstract
Proteinuria is observed in various kidney diseases and is frequently associated with a compromised glomerular filtration barrier. Podocytes, as a crucial component of this barrier, play an essential role in preserving the kidney's normal filtration function. Podocytes are terminally differentiated cells that typically do not proliferate. However, certain harmful stimuli can trigger podocytes to re-enter the cell cycle. Due to its unique cytoskeletal structure, podocytes are unable to maintain the structure of the foot process and complete cell division at the same time, eventually form binucleated or multinucleated podocytes. Studies have found that podocytes re-entering the cell cycle are more susceptible to injury, and are prone to detachment from the basement membrane or apoptosis, which are accompanied by the widening of foot processes. This eventually leads to podocyte mitotic catastrophe and the development of proteinuria. Podocyte cell cycle disorders have previously been found mainly in focal segmental glomerulosclerosis and IgA nephropathy. In recent years, this phenomenon has been frequently identified in diabetic kidney disease and lupus nephritis. An expanding body of research has begun to investigate the mechanisms underlying podocyte cell cycle disorders, including cell cycle re-entry, cell cycle arrest, and mitotic catastrophe. This review consolidates the existing literature on podocyte cell cycle disorders in renal diseases and summarizes the molecules that trigger podocyte re-entry into the cell cycle, thereby providing new drug targets for mitigating podocyte damage. This is essential for alleviating podocyte injury, reducing proteinuria, and delaying the progression of kidney diseases.
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Affiliation(s)
- Chaojie Zhang
- Department of Nephrology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
- Key Laboratory of Precision Diagnosis and Treatment for Chronic Kidney Disease in Henan Province, Zhengzhou, Henan, China
- Tianjian Laboratory of Advanced Biomedical Sciences, Academy of Medical Sciences, Zhengzhou University, Zhengzhou, Henan, China
| | - Jia Guo
- Department of Nephrology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China.
- Key Laboratory of Precision Diagnosis and Treatment for Chronic Kidney Disease in Henan Province, Zhengzhou, Henan, China.
- Tianjian Laboratory of Advanced Biomedical Sciences, Academy of Medical Sciences, Zhengzhou University, Zhengzhou, Henan, China.
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2
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Melica ME, Antonelli G, Semeraro R, La Regina G, Dafichi T, Fantini C, Carangelo G, Comito G, Conte C, Maggi L, Landini S, Raglianti V, Angelotti ML, Molli A, Buonvicino D, De Chiara L, Lazzeri E, Mazzinghi B, Peired AJ, Romagnani P, Lasagni L. Piezo1, F-Actin Remodeling, and Podocyte Survival and Regeneration. J Am Soc Nephrol 2025:00001751-990000000-00611. [PMID: 40172977 DOI: 10.1681/asn.0000000697] [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: 05/02/2024] [Accepted: 03/20/2025] [Indexed: 04/04/2025] Open
Abstract
Key Points
Piezo1 regulates perinuclear actin remodeling, and its loss induces nuclear envelope defects and accumulation of DNA damage.Piezo1 loss in podocytes leads to mitotic catastrophe.Podocyte-specific and podocyte progenitor–specific knockout of Piezo1 in mice result in severe albuminuria after adriamycin nephropathy.
Background
Podocytes and podocyte progenitors are interdependent components of the kidney's glomerular structure, with podocytes forming the glomerular filtration barrier and progenitors being key players in podocyte regeneration during pathophysiologic processes. Both cell types are subjected to constant mechanical forces, whose alterations can initiate podocytopathy and worsen glomerular injury. Despite this, the specific mechanosensors and mechanotransduction pathways involved in their response to mechanical cues remain only partially explored.
Methods
We used transcriptomics, immunofluorescence, and silencing experiments on human primary podocyte progenitor cell cultures to demonstrate the expression and function of Piezo1 channels. We generated inducible podocyte-specific and podocyte progenitor–specific Piezo1 knockout (KO) mice to evaluate the effects of Piezo1 loss in the context of adriamycin nephropathy and over 10 months of aging.
Results
Silencing of Piezo1 in progenitors triggered F-actin remodeling, which induced cell shape modification and nuclear envelope defects with accumulation of DNA damage that led to mitotic catastrophe in differentiated podocytes. Podocyte-specific KO of Piezo1 induced higher susceptibility to podocyte injury in adriamycin nephropathy and led to accumulation of DNA damage and mild albuminuria starting from adult age. Podocyte progenitor–specific KO of Piezo1 in mouse resulted in severe albuminuria during adriamycin nephropathy, leading to the generation of defective podocytes.
Conclusions
These results demonstrated that Piezo1, thanks to its role in F-actin cytoskeleton maintenance, is essential for the survival of podocytes exposed to mechanical stress conditions and for their correct regeneration.
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Affiliation(s)
- Maria Elena Melica
- Department of Experimental and Clinical Biomedical Sciences "Mario Serio," University of Florence, 50134, Florence, Italy
| | - Giulia Antonelli
- Department of Experimental and Clinical Biomedical Sciences "Mario Serio," University of Florence, 50134, Florence, Italy
| | - Roberto Semeraro
- Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy
| | - Gilda La Regina
- Department of Experimental and Clinical Biomedical Sciences "Mario Serio," University of Florence, 50134, Florence, Italy
| | - Tommaso Dafichi
- Department of Experimental and Clinical Biomedical Sciences "Mario Serio," University of Florence, 50134, Florence, Italy
| | - Camilla Fantini
- Department of Experimental and Clinical Biomedical Sciences "Mario Serio," University of Florence, 50134, Florence, Italy
| | - Giulia Carangelo
- Department of Experimental and Clinical Biomedical Sciences "Mario Serio," University of Florence, 50134, Florence, Italy
| | - Giuseppina Comito
- Department of Experimental and Clinical Biomedical Sciences "Mario Serio," University of Florence, 50134, Florence, Italy
| | - Carolina Conte
- Department of Experimental and Clinical Biomedical Sciences "Mario Serio," University of Florence, 50134, Florence, Italy
| | - Laura Maggi
- Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy
| | - Samuela Landini
- Medical Genetics Unit, Meyer Children's Hospital IRCCS, Florence, Italy
| | - Valentina Raglianti
- Department of Experimental and Clinical Biomedical Sciences "Mario Serio," University of Florence, 50134, Florence, Italy
| | - Maria Lucia Angelotti
- Department of Experimental and Clinical Biomedical Sciences "Mario Serio," University of Florence, 50134, Florence, Italy
| | - Alice Molli
- Section of Clinical Pharmacology and Oncology, Department of Health Sciences, University of Florence, Florence, Italy
| | - Daniela Buonvicino
- Section of Clinical Pharmacology and Oncology, Department of Health Sciences, University of Florence, Florence, Italy
| | - Letizia De Chiara
- Department of Experimental and Clinical Biomedical Sciences "Mario Serio," University of Florence, 50134, Florence, Italy
| | - Elena Lazzeri
- Department of Experimental and Clinical Biomedical Sciences "Mario Serio," University of Florence, 50134, Florence, Italy
| | - Benedetta Mazzinghi
- Nephrology and Dialysis Unit, Meyer Children's Hospital IRCCS, Florence, Italy
| | - Anna Julie Peired
- Department of Experimental and Clinical Biomedical Sciences "Mario Serio," University of Florence, 50134, Florence, Italy
| | - Paola Romagnani
- Department of Experimental and Clinical Biomedical Sciences "Mario Serio," University of Florence, 50134, Florence, Italy
- Nephrology and Dialysis Unit, Meyer Children's Hospital IRCCS, Florence, Italy
| | - Laura Lasagni
- Department of Experimental and Clinical Biomedical Sciences "Mario Serio," University of Florence, 50134, Florence, Italy
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Basu R, Boguszewski CL, Kopchick JJ. Growth Hormone Action as a Target in Cancer: Significance, Mechanisms, and Possible Therapies. Endocr Rev 2025; 46:224-280. [PMID: 39657053 DOI: 10.1210/endrev/bnae030] [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: 05/03/2024] [Revised: 08/29/2024] [Accepted: 12/03/2024] [Indexed: 12/17/2024]
Abstract
Growth hormone (GH) is a pituitary-derived endocrine hormone required for normal postnatal growth and development. Hypo- or hypersecretion of endocrine GH results in 2 pathologic conditions, namely GH deficiency (GHD) and acromegaly. Additionally, GH is also produced in nonpituitary and tumoral tissues, where it acts rather as a cellular growth factor with an autocrine/paracrine mode of action. An increasingly persuasive and large body of evidence over the last 70 years concurs that GH action is implicit in escalating several cancer-associated events, locally and systemically. This pleiotropy of GH's effects is puzzling, but the association with cancer risk automatically raises a concern for patients with acromegaly and for individuals treated with GH. By careful assessment of the available knowledge on the fundamental concepts of cancer, suggestions from epidemiological and clinical studies, and the evidence from specific reports, in this review we aimed to help clarify the distinction of endocrine vs autocrine/paracrine GH in promoting cancer and to reconcile the discrepancies between experimental and clinical data. Along this discourse, we critically weigh the targetability of GH action in cancer-first by detailing the molecular mechanisms which posit GH as a critical node in tumor circuitry; and second, by enumerating the currently available therapeutic options targeting GH action. On the basis of our discussion, we infer that a targeted intervention on GH action in the appropriate patient population can benefit a sizable subset of current cancer prognoses.
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Affiliation(s)
- Reetobrata Basu
- Edison Biotechnology Institute, Ohio University, Athens, OH 45701, USA
- Department of Biomedical Sciences, Ohio University Heritage College of Osteopathic Medicine (OU-HCOM), Athens, OH 45701, USA
- Diabetes Institute, Ohio University Heritage College of Osteopathic Medicine (OU-HCOM), Athens, OH 45701, USA
| | - Cesar L Boguszewski
- SEMPR, Endocrine Division, Department of Internal Medicine, Federal University of Parana, Curitiba 80060-900, Brazil
| | - John J Kopchick
- Edison Biotechnology Institute, Ohio University, Athens, OH 45701, USA
- Department of Biomedical Sciences, Ohio University Heritage College of Osteopathic Medicine (OU-HCOM), Athens, OH 45701, USA
- Diabetes Institute, Ohio University Heritage College of Osteopathic Medicine (OU-HCOM), Athens, OH 45701, USA
- Molecular and Cellular Biology Program, Ohio University, Athens, OH 45701, USA
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Ma P, Shao H, Xu D, Qi X. Sirt6 regulates the Notch signaling pathway and mediates autophagy and regulates podocyte damage in diabetic nephropathy. J Bioenerg Biomembr 2025; 57:49-55. [PMID: 39754634 DOI: 10.1007/s10863-024-10049-4] [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: 08/19/2024] [Accepted: 12/24/2024] [Indexed: 01/06/2025]
Abstract
To investigate the role of silent information regulator 6 (SIRT6) in regulating podocyte injury in diabetic nephropathy (DN) through autophagy mediated by Notch signaling pathway. A blank control group (group A), a diabetic nephropathy group (group B), and a Sirt6 intervention group (group C) were established. The group A cells were human normal glomerular podocyte cell lines (HGPCs) without any treatment. In group B, the cells were cultivated in glucose medium containing 30 mmol/L and a 10 µmol/L anti-LSirt6 antibody solution. Three sets of cells were tested for their capacity to proliferate via CCK8, for protein expression via Western blot, for associated mRNA expression levels via qPCR, and for cell migration and invasion ability via Transwell. The podocyte proliferation and migration activity in group B were reduced compared to group A, while these properties in group C were elevated compared to group B (DN). B Group is diabetes nephropathy. Compared with those in group B, the number of invading podocytes in group C were greater than those in group A, and the overall apoptosis rate in group C was lower than that in group B. The expression levels of apoptotic proteins in the podocytes in group C were greater than those in group B, and the bcl-2 level was lower than those in group B. The Notch1 and Jagged1 mRNA and protein levels in the podocytes in group B were greater than those in group A, whereas those in the podocytes in group C were lower than those in group B. Sirt6 can protect against podocyte autophagy injury in DN by regulating the Notch1 signaling pathway.
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Affiliation(s)
- Ping Ma
- Department of Endocrinology, Tianjin 4th Center Hospital, Tianjin, 300140, China.
| | - Hailin Shao
- Department of Endocrinology, Tianjin 4th Center Hospital, Tianjin, 300140, China
| | - Donghong Xu
- Department of Endocrinology, Tianjin 4th Center Hospital, Tianjin, 300140, China
| | - Xiaoyu Qi
- Department of Endocrinology, Tianjin 4th Center Hospital, Tianjin, 300140, China
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5
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Qi B, Chen Y, Chai S, Lu X, Kang L. O-linked β-N-acetylglucosamine (O-GlcNAc) modification: Emerging pathogenesis and a therapeutic target of diabetic nephropathy. Diabet Med 2025; 42:e15436. [PMID: 39279604 PMCID: PMC11733667 DOI: 10.1111/dme.15436] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/03/2024] [Revised: 08/29/2024] [Accepted: 08/30/2024] [Indexed: 09/18/2024]
Abstract
AIMS O-Linked β-N-acetylglucosamine (O-GlcNAc) modification, a unique post-translational modification of proteins, is elevated in diabetic nephropathy. This review aims to summarize the current knowledge on the mechanisms by which O-GlcNAcylation of proteins contributes to the pathogenesis and progression of diabetic nephropathy, as well as the therapeutic potential of targeting O-GlcNAc modification for its treatment. METHODS Current evidence in the literature was reviewed and synthesized in a narrative review. RESULTS Hyperglycemia increases glucose flux into the hexosamine biosynthesis pathway, which activates glucosamino-fructose aminotransferase expression and activity, leading to the production of O-GlcNAcylation substrate UDP-GlcNAc and an increase in protein O-GlcNAcylation in kidney cells. Protein O-GlcNAcylation regulates the function of kidney cells including mesangial cells, podocytes, and proximal tubular cells, and promotes renal interstitial fibrosis, resulting in kidney damage. Current treatments for diabetic nephropathy, such as sodium-glucose cotransporter 2 (SGLT-2) inhibitors and renin-angiotensin-aldosterone system (RAAS) inhibitors, delay disease progression, and suppress protein O-GlcNAcylation. CONCLUSIONS Increased protein O-GlcNAcylation mediates renal cell damage and promotes renal interstitial fibrosis, leading to diabetic nephropathy. Although the full significance of inhibition of O-GlcNAcylation is not yet understood, it may represent a novel target for treating diabetic nephropathy.
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Affiliation(s)
- Bingxue Qi
- Precision Molecular Medicine CenterJilin Province People's HospitalChangchunChina
| | - Yang Chen
- Clinical Medicine CollegeChangchun University of Chinese MedicineChangchunChina
| | - Siyang Chai
- Clinical Medicine CollegeChangchun University of Chinese MedicineChangchunChina
| | - Xiaodan Lu
- Precision Molecular Medicine CenterJilin Province People's HospitalChangchunChina
| | - Li Kang
- Division of Cellular and Systems MedicineSchool of Medicine, University of DundeeDundeeUK
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Feng J, Xie L, Lu W, Yu X, Dong H, Ma Y, Kong R. Hyperactivation of p53 contributes to mitotic catastrophe in podocytes through regulation of the Wee1/CDK1/cyclin B1 axis. Ren Fail 2024; 46:2365408. [PMID: 38874119 PMCID: PMC11182053 DOI: 10.1080/0886022x.2024.2365408] [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: 01/29/2024] [Accepted: 06/03/2024] [Indexed: 06/15/2024] Open
Abstract
Podocyte loss in glomeruli is a fundamental event in the pathogenesis of chronic kidney diseases. Currently, mitotic catastrophe (MC) has emerged as the main cause of podocyte loss. However, the regulation of MC in podocytes has yet to be elucidated. The current work aimed to study the role and mechanism of p53 in regulating the MC of podocytes using adriamycin (ADR)-induced nephropathy. In vitro podocyte stimulation with ADR triggered the occurrence of MC, which was accompanied by hyperactivation of p53 and cyclin-dependent kinase (CDK1)/cyclin B1. The inhibition of p53 reversed ADR-evoked MC in podocytes and protected against podocyte injury and loss. Further investigation showed that p53 mediated the activation of CDK1/cyclin B1 by regulating the expression of Wee1. Restraining Wee1 abolished the regulatory effect of p53 inhibition on CDK1/cyclin B1 and rebooted MC in ADR-stimulated podocytes via p53 inhibition. In a mouse model of ADR nephropathy, the inhibition of p53 ameliorated proteinuria and podocyte injury. Moreover, the inhibition of p53 blocked the progression of MC in podocytes in ADR nephropathy mice through the regulation of the Wee1/CDK1/cyclin B1 axis. Our findings confirm that p53 contributes to MC in podocytes through regulation of the Wee1/CDK1/Cyclin B1 axis, which may represent a novel mechanism underlying podocyte injury and loss during the progression of chronic kidney disorder.
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Affiliation(s)
- Jie Feng
- Department of Nephrology, the First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi, China
| | - Liyi Xie
- Department of Nephrology, the First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi, China
| | - Wanhong Lu
- Department of Nephrology, the First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi, China
| | - Xiaoyang Yu
- Department of Nephrology, the First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi, China
| | - Hongjuan Dong
- Department of Nephrology, the First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi, China
| | - Yuefeng Ma
- Department of Thoracic Surgery, the Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi, China
| | - Ranran Kong
- Department of Thoracic Surgery, the Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi, China
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Okamoto Y, Kitakaze K, Takenouchi Y, Matsui R, Koga D, Miyashima R, Ishimaru H, Tsuboi K. GPR176 promotes fibroblast-to-myofibroblast transition in organ fibrosis progression. BIOCHIMICA ET BIOPHYSICA ACTA. MOLECULAR CELL RESEARCH 2024; 1871:119798. [PMID: 39047914 DOI: 10.1016/j.bbamcr.2024.119798] [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: 01/31/2024] [Revised: 06/20/2024] [Accepted: 07/14/2024] [Indexed: 07/27/2024]
Abstract
Fibrosis is characterized by excessive deposition of extracellular matrix proteins, particularly collagen, caused by myofibroblasts in response to chronic inflammation. Although G protein-coupled receptors (GPCRs) are among the targets of current antifibrotic drugs, no drug has yet been approved to stop fibrosis progression. Herein, we aimed to identify GPCRs with profibrotic effects. In gene expression analysis of mouse lungs with induced fibrosis, eight GPCRs were identified, showing a >2-fold increase in mRNA expression after fibrosis induction. Among them, we focused on Gpr176 owing to its significant correlation with a myofibroblast marker α-smooth muscle actin (αSMA), the profibrotic factor transforming growth factor β1 (TGFβ1), and collagen in a human lung gene expression database. Similar to the lung fibrosis model, increased Gpr176 expression was also observed in other organs affected by fibrosis, including the kidney, liver, and heart, suggesting its role in fibrosis across various organs. Furthermore, fibroblasts abundantly expressed Gpr176 compared to alveolar epithelial cells, endothelial cells, and macrophages in the fibrotic lung. GPR176 expression was unaffected by TGFβ1 stimulation in rat renal fibroblast NRK-49 cells, whereas knockdown of Gpr176 by siRNA reduced TGFβ1-induced expression of αSMA, fibronectin, and collagen as well as Smad2 phosphorylation. This suggested that Gpr176 regulates fibroblast activation. Consequently, Gpr176 acts in a profibrotic manner, and inhibiting its activity could potentially prevent myofibroblast differentiation and improve fibrosis. Developing a GPR176 inverse agonist or allosteric modulator is a promising therapeutic approach for fibrosis.
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Affiliation(s)
- Yasuo Okamoto
- Department of Pharmacology, Kawasaki Medical School, 577 Matsushima, Kurashiki, Okayama 701-0192, Japan.
| | - Keisuke Kitakaze
- Department of Pharmacology, Kawasaki Medical School, 577 Matsushima, Kurashiki, Okayama 701-0192, Japan
| | - Yasuhiro Takenouchi
- Department of Pharmacology, Kawasaki Medical School, 577 Matsushima, Kurashiki, Okayama 701-0192, Japan
| | - Rena Matsui
- Department of Medical Technology, Kawasaki University of Medical Welfare, Kurashiki, Okayama 701-0192, Japan
| | - Daisuke Koga
- Department of Pharmacology, Kawasaki Medical School, 577 Matsushima, Kurashiki, Okayama 701-0192, Japan
| | - Ryo Miyashima
- Department of Pharmacology, Kawasaki Medical School, 577 Matsushima, Kurashiki, Okayama 701-0192, Japan
| | - Hironobu Ishimaru
- Department of Pharmacology, Kawasaki Medical School, 577 Matsushima, Kurashiki, Okayama 701-0192, Japan
| | - Kazuhito Tsuboi
- Department of Pharmacology, Kawasaki Medical School, 577 Matsushima, Kurashiki, Okayama 701-0192, Japan
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Wu C, Tang H, Cui X, Li N, Fei J, Ge H, Wu L, Wu J, Gu HF. A single-cell profile reveals the transcriptional regulation responded for Abelmoschus manihot (L.) treatment in diabetic kidney disease. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2024; 130:155642. [PMID: 38759315 DOI: 10.1016/j.phymed.2024.155642] [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: 01/07/2024] [Revised: 04/08/2024] [Accepted: 04/13/2024] [Indexed: 05/19/2024]
Abstract
BACKGROUND Huangkui capsule (HKC), as an ethanol extract of Abelmoschus manihot (L.), has a significant efficacy in treatment of the patients with diabetic kidney disease (DKD). The bioactive ingredients of HKC mainly include the flavonoids such as rutin, hyperoside, hibifolin, isoquercetin, myricetin, quercetin and quercetin-3-O-robinobioside. PURPOSE To explore the molecular mechanisms of A. manihot in treatment of DKD. STUDY DESIGN A single-cell RNA sequencing analysis of kidneys in db/db mice with and without HKC administration. METHODS Urinary biochemical and histopathological examination in C57BL/6 and db/db mice of DKD and HKC groups was done. Single-cell RNA sequencing pipeline was then performed. The regulatory mechanisms of seven flavonoids in HKC were revealed by cell communication, prediction of transcription factor regulatory network, and molecular docking. RESULTS By constructing ligand-receptor regulatory network and performing molecular docking between 75 receptors with different activities and seven flavonoids. 11 key receptors in 4 cell types (segment 3 proximal convoluted tubular cell, ascending limbs of the loop of Henle, distal convoluted tubule, and T cell) in kidneys were found to be directly interacted with HKC. The interactions regulated 8 downstream regulons. The docking receptors in T cell led to transcriptional event differences in the regulons such as Cebpb, Rel, Tbx21 and Klf2 and consequently affected the activation, differentiation, and infiltration of T cell, while the receptors Tgfbr1 and Ldlr in stromal cells of kidneys were closely associated with the downstream transcriptional events of renal injury and proteinuria in DKD. CONCLUSION The current study provides novel information of the key receptors and regulons in renal cells for a better understanding of the cell type specific molecular mechanisms of A. manihot in treatment of DKD.
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Affiliation(s)
- Chenhua Wu
- Laboratory of Molecular Medicine, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, Jiangsu Province, 210009, China; Laboratory of Minigene Pharmacy, School of Life Science and Technology, China Pharmaceutical University, Nanjing, Jiangsu Province, 211198, China
| | - Haitao Tang
- Suzhong Pharmaceutical Research Institute, Nanjing, Jiangsu Province, 210018, China
| | - Xu Cui
- Laboratory of Molecular Medicine, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, Jiangsu Province, 210009, China
| | - Nan Li
- Department of Endocrinology, Jiangsu Province Hospital of Chinese Medicine, The Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, Jiangsu Province, 210029, China
| | - Jingjin Fei
- Laboratory of Minigene Pharmacy, School of Life Science and Technology, China Pharmaceutical University, Nanjing, Jiangsu Province, 211198, China
| | - Haitao Ge
- Suzhong Pharmaceutical Research Institute, Nanjing, Jiangsu Province, 210018, China
| | - Liang Wu
- Jiangsu Key Laboratory of Drug Screening, Institute of Pharmaceutical Sciences, China Pharmaceutical University, Nanjing, Jiangsu Province, 210009, China
| | - Jie Wu
- Laboratory of Minigene Pharmacy, School of Life Science and Technology, China Pharmaceutical University, Nanjing, Jiangsu Province, 211198, China.
| | - Harvest F Gu
- Laboratory of Molecular Medicine, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, Jiangsu Province, 210009, China.
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Kleibert M, Zygmunciak P, Łakomska K, Mila K, Zgliczyński W, Mrozikiewicz-Rakowska B. Insight into the Molecular Mechanism of Diabetic Kidney Disease and the Role of Metformin in Its Pathogenesis. Int J Mol Sci 2023; 24:13038. [PMID: 37685845 PMCID: PMC10487922 DOI: 10.3390/ijms241713038] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2023] [Revised: 08/10/2023] [Accepted: 08/13/2023] [Indexed: 09/10/2023] Open
Abstract
Diabetic kidney disease (DKD) is one of the leading causes of death among patients diagnosed with diabetes mellitus. Despite the growing knowledge about the pathogenesis of DKD, we still do not have effective direct pharmacotherapy. Accurate blood sugar control is essential in slowing down DKD. It seems that metformin has a positive impact on kidneys and this effect is not only mediated by its hypoglycemic action, but also by direct molecular regulation of pathways involved in DKD. The molecular mechanism of DKD is complex and we can distinguish polyol, hexosamine, PKC, and AGE pathways which play key roles in the development and progression of this disease. Each of these pathways is overactivated in a hyperglycemic environment and it seems that most of them may be regulated by metformin. In this article, we summarize the knowledge about DKD pathogenesis and the potential mechanism of the nephroprotective effect of metformin. Additionally, we describe the impact of metformin on glomerular endothelial cells and podocytes, which are harmed in DKD.
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Affiliation(s)
- Marcin Kleibert
- Chair and Department of Experimental and Clinical Physiology, Laboratory of Centre for Preclinical Research, Medical University of Warsaw, 02-097 Warsaw, Poland;
| | - Przemysław Zygmunciak
- Faculty of Medicine, Medical University of Warsaw, 02-091 Warsaw, Poland; (P.Z.); (K.M.)
| | - Klaudia Łakomska
- Faculty of Medicine, Wroclaw Medical University, 50-367 Wroclaw, Poland;
| | - Klaudia Mila
- Faculty of Medicine, Medical University of Warsaw, 02-091 Warsaw, Poland; (P.Z.); (K.M.)
| | - Wojciech Zgliczyński
- Department of Endocrinology, Centre of Postgraduate Medical Education, Bielanski Hospital, 01-809 Warsaw, Poland;
| | - Beata Mrozikiewicz-Rakowska
- Department of Endocrinology, Centre of Postgraduate Medical Education, Bielanski Hospital, 01-809 Warsaw, Poland;
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Pasupulati AK, Kilari S, Sahay M. Editorial: Endocrine abnormalities and renal complications. Front Endocrinol (Lausanne) 2023; 14:1274669. [PMID: 37670892 PMCID: PMC10476490 DOI: 10.3389/fendo.2023.1274669] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/08/2023] [Accepted: 08/10/2023] [Indexed: 09/07/2023] Open
Affiliation(s)
| | - Sreenivasulu Kilari
- Vascular and Interventional Radiology Translational Laboratory, Department of Radiology, Mayo Clinic, Rochester, MN, United States
| | - Manisha Sahay
- Department of Nephrology, Osmania Medical College and General Hospital, Hyderabad, India
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Liang Y, Liang Z, Huang J, Jia M, Liu D, Zhang P, Fang Z, Hu X, Li H. Identification and validation of aging-related gene signatures and their immune landscape in diabetic nephropathy. Front Med (Lausanne) 2023; 10:1158166. [PMID: 37404805 PMCID: PMC10316791 DOI: 10.3389/fmed.2023.1158166] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2023] [Accepted: 05/24/2023] [Indexed: 07/06/2023] Open
Abstract
Background Aging and immune infiltration have essential role in the physiopathological mechanisms of diabetic nephropathy (DN), but their relationship has not been systematically elucidated. We identified aging-related characteristic genes in DN and explored their immune landscape. Methods Four datasets from the Gene Expression Omnibus (GEO) database were screened for exploration and validation. Functional and pathway analysis was performed using Gene Set Enrichment Analysis (GSEA). Characteristic genes were obtained using a combination of Random Forest (RF) and Support Vector Machine Recursive Feature Elimination (SVM-RFE) algorithm. We evaluated and validated the diagnostic performance of the characteristic genes using receiver operating characteristic (ROC) curve, and the expression pattern of the characteristic genes was evaluated and validated. Single-Sample Gene Set Enrichment Analysis (ssGSEA) was adopted to assess immune cell infiltration in samples. Based on the TarBase database and the JASPAR repository, potential microRNAs and transcription factors were predicted to further elucidate the molecular regulatory mechanisms of the characteristic genes. Results A total of 14 differentially expressed genes related to aging were obtained, of which 10 were up-regulated and 4 were down-regulated. Models were constructed by the RF and SVM-RFE algorithms, contracted to three signature genes: EGF-containing fibulin-like extracellular matrix (EFEMP1), Growth hormone receptor (GHR), and Vascular endothelial growth factor A (VEGFA). The three genes showed good efficacy in three tested cohorts and consistent expression patterns in the glomerular test cohorts. Most immune cells were more infiltrated in the DN samples compared to the controls, and there was a negative correlation between the characteristic genes and most immune cell infiltration. 24 microRNAs were involved in the transcriptional regulation of multiple genes simultaneously, and Endothelial transcription factor GATA-2 (GATA2) had a potential regulatory effect on both GHR and VEGFA. Conclusion We identified a novel aging-related signature allowing assessment of diagnosis for DN patients, and further can be used to predict immune infiltration sensitivity.
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Affiliation(s)
- Yingchao Liang
- Graduate School of Guangzhou University of Traditional Chinese Medicine, Guangzhou, China
- The Fourth Clinical Medical College of Guangzhou University of Chinese Medicine, Shenzhen, China
| | - Zhiyi Liang
- Graduate School of Guangzhou University of Traditional Chinese Medicine, Guangzhou, China
- Guangdong Provincial Hospital of Integrated Traditional Chinese and Western Medicine Affiliated to Guangzhou University of Chinese Medicine, Foshan, China
| | - Jinxian Huang
- Graduate School of Guangzhou University of Traditional Chinese Medicine, Guangzhou, China
- The Fourth Clinical Medical College of Guangzhou University of Chinese Medicine, Shenzhen, China
| | - Mingjie Jia
- Graduate School of Guangzhou University of Traditional Chinese Medicine, Guangzhou, China
- The Fourth Clinical Medical College of Guangzhou University of Chinese Medicine, Shenzhen, China
| | - Deliang Liu
- Department of Endocrinology, Shenzhen Traditional Chinese Medicine Hospital, Shenzhen, China
| | - Pengxiang Zhang
- Graduate School of Guangzhou University of Traditional Chinese Medicine, Guangzhou, China
- The Fourth Clinical Medical College of Guangzhou University of Chinese Medicine, Shenzhen, China
| | - Zebin Fang
- Graduate School of Guangzhou University of Traditional Chinese Medicine, Guangzhou, China
- The Fourth Clinical Medical College of Guangzhou University of Chinese Medicine, Shenzhen, China
| | - Xinyu Hu
- Graduate School of Guangzhou University of Traditional Chinese Medicine, Guangzhou, China
- The Fourth Clinical Medical College of Guangzhou University of Chinese Medicine, Shenzhen, China
| | - Huilin Li
- Department of Endocrinology, Shenzhen Traditional Chinese Medicine Hospital, Shenzhen, China
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Martinez-Arroyo O, Flores-Chova A, Sanchez-Garcia B, Redon J, Cortes R, Ortega A. Rab3A/Rab27A System Silencing Ameliorates High Glucose-Induced Injury in Podocytes. BIOLOGY 2023; 12:biology12050690. [PMID: 37237503 DOI: 10.3390/biology12050690] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/29/2023] [Revised: 05/04/2023] [Accepted: 05/06/2023] [Indexed: 05/28/2023]
Abstract
Diabetic nephropathy is a major complication in diabetic patients. Podocytes undergo loss and detachment from the basal membrane. Intra- and intercellular communication through exosomes are key processes for maintaining function, and the Rab3A/Rab27A system is an important counterpart. Previously, we observed significant changes in the Rab3A/Rab27A system in podocytes under glucose overload, demonstrating its important role in podocyte injury. We investigated the implication of silencing the Rab3A/Rab27A system in high glucose-treated podocytes and analysed the effect on differentiation, apoptosis, cytoskeletal organisation, vesicle distribution, and microRNA expression in cells and exosomes. For this, we subjected podocytes to high glucose and transfection through siRNAs, and we isolated extracellular vesicles and performed western blotting, transmission electron microscopy, RT-qPCR, immunofluorescence and flow cytometry assays. We found that silencing RAB3A and RAB27A generally leads to a decrease in podocyte differentiation and cytoskeleton organization and an increase in apoptosis. Moreover, CD63-positive vesicles experienced a pattern distribution change. Under high glucose, Rab3A/Rab27A silencing ameliorates some of these detrimental processes, suggesting a differential influence depending on the presence or absence of cellular stress. We also observed substantial expression changes in miRNAs that were relevant in diabetic nephropathy upon silencing and glucose treatment. Our findings highlight the Rab3A/Rab27A system as a key participant in podocyte injury and vesicular traffic regulation in diabetic nephropathy.
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Affiliation(s)
- Olga Martinez-Arroyo
- Cardiometabolic and Renal Risk Research Group, Biomedical Research Institute of Hospital Clinico de Valencia INCLIVA, 46010 Valencia, Spain
| | - Ana Flores-Chova
- Cardiometabolic and Renal Risk Research Group, Biomedical Research Institute of Hospital Clinico de Valencia INCLIVA, 46010 Valencia, Spain
| | - Belen Sanchez-Garcia
- Cardiometabolic and Renal Risk Research Group, Biomedical Research Institute of Hospital Clinico de Valencia INCLIVA, 46010 Valencia, Spain
| | - Josep Redon
- Cardiometabolic and Renal Risk Research Group, Biomedical Research Institute of Hospital Clinico de Valencia INCLIVA, 46010 Valencia, Spain
- CIBEROBN (CIBER of Obesity and Nutrition Physiopathology), Institute of Health Carlos III, Minister of Health, 28029 Madrid, Spain
| | - Raquel Cortes
- Cardiometabolic and Renal Risk Research Group, Biomedical Research Institute of Hospital Clinico de Valencia INCLIVA, 46010 Valencia, Spain
| | - Ana Ortega
- Cardiometabolic and Renal Risk Research Group, Biomedical Research Institute of Hospital Clinico de Valencia INCLIVA, 46010 Valencia, Spain
- CIBERCV (CIBER of Cardiovascular Diseases), Institute of Health Carlos III, Minister of Health, 28029 Madrid, Spain
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13
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Chen S, Li B, Chen L, Jiang H. Identification and validation of immune-related biomarkers and potential regulators and therapeutic targets for diabetic kidney disease. BMC Med Genomics 2023; 16:90. [PMID: 37127580 PMCID: PMC10150481 DOI: 10.1186/s12920-023-01519-6] [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: 11/30/2022] [Accepted: 04/14/2023] [Indexed: 05/03/2023] Open
Abstract
BACKGROUND Diabetic kidney disease (DKD) is a major complication of diabetes and the leading cause of end-stage renal disease worldwide. Renal inflammation and infiltration of immune cells contribute to the development and progression of DKD. Thus, the aim of the present study was to identify and validate immune-related biomarkers and analyze potential regulators including transcription factors (TFs), microRNAs (miRNAs), and drugs for DKD. METHODS Immune-related genes from the ImmPort database and glomeruli samples from GSE1009 and GSE30528 were used to identify differentially expressed immune-related genes (DEIRGs) of DKD. The expression level and clinical correlation analyses of DEIRGs were verified in the Nephroseq database. Murine podocytes were cultured to construct the high glucose-induced podocyte injury model. The reliability of the bioinformatics analysis was experimentally validated by RT-qPCR in podocytes. Networks among DEIRGs, regulators, and drugs were constructed to predict potential regulatory mechanisms for DKD. RESULTS DKD-associated DEIRGs were identified. CCL19 and IL7R were significantly upregulated in the DKD group and negatively correlated with glomerular filtration rate (GFR). GHR, FGF1, FYN, VEGFA, F2R, TGFBR3, PTGDS, FGF9, and SEMA5A were significantly decreased in the DKD group and positively correlated with GFR. RT-qPCR showed that the relative mRNA expression levels of GHR, FGF1, FYN, TGFBR3, PTGDS, FGF9, and SEMA5A were significantly down-regulated in the high glucose-induced podocyte injury group. The enriched regulators for DEIRGs included 110 miRNAs and 8 TFs. The abnormal expression of DEIRGs could be regulated by 16 established drugs. CONCLUSIONS This study identified immune-related biomarkers, regulators, and drugs of DKD. The findings of the present study provide novel insights into immune-related diagnosis and treatment of DKD.
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Affiliation(s)
- Shengnan Chen
- Department of Blood Purification, Kidney Hospital, The First Affiliated Hospital of Xi'an Jiaotong University, West Yanta Road No. 277, Xi'an, 710061, Shannxi, China
| | - Bo Li
- Department of Nephrology, Ningxia Medical University Affiliated People's Hospital of Autonomous Region of Ningxia, Yinchuan, 750002, Ningxia, China
| | - Lei Chen
- Department of Blood Purification, Kidney Hospital, The First Affiliated Hospital of Xi'an Jiaotong University, West Yanta Road No. 277, Xi'an, 710061, Shannxi, China
| | - Hongli Jiang
- Department of Blood Purification, Kidney Hospital, The First Affiliated Hospital of Xi'an Jiaotong University, West Yanta Road No. 277, Xi'an, 710061, Shannxi, China.
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Song LL, Wang N, Zhang JP, Yu LP, Chen XP, Zhang B, Yang WY. Postprandial glucagon-like peptide 1 secretion is associated with urinary albumin excretion in newly diagnosed type 2 diabetes patients. World J Diabetes 2023; 14:279-289. [PMID: 37035218 PMCID: PMC10075041 DOI: 10.4239/wjd.v14.i3.279] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/27/2022] [Revised: 12/21/2022] [Accepted: 02/16/2023] [Indexed: 03/15/2023] Open
Abstract
BACKGROUND Microalbuminuria is an early and informative marker of diabetic nephropathy. Our study found that microalbuminuria developed in patients with newly diagnosed type 2 diabetes mellitus (T2DM).
AIM To investigate the association between glucagon-like peptide 1 (GLP-1) and microalbuminuria in newly diagnosed T2DM patients.
METHODS In total, 760 patients were recruited for this cross-sectional study. The GLP-1 levels during a standard meal test and urinary albumin-creatinine ratio (UACR) were determined.
RESULTS Patients with microalbuminuria exhibited lower GLP-1 levels at 30 min and 120 min during a standard meal test than patients with normal albuminuria (30 min GLP-1, 16.7 ± 13.3 pmol vs 19.9 ± 15.6 pmol, P = 0.007; 120 min GLP-1, 16.0 ± 14.1 pmol vs 18.4 ± 13.8 pmol, P = 0.037). The corresponding area under the curve for active GLP-1 (AUCGLP-1) was also lower in microalbuminuria patients (2257, 1585 to 3506 vs 2896, 1763 to 4726, pmol × min, P = 0.003). Postprandial GLP-1 levels at 30 min and 120 min and AUCGLP-1 were negatively correlated with the UACR (r = 0.159, r = 0.132, r = 0.206, respectively, P < 0.001). The prevalence of microalbuminuria in patients with newly diagnosed T2DM was 21.7%, which decreased with increasing quartiles of AUCGLP-1 levels (27.4%, 25.3%, 18.9% and 15.8%). After logistic regression analysis adjusted for sex, age, hemoglobin A1c, body mass index, systolic blood pressure, estimated glomerular filtration rate, homeostasis model assessment of insulin resistance, AUCglucose and AUCglucagon, patients in quartile 4 of the AUCGLP-1 presented a lower risk of microalbuminuria compared with the patients in quartile 1 (odds ratio = 0.547, 95% confidence interval: 0.325-0.920, P = 0.01). A consistent association was also found between 30 min GLP-1 or 120 min GLP-1 and microalbuminuria.
CONCLUSION Postprandial GLP-1 levels were independently associated with microalbuminuria in newly diagnosed Chinese T2DM patients.
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Affiliation(s)
- Lu-Lu Song
- Department of Endocrinology, China-Japan Friendship Hospital, Beijing 100029, China
| | - Na Wang
- Department of Endocrinology, China-Japan Friendship Hospital, Beijing 100029, China
| | - Jin-Ping Zhang
- Department of Endocrinology, China-Japan Friendship Hospital, Beijing 100029, China
| | - Li-Ping Yu
- Department of Endocrinology, China-Japan Friendship Hospital, Beijing 100029, China
| | - Xiao-Ping Chen
- Department of Endocrinology, China-Japan Friendship Hospital, Beijing 100029, China
| | - Bo Zhang
- Department of Endocrinology, China-Japan Friendship Hospital, Beijing 100029, China
| | - Wen-Ying Yang
- Department of Endocrinology, China-Japan Friendship Hospital, Beijing 100029, China
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15
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Bell S, Young JA, List EO, Basu R, Geitgey DK, Lach G, Lee K, Swegan D, Caggiano LJ, Okada S, Kopchick JJ, Berryman DE. Increased Fibrosis in White Adipose Tissue of Male and Female bGH Transgenic Mice Appears Independent of TGF-β Action. Endocrinology 2023; 164:7069260. [PMID: 36869769 DOI: 10.1210/endocr/bqad038] [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: 11/17/2022] [Revised: 02/21/2023] [Accepted: 02/24/2023] [Indexed: 03/05/2023]
Abstract
Fibrosis is a pathological state caused by excess deposition of extracellular matrix proteins in a tissue. Male bovine growth hormone (bGH) transgenic mice experience metabolic dysfunction with a marked decrease in lifespan and with increased fibrosis in several tissues including white adipose tissue (WAT), which is more pronounced in the subcutaneous (Sc) depot. The current study expanded on these initial findings to evaluate WAT fibrosis in female bGH mice and the role of transforming growth factor (TGF)-β in the development of WAT fibrosis. Our findings established that female bGH mice, like males, experience a depot-dependent increase in WAT fibrosis, and bGH mice of both sexes have elevated circulating levels of several markers of collagen turnover. Using various methods, TGF-β signaling was found unchanged or decreased-as opposed to an expected increase-despite the marked fibrosis in WAT of bGH mice. However, acute GH treatments in vivo, in vitro, or ex vivo did elicit a modest increase in TGF-β signaling in some experimental systems. Finally, single nucleus RNA sequencing confirmed no perturbation in TGF-β or its receptor gene expression in any WAT cell subpopulations of Sc bGH WAT; however, a striking increase in B lymphocyte infiltration in bGH WAT was observed. Overall, these data suggest that bGH WAT fibrosis is independent of the action of TGF-β and reveals an intriguing shift in immune cells in bGH WAT that should be further explored considering the increasing importance of B cell-mediated WAT fibrosis and pathology.
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Affiliation(s)
- Stephen Bell
- Heritage College of Osteopathic Medicine, Ohio University, Athens, OH 45701, USA
- Edison Biotechnology Institute, Ohio University, Athens, OH 45701, USA
| | - Jonathan A Young
- Heritage College of Osteopathic Medicine, Ohio University, Athens, OH 45701, USA
- Edison Biotechnology Institute, Ohio University, Athens, OH 45701, USA
| | - Edward O List
- Edison Biotechnology Institute, Ohio University, Athens, OH 45701, USA
| | - Reetobrata Basu
- Edison Biotechnology Institute, Ohio University, Athens, OH 45701, USA
| | | | - Grace Lach
- Heritage College of Osteopathic Medicine, Ohio University, Athens, OH 45701, USA
- Edison Biotechnology Institute, Ohio University, Athens, OH 45701, USA
| | - Kevin Lee
- Heritage College of Osteopathic Medicine, Ohio University, Athens, OH 45701, USA
- Diabetes Institute, Ohio University, Athens, OH 45701, USA
| | - Deborah Swegan
- College of Arts and Sciences, Ohio University, Athens, OH 45701, USA
| | | | - Shigeru Okada
- Heritage College of Osteopathic Medicine, Ohio University, Athens, OH 45701, USA
- Edison Biotechnology Institute, Ohio University, Athens, OH 45701, USA
| | - John J Kopchick
- Heritage College of Osteopathic Medicine, Ohio University, Athens, OH 45701, USA
- Edison Biotechnology Institute, Ohio University, Athens, OH 45701, USA
- Diabetes Institute, Ohio University, Athens, OH 45701, USA
| | - Darlene E Berryman
- Heritage College of Osteopathic Medicine, Ohio University, Athens, OH 45701, USA
- Edison Biotechnology Institute, Ohio University, Athens, OH 45701, USA
- Diabetes Institute, Ohio University, Athens, OH 45701, USA
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16
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Guo F, Song Y, Wu L, Zhao Y, Ma X, Wang J, Shao M, Ji H, Huang F, Fan X, Wang S, Qin G, Yang B. SUMO specific peptidase 6 regulates the crosstalk between podocytes and glomerular endothelial cells in diabetic kidney disease. Biochim Biophys Acta Mol Basis Dis 2023; 1869:166685. [PMID: 36889557 DOI: 10.1016/j.bbadis.2023.166685] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2022] [Revised: 02/19/2023] [Accepted: 03/01/2023] [Indexed: 03/08/2023]
Abstract
There is increasing evidence that the crosstalk between podocytes and glomerular endothelial cells (GECs) exacerbates the progression of diabetic kidney disease (DKD). Here, we investigated the underlying role of SUMO specific peptidase 6 (SENP6) in this crosstalk. In the diabetic mice, SENP6 was decreased in glomerular tissues and its knockdown further exacerbated glomerular filtration barrier injury. In the mouse podocyte cell line MPC5 cells, SENP6 overexpression reversed HG-induced podocyte loss by suppressing the activation of Notch1 signaling. Notch1 intracellular domain (N1ICD) is the active form of Notch1. SENP6 upregulated the ubiquitination of N1ICD by deSUMOylating Notch1, thereby reducing N1ICD and suppressing Notch1 signaling activation in MPC5 cells. Endothelin-1 (EDN1) is a protein produced by podocytes and has been reported to promote GEC dysfunction. The supernatant from HG-treated MPC5 cells induced mitochondrial dysfunction and surface layer injury in GECs, and the supernatant from SENP6-deficient podocytes further exacerbated the above GEC dysfunction, while this trend was reversed by an EDN1 antagonist. The following mechanism study showed that SENP6 deSUMOylated KDM6A (a histone lysine demethylase) and then decreased the binding potency of KDM6A to EDN1. The latter led to the upregulation of H3K27me2 or H3K27me3 of EDN1 and suppressed its expression in podocytes. Taken together, SENP6 suppressed the HG-induced podocyte loss and ameliorated GEC dysfunction caused by crosstalk between podocytes and GECs, and the protective effect of SENP6 on DKD is attributed to its deSUMOylation activity.
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Affiliation(s)
- Feng Guo
- Division of Endocrinology, Department of Internal Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China
| | - Yi Song
- Division of Endocrinology, Department of Internal Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China
| | - Lina Wu
- Division of Endocrinology, Department of Internal Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China
| | - Yanyan Zhao
- Division of Endocrinology, Department of Internal Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China
| | - Xiaojun Ma
- Division of Endocrinology, Department of Internal Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China
| | - Jiao Wang
- Division of Endocrinology, Department of Internal Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China
| | - Mingwei Shao
- Division of Endocrinology, Department of Internal Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China
| | - Hongfei Ji
- Division of Endocrinology, Department of Internal Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China
| | - Fengjuan Huang
- Division of Endocrinology, Department of Internal Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China
| | - Xunjie Fan
- Division of Endocrinology, Department of Internal Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China
| | - Shasha Wang
- Division of Endocrinology, Department of Internal Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China
| | - Guijun Qin
- Division of Endocrinology, Department of Internal Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China.
| | - Baofeng Yang
- Division of Endocrinology, Department of Internal Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China; Department of Pharmacology, State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Medicine Research, Ministry of Education, College of Pharmacy, Harbin Medical University, Harbin 150081, China; Research Unit of Noninfectious Chronic Diseases in Frigid Zone (2019RU070), Chinese Academy of Medical Sciences, Harbin 150081, China.
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17
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Mukhi D, Kolligundla LP, Maruvada S, Nishad R, Pasupulati AK. Growth hormone induces transforming growth factor-β1 in podocytes: Implications in podocytopathy and proteinuria. BIOCHIMICA ET BIOPHYSICA ACTA. MOLECULAR CELL RESEARCH 2023; 1870:119391. [PMID: 36400249 DOI: 10.1016/j.bbamcr.2022.119391] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/15/2022] [Revised: 10/31/2022] [Accepted: 11/06/2022] [Indexed: 11/17/2022]
Abstract
Pituitary growth hormone (GH) is essential for growth, metabolism, and renal function. Overactive GH signaling is associated with impaired kidney function. Glomerular podocytes, a key kidney cell type, play an indispensable role in the renal filtration and express GH receptors (GHR), suggesting the direct action of GH on these cells. However, the precise mechanism and the downstream signaling events by which GH leads to diabetic nephropathy remain to be elucidated. Here we performed proteome analysis of the condition media from human podocytes and confirmed that GH-induces TGF-β1. Inhibition of GH/GHR stimulated-JAK2 signaling abrogates GH-induced TGF-β1 secretion. Mice administered with GH showed glomerular manifestations concomitant with proteinuria. Pharmacological inhibition of TGF-βR1 in mice prevented GH-induced TGF-β dependent SMAD signaling and proteinuria. Conditional deletion of GHR in podocytes protected mice from streptozotocin-induced diabetic nephropathy. GH and TGF-β1 signaling components expression was elevated in the kidneys of human diabetic nephropathy patients. Our study identifies that GH induces TGF-β1 in podocytes, contributing to diabetic nephropathy.
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Affiliation(s)
- Dhanunjay Mukhi
- Department of Biochemistry, School of Life Sciences, University of Hyderabad, Hyderabad, India
| | - Lakshmi P Kolligundla
- Department of Biochemistry, School of Life Sciences, University of Hyderabad, Hyderabad, India
| | - Saikrishna Maruvada
- Department of Biochemistry, School of Life Sciences, University of Hyderabad, Hyderabad, India
| | - Rajkishor Nishad
- Department of Biochemistry, School of Life Sciences, University of Hyderabad, Hyderabad, India
| | - Anil K Pasupulati
- Department of Biochemistry, School of Life Sciences, University of Hyderabad, Hyderabad, India.
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18
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Kolligundla LP, Kavvuri R, Singh AK, Mukhi D, Pasupulati AK. Metformin prevents hypoxia-induced podocyte injury by regulating the ZEB2/TG2 axis. Nephrology (Carlton) 2023; 28:60-71. [PMID: 36217796 DOI: 10.1111/nep.14121] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2022] [Revised: 08/26/2022] [Accepted: 10/01/2022] [Indexed: 12/01/2022]
Abstract
AIM Podocytes, a vital component of the glomerular filtration barrier, are vulnerable to various noxious stimuli, including Hypoxic. HIF1α that transduces hypoxic adaptations induces Transglutaminase 2 (TG2), which catalyses cross-linking of extracellular matrix proteins. In this study, we investigated the mechanism of regulation of TG2 by HIF1α. METHODS HIF1α was induced in podocytes by treating with FG4592 (Roxadustat) or hypoxia (1% oxygen) and in mice by treating with FG4592. Gene expression and protein analysis of ZEB2, TRPC6 and TG2 were performed in both experimental models. Histological and kidney function analyses were performed in mice. RESULTS Data mining revealed co-expression of HIF1α, ZEB2, TRPC6 and TG2 in the chronic kidney diseases (CKD)-validated dataset. We observed elevated expression of ZEB2, TRPC6 and TG2 in FG4592-treated podocytes. Ectopic expression of ZEB2 resulted in high TRPC6 expression, elevated intracellular calcium levels and increased TG2 activity. Blocking the TRPC6 channel or inhibiting its expression partially attenuated FG4592-induced TG2 activity, whereas suppression of ZEB2 expression significantly abolished TG2 activity. Furthermore, we noticed the induction of the ZEB2/TRPC6/TG2 axis in podocytes in mice administered with FG-4592. Metformin ameliorated the HIF1α-induced podocyte injury and proteinuria in mice administered with FG-4592. CONCLUSION This study demonstrates that HIF1α stimulates both TG2 expression and activity via ZEB2/TRPC6 axis, whereas abrogation of HIF1α by metformin prevented hypoxia-induced glomerular injury. Metformin could be explored to treat proteinuric diseases such as CKD, sleep apnea and renal Ischemia-reperfusion-injury, where hypoxia is considered a risk factor.
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Affiliation(s)
- Lakshmi P Kolligundla
- Department of Biochemistry, School of Life Sciences, University of Hyderabad, Hyderabad, India
| | - Rajesh Kavvuri
- Department of Biochemistry, School of Life Sciences, University of Hyderabad, Hyderabad, India
| | - Ashish K Singh
- Department of Biochemistry, School of Life Sciences, University of Hyderabad, Hyderabad, India
| | - Dhanunjay Mukhi
- Department of Biochemistry, School of Life Sciences, University of Hyderabad, Hyderabad, India
| | - Anil K Pasupulati
- Department of Biochemistry, School of Life Sciences, University of Hyderabad, Hyderabad, India
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19
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Nishad R, Mukhi D, Kethavath S, Raviraj S, Paturi ASV, Motrapu M, Kurukuti S, Pasupulati AK. Podocyte derived TNF-α mediates monocyte differentiation and contributes to glomerular injury. FASEB J 2022; 36:e22622. [PMID: 36421039 DOI: 10.1096/fj.202200923r] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2022] [Revised: 08/31/2022] [Accepted: 10/10/2022] [Indexed: 11/26/2022]
Abstract
Diabetes shortens the life expectancy by more than a decade, and the excess mortality in diabetes is correlated with the incidence of kidney disease. Diabetic kidney disease (DKD) is the leading cause of end-stage kidney disease. Macrophage accumulation predicts the severity of kidney injury in human biopsies and experimental models of DKD. However, the mechanism underlying macrophage recruitment in diabetes glomeruli is unclear. Elevated plasma growth hormone (GH) levels in type I diabetes and acromegalic individuals impaired glomerular biology. In this study, we examined whether GH-stimulated podocytes contribute to macrophage accumulation. RNA-seq analysis revealed elevated TNF-α signaling in GH-treated human podocytes. Conditioned media from GH-treated podocytes (GH-CM) induced differentiation of monocytes to macrophages. On the other hand, neutralization of GH-CM with the TNF-α antibody diminished GH-CM's action on monocytes. The treatment of mice with GH resulted in increased macrophage recruitment, podocyte injury, and proteinuria. Furthermore, we noticed the activation of TNF-α signaling, macrophage accumulation, and fibrosis in DKD patients' kidney biopsies. Our findings suggest that podocytes could secrete TNF-α and contribute to macrophage migration, resulting in DKD-related renal inflammation. Inhibition of either GH action or TNF-α expression in podocytes could be a novel therapeutic approach for DKD treatment.
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Affiliation(s)
- Rajkishor Nishad
- Department of Biochemistry, School of Life Sciences, University of Hyderabad, Hyderabad, India
| | - Dhanunjay Mukhi
- Department of Biochemistry, School of Life Sciences, University of Hyderabad, Hyderabad, India
| | - Srinivas Kethavath
- Department of Animal Biology, School of Life Sciences, University of Hyderabad, Hyderabad, India
| | - Sumathi Raviraj
- Department of Biochemistry, School of Life Sciences, University of Hyderabad, Hyderabad, India
| | - Atreya S V Paturi
- Department of Biochemistry, School of Life Sciences, University of Hyderabad, Hyderabad, India
| | - Manga Motrapu
- Department of Biochemistry, School of Life Sciences, University of Hyderabad, Hyderabad, India
| | - Sreenivasulu Kurukuti
- Department of Animal Biology, School of Life Sciences, University of Hyderabad, Hyderabad, India
| | - Anil Kumar Pasupulati
- Department of Biochemistry, School of Life Sciences, University of Hyderabad, Hyderabad, India
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20
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Pan X, Chen S, Shen R, Liu S, You Y. HOXA11-OS participates in lupus nephritis by targeting miR-124-3p mediating Cyr61 to regulate podocyte autophagy. Mol Med 2022; 28:138. [PMID: 36418932 PMCID: PMC9682779 DOI: 10.1186/s10020-022-00570-w] [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: 05/18/2022] [Accepted: 11/07/2022] [Indexed: 11/24/2022] Open
Abstract
BACKGROUND The long chain non-coding RNA HOXA11-OS was recently identified. Increasing studies have shown that HOXA11-OS has regulatory effects on genes in gastric cancer, prostate cancer, and various kidney diseases, but research on its role in systemic lupus erythematosus is still lacking. The present study aimed to investigate the role of HOXA11-OS in the regulation of podocyte autophagy in the development of lupus nephritis (LN) and its potential molecular mechanism. METHODS mRNA and protein expression of the target gene (i.e., Cyr61) was detected by quantitative real-time polymerase chain reaction, western blotting, and immunofluorescence. Mouse podocytes were induced using serum immunoglobulin G (IgG) from patients with lupus and their viability was detected using the cell counting kit-8 assay. The interaction of miR-124-3p with HOXA11-OS and Cyr61 was analyzed by double luciferase reporter gene assay. Serum autoantibody levels were detected by enzyme-linked immunosorbent assay. Pathological lesions in the kidney tissue were detected by hematoxylin-eosin and periodate-Schiff staining. The independent samples t-test was used for comparing two groups, and one-way analysis of variance for comparing multiple groups. RESULTS HOXA11-OS was highly expressed in LN tissues, serum, and cells, and the expression of some key autophagy factors and Cyr61 was significantly increased, while miR-124-3p expression was significantly decreased. In vitro, LN-IgG inhibited podocyte activity, increased autophagy and Cyr61 expression, and aggravated podocyte injury in a time- and dose-dependent manner. As a competitive endogenous RNA of miR-124-3p, HOXA11-OS promoted the expression of Cyr61, thus enhancing the autophagy increase induced by LN-IgG and aggravating podocyte injury. Knockdown of HOXA11-OS had the opposite effect. miR-124-3p mimic or Cyr61 knockdown restored the high expression of autophagy factors and Cyr61 induced by HOXA11-OS overexpression and alleviated podocyte injury. Further in vivo experiments showed that injection of sh-HOXA11-OS adeno-associated virus downregulated HOXA11-OS and significantly alleviated renal damage in lupus mice. CONCLUSIONS HOXA11-OS is involved in the occurrence and development of LN by regulating podocyte autophagy through miR-124-3p/Cyr61 sponging, which may provide a good potential therapeutic target for LN.
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Affiliation(s)
- Xiuhong Pan
- grid.460081.bDepartment of Nephrology, Affiliated Hospital of Youjiang Medical University for Nationalities, No.18 Zhongshan Road II, Baise, 533000 Guangxi Zhuang Autonomous Region China
| | - Shanshan Chen
- grid.460081.bDepartment of Nephrology, Affiliated Hospital of Youjiang Medical University for Nationalities, No.18 Zhongshan Road II, Baise, 533000 Guangxi Zhuang Autonomous Region China
| | - Ruiwen Shen
- grid.460081.bDepartment of Nephrology, Affiliated Hospital of Youjiang Medical University for Nationalities, No.18 Zhongshan Road II, Baise, 533000 Guangxi Zhuang Autonomous Region China
| | - Sen Liu
- grid.460081.bDepartment of Nephrology, Affiliated Hospital of Youjiang Medical University for Nationalities, No.18 Zhongshan Road II, Baise, 533000 Guangxi Zhuang Autonomous Region China
| | - Yanwu You
- grid.410652.40000 0004 6003 7358Department of Nephrology, People’s Hospital of Guangxi Zhuang Autonomous Region, No. 6 Taoyuan Road, Qingxiu District, Nanning, 530000 China
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21
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Marked reduction of proteinuria after removal of a growth hormone-producing pituitary adenoma in a patient with focal segmental glomerulosclerosis: a case report and literature review. CEN Case Rep 2022; 12:164-170. [PMID: 36201148 PMCID: PMC10151435 DOI: 10.1007/s13730-022-00739-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2022] [Accepted: 09/27/2022] [Indexed: 11/06/2022] Open
Abstract
Focal segmental glomerulosclerosis is a rare complication of acromegaly. A 74-year-old man was found to have acromegaly features such as enlargement of the forehead, nose, and hands. Laboratory tests showed a urine protein/creatinine ratio of 3.16 g/gCr and serum creatinine of 1.34 mg/dL. The levels of growth hormone and insulin-like growth factor I were markedly elevated, and the growth hormone level was not suppressed after 75 g oral glucose loading. Magnetic resonance imaging revealed a pituitary tumor with a diameter of 1.2 cm. Renal biopsy confirmed the diagnosis of focal segmental glomerulosclerosis. Transsphenoidal resection of the pituitary tumor led to remission of acromegaly and reduction in proteinuria highlighting the causal link between growth hormone overproduction and proteinuria. Treatment of acromegaly may be effective for acromegaly-associated focal segmental glomerulosclerosis.
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22
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Zhan P, Zhang Y, Shi W, Liu X, Qiao Z, Wang Z, Wang X, Wu J, Tang W, Sun Y, Zhang Y, Zhen J, Shang J, Liu M, Yi F. Myeloid-derived Growth Factor Deficiency Exacerbates Mitotic Catastrophe of Podocytes in Glomerular Disease. Kidney Int 2022; 102:546-559. [PMID: 35623505 DOI: 10.1016/j.kint.2022.04.027] [Citation(s) in RCA: 25] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2021] [Revised: 04/17/2022] [Accepted: 04/27/2022] [Indexed: 01/17/2023]
Abstract
Podocytes are unique, highly specialized, terminally differentiated cells, which are restricted in a post-mitotic state with limited ability to repair or regenerate. Re-entering mitotic phase causes podocyte mitotic catastrophe, thereby leading to podocyte death and glomerular injury. Myeloid-derived growth factor (MYDGF) is a novel secreted protein and plays an important role on the regulation of cardiovascular function. However, whether MYDGF is expressed in kidney parenchymal cells and whether it has biological functions in the kidney remain unknown. Here, we found that MYDGF was expressed in kidney parenchymal cells and was significantly reduced in podocytes from mice with models of focal segmental glomerulosclerosis and diabetic kidney disease. Podocyte-specific deletion of MYDGF in mice exacerbated podocyte injury and proteinuria in both disease models. Functionally, MYDGF protected podocytes against mitotic catastrophe by reducing accumulation of podocytes in S phase, a portion of the cell cycle in which DNA is replicated. Mechanistically, MYDGF regulates the expression of the transcription factor RUNX2 which mediates part of MYDGF effects. Importantly, a significant reduction of MYDGF was found in glomeruli from patients with glomerular disease due to focal segmental glomerulosclerosis and diabetic kidney disease and the level of MYDGF was correlated with glomerular filtration rate, serum creatinine and podocyte loss. Thus, our studies indicate that MYDGF may be an attractive therapeutic target for glomerular disease.
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Affiliation(s)
- Ping Zhan
- Key Laboratory of Infection and Immunity of Shandong Province, Department of Pharmacology, School of Basic Medical Sciences, Shandong University, Jinan, China
| | - Yang Zhang
- Key Laboratory of Infection and Immunity of Shandong Province, Department of Pharmacology, School of Basic Medical Sciences, Shandong University, Jinan, China
| | - Weichen Shi
- Department of General Surgery, First Affiliated Hospital of Shandong First Medical University, Jinan, China
| | - Xiaohan Liu
- Key Laboratory of Infection and Immunity of Shandong Province, Department of Pharmacology, School of Basic Medical Sciences, Shandong University, Jinan, China
| | - Zhe Qiao
- Key Laboratory of Infection and Immunity of Shandong Province, Department of Pharmacology, School of Basic Medical Sciences, Shandong University, Jinan, China
| | - Ziying Wang
- Key Laboratory of Infection and Immunity of Shandong Province, Department of Pharmacology, School of Basic Medical Sciences, Shandong University, Jinan, China
| | - Xiaojie Wang
- Key Laboratory of Infection and Immunity of Shandong Province, Department of Pharmacology, School of Basic Medical Sciences, Shandong University, Jinan, China
| | - Jichao Wu
- Key Laboratory of Infection and Immunity of Shandong Province, Department of Pharmacology, School of Basic Medical Sciences, Shandong University, Jinan, China
| | - Wei Tang
- Key Laboratory of Infection and Immunity of Shandong Province, Department of Pharmacology, School of Basic Medical Sciences, Shandong University, Jinan, China
| | - Yu Sun
- Key Laboratory of Infection and Immunity of Shandong Province, Department of Pharmacology, School of Basic Medical Sciences, Shandong University, Jinan, China
| | - Yan Zhang
- Key Laboratory of Infection and Immunity of Shandong Province, Department of Pharmacology, School of Basic Medical Sciences, Shandong University, Jinan, China
| | - Junhui Zhen
- Department of Pathology, School of Basic Medical Sciences, Shandong University, Jinan, China
| | - Jin Shang
- Department of Nephrology, First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Min Liu
- Key Laboratory of Infection and Immunity of Shandong Province, Department of Pharmacology, School of Basic Medical Sciences, Shandong University, Jinan, China.
| | - Fan Yi
- Key Laboratory of Infection and Immunity of Shandong Province, Department of Pharmacology, School of Basic Medical Sciences, Shandong University, Jinan, China.
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23
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Yin L, Yu L, He JC, Chen A. Controversies in Podocyte Loss: Death or Detachment? Front Cell Dev Biol 2021; 9:771931. [PMID: 34881244 PMCID: PMC8645964 DOI: 10.3389/fcell.2021.771931] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2021] [Accepted: 11/03/2021] [Indexed: 12/21/2022] Open
Abstract
Glomerular podocytes are characterized by terminally differentiated epithelial cells with limited proliferating ability; thus, podocyte loss could not be fully compensated by podocyte regeneration. A large body of clinical studies collectively demonstrated that podocyte loss correlated with glomerular diseases progression. Both podocyte death and podocyte detachment lead to podocyte loss; however, which one is the main cause remains controversial. Up to date, multiple mechanisms are involved in podocyte death, including programmed apoptotic cell death (apoptosis and anoikis), programmed nonapoptotic cell death (autophagy, entosis, and podoptosis), immune-related cell death (pyroptosis), and other types of cell death (necroptosis and mitotic catastrophe-related cell death). Apoptosis is considered a common mechanism of podocyte loss; however, most of the data were generated in vitro and the evidence of in vivo podocyte apoptosis is limited. The isolation of podocytes in the urine and subsequent culture of urinary podocytes in vitro suggest that detachment of viable podocytes could be another important mechanism for podocyte loss. In this review, we summarize recent advances that address this controversial topic on the specific circumstances of podocyte loss.
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Affiliation(s)
- Lijun Yin
- Hunan Key Laboratory of Kidney Disease and Blood Purification, Department of Nephrology, Institute of Nephrology, The Second Xiangya Hospital at Central South University, Changsha, China
| | - Lu Yu
- Hunan Key Laboratory of Kidney Disease and Blood Purification, Department of Nephrology, Institute of Nephrology, The Second Xiangya Hospital at Central South University, Changsha, China.,Department of Health Sciences, Boston University College of Health and Rehabilitation Sciences: Sargent College, Boston University, Boston, MA, United States
| | - John Cijiang He
- Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, United States.,Renal Program, James J. Peters Veterans Affairs Medical Center at Bronx, New York, NY, United States
| | - Anqun Chen
- Hunan Key Laboratory of Kidney Disease and Blood Purification, Department of Nephrology, Institute of Nephrology, The Second Xiangya Hospital at Central South University, Changsha, China
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24
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Zhang Z, Qiao Y, Yang L, Chen Z, Li T, Gu M, Li C, Liu M, Li R. Kaempferol 3-O-gentiobioside, an ALK5 inhibitor, affects the proliferation, migration, and invasion of tumor cells via blockade of the TGF-β/ALK5/Smad signaling pathway. Phytother Res 2021; 35:6310-6323. [PMID: 34514657 DOI: 10.1002/ptr.7278] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2021] [Revised: 08/08/2021] [Accepted: 08/24/2021] [Indexed: 12/17/2022]
Abstract
Overactivation of TGF-β/ALK5/Smad signaling pathway has been observed in the advanced stage of various human malignancies. As a key component of TGF-β/ALK5/Smad signaling pathway transduction, TGF-β type I receptor (also known as ALK5) has emerged as a promising therapeutic target for cancer treatment. In this study, to discover a novel ALK5 inhibitor, a commercial natural products library was screened using docking-based virtual screening, followed by luciferase reporter assay. A flavonoid glycoside kaempferol 3-O-gentiobioside (KPF 3-O-G) was identified as a potent ALK5 inhibitor through directly bound to the ATP-site of ALK5, resulting in the inhibitory effects on phosphorylation and translocation of Smad2 and expression of Smad4. Additionally, we found that KPF 3-O-G reduced cell proliferation and inhibited TGF-β-induced cell migration and invasion. Moreover, western blotting and immunofluorescent analysis showed that KPF 3-O-G significantly reversed the TGF-β-induced EMT biomarkers, including upregulation of E-cadherin and downregulation of N-cadherin, vimentin, and snail. In vivo study showed that KPF 3-O-G administration reduced tumor growth in human ovarian cancer xenograft mouse model, without obvious toxic effect. This study provided novel insight into the anticancer effects of KPF-3-O-G and indicated that KPF-3-O-G might be developed as potential therapeutics for cancer treatment after further validation.
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Affiliation(s)
- Zihao Zhang
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, School of Pharmacy, Anhui Medical University, Hefei, China
| | - Yu Qiao
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, School of Pharmacy, Anhui Medical University, Hefei, China
| | - Li Yang
- Department of Gynecologic Oncology, The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Institute of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou, China
| | - Zuwang Chen
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, School of Pharmacy, Anhui Medical University, Hefei, China
| | - Tao Li
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, School of Pharmacy, Anhui Medical University, Hefei, China
| | - MingZhen Gu
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, School of Pharmacy, Anhui Medical University, Hefei, China
| | - Chong Li
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, School of Pharmacy, Anhui Medical University, Hefei, China
| | - Mingming Liu
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, School of Pharmacy, Anhui Medical University, Hefei, China
| | - Rong Li
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, School of Pharmacy, Anhui Medical University, Hefei, China
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25
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The Notch pathway regulates KLF4 in podocyte injury induced by high glucose. Int J Diabetes Dev Ctries 2021. [DOI: 10.1007/s13410-021-00988-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/20/2022] Open
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