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da Cunha RS, Azevedo CAB, Miniskiskosky G, Gregório PC, Stinghen AEM. MicroRNAs and vascular damage in chronic kidney disease: advances and clinical implications. J Bras Nefrol 2025; 47:e20240223. [PMID: 40388304 PMCID: PMC12088645 DOI: 10.1590/2175-8239-jbn-2024-0223en] [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: 11/11/2024] [Accepted: 04/06/2025] [Indexed: 05/21/2025] Open
Abstract
Chronic kidney disease (CKD) is closely associated with endothelial dysfunction and vascular calcification, which are major contributors to the development of cardiovascular disease in this population. MicroRNAs (miRNAs) are a group of non-coding RNAs that regulate gene expression and other cellular processes. Recent studies have demonstrated that changes in the levels of several miRNAs are associated with the progression of renal dysfunction. Patients with CKD have reduced levels of miR-126, a microRNA produced by the endothelium that has an atheroprotective function. Reduced miRNA levels that inhibit vascular calcification, such as miR-133a and miR-204-5p, are also found in patients with CKD. These changes may contribute to vascular dysfunction in these patients. Therefore, understanding the profile of microRNAs in the context of CKD may be important for the identification of new biomarkers and potential therapeutic targets. Given the growing relevance of microRNA analysis, this review addresses recent advances in the study of microRNAs related to vascular dysfunction in CKD and their potential applications in translational clinical practice.
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Affiliation(s)
- Regiane Stafim da Cunha
- Universidade Federal do Paraná, Laboratório de Nefrologia Experimental, Departamento de Patologia Básica, Curitiba, PR, Brazil
| | - Carolina Amaral Bueno Azevedo
- Universidade Federal do Paraná, Laboratório de Nefrologia Experimental, Departamento de Patologia Básica, Curitiba, PR, Brazil
| | - Guilherme Miniskiskosky
- Universidade Federal do Paraná, Laboratório de Nefrologia Experimental, Departamento de Patologia Básica, Curitiba, PR, Brazil
| | - Paulo Cézar Gregório
- Universidade Federal do Paraná, Laboratório de Nefrologia Experimental, Departamento de Patologia Básica, Curitiba, PR, Brazil
| | - Andréa Emilia Marques Stinghen
- Universidade Federal do Paraná, Laboratório de Nefrologia Experimental, Departamento de Patologia Básica, Curitiba, PR, Brazil
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Singh V, Adam RJ, Paterson MR, Kriegel AJ. Vacuole membrane protein 1 and acute response to renal ischemia and ischemia/reperfusion. Physiol Genomics 2025; 57:172-178. [PMID: 39928961 DOI: 10.1152/physiolgenomics.00135.2024] [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: 08/30/2024] [Revised: 09/23/2024] [Accepted: 01/10/2025] [Indexed: 02/12/2025] Open
Abstract
Ischemia-reperfusion (I/R) injury is an important initiating cause of chronic kidney disease and renal failure. Changes in proximal tubule (PT) morphology, including brush border loss, occur rapidly in response to ischemic stress and I/R injury. Vacuole membrane protein 1 (VMP1) is a compelling target for ischemia-associated renal damage because it is a necessary regulator of autophagy, and the genomic location of hypoxia-responsive microRNA miR-21 lies within an intronic region of the Vmp1 gene. Autophagy is reported to have protective and pathological effects on I/R injury. In this study, we find that VMP1 is rapidly upregulated in renal cortex tissue in response to 15 and 30 min of ischemia. Intravenous delivery of Vmp1-targeting GameR or a scrambled GapmeR was performed on adult male Sprague-Dawley rats for 2 days before either 30 min of renal ischemia, 30 min of ischemia followed by 24 h of reperfusion (I/R), or corresponding control procedures. Autophagy markers and PT morphology were assessed in the renal cortex. Suppression of ischemia-induced upregulation of VMP1 attenuated PT brush border loss following 30 min of ischemia and 24 h post-I/R. Our study reveals a novel and mechanistically important dissociation between VMP1 expression, miR-21-5p expression, autophagy markers, and I/R tubular injury in the renal cortex.NEW & NOTEWORTHY The impact of autophagy on renal ischemia/reperfusion injury (IRI) remains unclear. VMP1 promotes autophagy through interaction with beclin-1 and subsequent localization to the endoplasmic reticulum. In this study, GapmeR-mediated suppression of VMP1 in rats and attenuated proximal tubule damage following 30 min of ischemia or following 24 h of reperfusion, without altering autophagy markers following reperfusion. This new insight suggests that increased VMP1 did not afford autophagy-mediated protection from IRI in proximal tubules.
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Affiliation(s)
- Vaishali Singh
- Department of Pediatrics, Division of Nephrology, Medical College of Wisconsin, Milwaukee, Wisconsin, United States
- Department of Physiology, Medical College of Wisconsin, Milwaukee, Wisconsin, United States
| | - Ryan J Adam
- Department of Physiology, Medical College of Wisconsin, Milwaukee, Wisconsin, United States
- Cardiovascular Center, Medical College of Wisconsin, Milwaukee, Wisconsin, United States
| | - Mark R Paterson
- Department of Physiology, Medical College of Wisconsin, Milwaukee, Wisconsin, United States
- Cardiovascular Center, Medical College of Wisconsin, Milwaukee, Wisconsin, United States
| | - Alison J Kriegel
- Department of Pediatrics, Division of Nephrology, Medical College of Wisconsin, Milwaukee, Wisconsin, United States
- Department of Physiology, Medical College of Wisconsin, Milwaukee, Wisconsin, United States
- Cardiovascular Center, Medical College of Wisconsin, Milwaukee, Wisconsin, United States
- Department of Physiology, Medical College of Georgia, Augusta University, Augusta, Georgia, United States
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Gheitasi I, Akbari G, Savari F. Physiological and cellular mechanisms of ischemic preconditioning microRNAs-mediated in underlying of ischemia/reperfusion injury in different organs. Mol Cell Biochem 2025; 480:855-868. [PMID: 39001984 DOI: 10.1007/s11010-024-05052-7] [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: 06/10/2024] [Indexed: 07/15/2024]
Abstract
Ischemia-reperfusion (I/R) injury, as a pathological phenomenon, takes place when blood supply to an organ is disrupted and then aggravated during restoration of blood flow. Ischemic preconditioning (IPC) is a potent method for attenuating subsequent events of IR damage in numerous organs. IPC protocol is determined by a brief and sequential time periods of I/R before the main ischemia. MicroRNAs are endogenous non-coding RNAs that regulate post-transcriptionally target mRNA translation via degrading it and/or suppressing protein synthesis. This review introduces the physiological and cellular mechanisms of ischemic preconditioning microRNAs-mediated after I/R insult in different organs such as the liver, kidney, heart, brain, and intestine. Data of this review have been collected from the scientific articles published in databases such as Science Direct, Scopus, PubMed, Web of Science, and Scientific Information Database from 2000 to 2023. Based on these literature studies, IPC/IR intervention can affect cellular mechanisms including oxidative stress, apoptosis, angiogenesis, and inflammation through up-regulation or down-regulation of multiple microRNAs and their target genes.
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Affiliation(s)
- Izadpanah Gheitasi
- Department of Physiology, Faculty of Medicine, Yasuj University of Medical Sciences, Yasuj, Iran
| | - Ghaidafeh Akbari
- Department of Physiology, Faculty of Medicine, Yasuj University of Medical Sciences, Yasuj, Iran.
| | - Feryal Savari
- Department of Medical Basic Sciences, Shoushtar Faculty of Medical Sciences, Shoushtar, Iran.
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Zhong Q, Zeng J, Li Y, Zhang H, Lin T, Song T. Senescent renal tubular cells derived extracellular vesicles transported miR-20a and miR-21 induced macrophage-to-myofibroblast transition in renal fibrosis after ischemia reperfusion injury. Int J Biol Sci 2025; 21:940-954. [PMID: 39897045 PMCID: PMC11781180 DOI: 10.7150/ijbs.97579] [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: 04/21/2024] [Accepted: 12/09/2024] [Indexed: 02/04/2025] Open
Abstract
In our investigation, we aimed to shed light on the role of senescent cells in renal fibrosis, considering the observed correlation between renal tubular epithelial cell senescence and the presence of renal fibrosis. Our findings confirm the manifestation of senescence characteristics in renal tubular epithelial cells during renal fibrosis and establish their capacity to trigger a transition from macrophages to myofibroblasts, known as macrophage-myofibroblast transition (MMT). Additionally, our study uncovered that extracellular vesicles released by senescent HK-2 cells (sHK-2) play a pivotal role in facilitating MMT. Subsequently, we investigated the miRNA profile in sHK-2-derived extracellular vesicles (sHK-2-EVs) and confirmed the elevated abundance of specific miRNAs, including miR-20a-5p and miR-21-5p, compared to normal HK-2-EVs. Notably, these miRNAs possess the capability to induce M2-like polarization in macrophages and enhance the expression of TGF-β. Moreover, TGF-β can stimulate macrophages to produce miR-20a-5p and miR-21-5p, establishing a positive feedback loop that amplifies the TGF-β/Smad pathway and facilitates the process of macrophage-myofibroblast transition.
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Affiliation(s)
- Qiang Zhong
- Department of Organ Transplantation Center, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou, China
| | - Jun Zeng
- Department of Urology, Institute of Urology, Organ Transplantation Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Yue Li
- Department of Urology, Institute of Urology, Organ Transplantation Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Haohan Zhang
- Department of Urology, Institute of Urology, Organ Transplantation Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Tao Lin
- Department of Urology, Institute of Urology, Organ Transplantation Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Turun Song
- Department of Urology, Institute of Urology, Organ Transplantation Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China
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Li J, Yan X, Wu Z, Shen J, Li Y, Zhao Y, Du F, Li M, Wu X, Chen Y, Xiao Z, Wang S. Role of miRNAs in macrophage-mediated kidney injury. Pediatr Nephrol 2024; 39:3397-3410. [PMID: 38801452 DOI: 10.1007/s00467-024-06414-5] [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: 01/15/2024] [Revised: 04/13/2024] [Accepted: 05/03/2024] [Indexed: 05/29/2024]
Abstract
Macrophages, crucial components of the human immune system, can be polarized into M1/M2 phenotypes, each with distinct functions and roles. Macrophage polarization has been reported to be significantly involved in the inflammation and fibrosis observed in kidney injury. MicroRNA (miRNA), a type of short RNA lacking protein-coding function, can inhibit specific mRNA by partially binding to its target mRNA. The intricate association between miRNAs and macrophages has been attracting increasing interest in recent years. This review discusses the role of miRNAs in regulating macrophage-mediated kidney injury. It shows how miRNAs can influence macrophage polarization, thereby altering the biological function of macrophages in the kidney. Furthermore, this review highlights the significance of miRNAs derived from exosomes and extracellular vesicles as a crucial mediator in the crosstalk between macrophages and kidney cells. The potential of miRNAs as treatment applications and biomarkers for macrophage-mediated kidney injury is also discussed.
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Affiliation(s)
- Junxin Li
- Department of Pharmacy, Affiliated Hospital, Southwest Medical University, Luzhou, 646000, China
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, 646000, China
- South Sichuan Institute of Translational Medicine, Luzhou, 646000, China
- Laboratory of Personalised Cell Therapy and Cell Medicine, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, 646000, China
| | - Xida Yan
- Department of Pharmacy, Affiliated Hospital, Southwest Medical University, Luzhou, 646000, China
- Department of Pharmacy, Mianyang Central Hospital, Mianyang, China
| | - Zhigui Wu
- Department of Pharmacy, Affiliated Hospital, Southwest Medical University, Luzhou, 646000, China
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, 646000, China
- South Sichuan Institute of Translational Medicine, Luzhou, 646000, China
- Laboratory of Personalised Cell Therapy and Cell Medicine, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, 646000, China
| | - Jing Shen
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, 646000, China
- South Sichuan Institute of Translational Medicine, Luzhou, 646000, China
- Laboratory of Personalised Cell Therapy and Cell Medicine, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, 646000, China
| | - Yalin Li
- Department of Pharmacy, Affiliated Hospital, Southwest Medical University, Luzhou, 646000, China
| | - Yueshui Zhao
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, 646000, China
- South Sichuan Institute of Translational Medicine, Luzhou, 646000, China
- Laboratory of Personalised Cell Therapy and Cell Medicine, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, 646000, China
| | - Fukuan Du
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, 646000, China
- South Sichuan Institute of Translational Medicine, Luzhou, 646000, China
- Laboratory of Personalised Cell Therapy and Cell Medicine, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, 646000, China
| | - Mingxing Li
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, 646000, China
- South Sichuan Institute of Translational Medicine, Luzhou, 646000, China
- Laboratory of Personalised Cell Therapy and Cell Medicine, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, 646000, China
| | - Xu Wu
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, 646000, China
- South Sichuan Institute of Translational Medicine, Luzhou, 646000, China
- Laboratory of Personalised Cell Therapy and Cell Medicine, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, 646000, China
| | - Yu Chen
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, 646000, China
- South Sichuan Institute of Translational Medicine, Luzhou, 646000, China
- Laboratory of Personalised Cell Therapy and Cell Medicine, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, 646000, China
| | - Zhangang Xiao
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, 646000, China
- South Sichuan Institute of Translational Medicine, Luzhou, 646000, China
- Laboratory of Personalised Cell Therapy and Cell Medicine, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, 646000, China
| | - Shurong Wang
- Department of Pharmacy, Affiliated Hospital, Southwest Medical University, Luzhou, 646000, China.
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Shi L, Zha H, Huang H, Xia Y, Li H, Huang J, Yue R, Li C, Zhu J, Song Z. miR-199a-5p aggravates renal ischemia-reperfusion and transplant injury by targeting AKAP1 to disrupt mitochondrial dynamics. Am J Physiol Renal Physiol 2024; 327:F910-F929. [PMID: 39265082 DOI: 10.1152/ajprenal.00409.2023] [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: 12/18/2023] [Revised: 08/27/2024] [Accepted: 09/09/2024] [Indexed: 09/14/2024] Open
Abstract
Renal ischemia-reperfusion injury (IRI) is a complex pathophysiological process and a major cause of delayed graft function (DGF) after transplantation. MicroRNA (miRNA) has important roles in the pathogenesis of IRI and may represent promising therapeutic targets for mitigating renal IRI. miRNA sequencing was performed to profile microRNA expression in mouse kidneys after cold storage and transplantation (CST). Lentivirus incorporating a miR-199a-5p modulator was injected into mouse kidney in situ before syngenetic transplantation and unilateral IRI to determine the effect of miR-199a-5p in vivo. miR-199a-5p mimic or inhibitor was transfected cultured tubular cells before ATP depletion recovery treatment to examine the role of miR-199a-5p in vitro. Sequencing data and microarray showed upregulation of miR-199a-5p in mice CST and human DGF samples. Lentivirus incorporating a miR-199a-5p mimic aggravated renal IRI, and protective effects were obtained with a miR-199a-5p inhibitor. Treatment with the miR-199a-5p inhibitor ameliorated graft function loss, tubular injury, and immune response after CST. In vitro experiments revealed exacerbation of mitochondria dysfunction upon ATP depletion and repletion model in the presence of the miR-199a-5p mimic, whereas dysfunction was attenuated when the miR-199a-5p inhibitor was applied. miR-199a-5p was shown to target A-kinase anchoring protein 1 (AKAP1) by double luciferase assay and miR-199a-5p activation reduced dynamin-related protein 1 (Drp1)-s637 phosphorylation and mitochondrial length. Overexpression of AKAP1 preserved Drp1-s637 phosphorylation and reduced mitochondrial fission. miR-199a-5p activation reduced AKAP1 expression, promoted Drp1-s637 dephosphorylation, aggravated the disruption of mitochondrial dynamics, and contributed to renal IRI.NEW & NOTEWORTHY This study identifies miR-199a-5p as a key regulator in renal ischemia-reperfusion injury through microRNA sequencing in mouse models and human delayed graft function. miR-199a-5p worsens renal IRI by aggravating graft dysfunction, tubular injury, and immune response, while its inhibition shows protective effects. miR-199a-5p downregulates A-kinase anchoring protein 1 (AKAP1), reducing dynamin-related protein 1 (Drp1)-s637 phosphorylation, increasing mitochondrial fission, and causing dysfunction. Targeting the miR-199a-5p/AKAP1/Drp1 axis offers therapeutic potential for renal IRI, as AKAP1 overexpression preserves mitochondrial integrity by maintaining Drp1-s637 phosphorylation.
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Affiliation(s)
- Lang Shi
- Department of Nephrology, The First Hospital of Lanzhou University, Lanzhou, China
- Department of Nephrology, Renmin Hospital of Wuhan University, Wuhan, China
| | - Hongchu Zha
- Department of Nephrology, The First Clinical Medical College of Three Gorges University, Center People's Hospital of Yichang, Yichang, China
| | - Hua Huang
- Department of Nephrology, The First Clinical Medical College of Three Gorges University, Center People's Hospital of Yichang, Yichang, China
| | - Yao Xia
- Department of Nephrology, The First Clinical Medical College of Three Gorges University, Center People's Hospital of Yichang, Yichang, China
| | - Huimin Li
- Department of Nephrology, The First Clinical Medical College of Three Gorges University, Center People's Hospital of Yichang, Yichang, China
| | - Jing Huang
- Department of Nephrology, Renmin Hospital of Wuhan University, Wuhan, China
| | - Ruchi Yue
- Department of Nephrology, The First Clinical Medical College of Three Gorges University, Center People's Hospital of Yichang, Yichang, China
| | - Chenglong Li
- Department of Urology, Renmin Hospital of Wuhan University, Wuhan, China
| | - Jiefu Zhu
- Department of Urology, Renmin Hospital of Wuhan University, Wuhan, China
- Department of Organ Transplantation, Renmin Hospital of Wuhan University, Wuhan, China
| | - Zhixia Song
- Department of Nephrology, The People's Hospital of Longhua, Shenzhen, China
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Wei Q, Huang J, Livingston MJ, Wang S, Dong G, Xu H, Zhou J, Dong Z. Pseudogene GSTM3P1 derived long non-coding RNA promotes ischemic acute kidney injury by target directed microRNA degradation of kidney-protective mir-668. Kidney Int 2024; 106:640-657. [PMID: 39074555 PMCID: PMC11416318 DOI: 10.1016/j.kint.2024.06.027] [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: 10/17/2023] [Revised: 05/21/2024] [Accepted: 06/17/2024] [Indexed: 07/31/2024]
Abstract
Long non-coding RNAs (lncRNAs) are a group of epigenetic regulators that have been implicated in kidney diseases including acute kidney injury (AKI). However, very little is known about the specific lncRNAs involved in AKI and the mechanisms underlying their pathologic roles. Here, we report a new lncRNA derived from the pseudogene GSTM3P1, which mediates ischemic AKI by interacting with and promoting the degradation of mir-668, a kidney-protective microRNA. GSTM3P1 and its mouse orthologue Gstm2-ps1 were induced by hypoxia in cultured kidney proximal tubular cells. In mouse kidneys, Gstm2-ps1 was significantly upregulated in proximal tubules at an early stage of ischemic AKI. This transient induction of Gstm2-ps1 depends on G3BP1, a key component in stress granules. GSTM3P1 overexpression increased kidney proximal tubular apoptosis after ATP depletion, which was rescued by mir-668. Notably, kidney proximal tubule-specific knockout of Gstm2-ps1 protected mice from ischemic AKI, as evidenced by improved kidney function, diminished tubular damage and apoptosis, and reduced kidney injury biomarker (NGAL) induction. To test the therapeutic potential, Gstm2-ps1 siRNAs were introduced into cultured mouse proximal tubular cells or administered to mice. In cultured cells, Gstm2-ps1 knockdown suppressed ATP depletion-associated apoptosis. In mice, Gstm2-ps1 knockdown ameliorated ischemic AKI. Mechanistically, both GSTM3P1 and Gstm2-ps1 possessed mir-668 binding sites and downregulated the mature form of mir-668. Specifically, GSTM3P1 directly bound to mature mir-668 to induce its decay via target-directed microRNA degradation. Thus, our results identify GSTM3P1 as a novel lncRNA that promotes kidney tubular cell death in AKI by binding mir-668 to inducing its degradation.
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Affiliation(s)
- Qingqing Wei
- Department of Cellular Biology and Anatomy, Medical College of Georgia, Augusta University, Augusta, Georgia, USA.
| | - Jing Huang
- Department of Cellular Biology and Anatomy, Medical College of Georgia, Augusta University, Augusta, Georgia, USA; Department of Nephrology, Renmin Hospital of Wuhan University, Wuhan, Hubei, China
| | - Man Jiang Livingston
- Department of Cellular Biology and Anatomy, Medical College of Georgia, Augusta University, Augusta, Georgia, USA
| | - Shixuan Wang
- Department of Cellular Biology and Anatomy, Medical College of Georgia, Augusta University, Augusta, Georgia, USA
| | - Guie Dong
- Department of Cellular Biology and Anatomy, Medical College of Georgia, Augusta University, Augusta, Georgia, USA
| | - Hongyan Xu
- Department of Biostatistics, Data Science and Epidemiology, School of Public Health, Augusta University, Augusta, Georgia, USA
| | - Jiliang Zhou
- Department of Pharmacology and Toxicology, Medical College of Georgia, Augusta University, Augusta, Georgia, USA
| | - Zheng Dong
- Department of Cellular Biology and Anatomy, Medical College of Georgia, Augusta University, Augusta, Georgia, USA; Charlie Norwood VA Medical Center, Augusta, Georgia, USA.
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Gupta S, Mandal S, Banerjee K, Almarshood H, Pushpakumar SB, Sen U. Complex Pathophysiology of Acute Kidney Injury (AKI) in Aging: Epigenetic Regulation, Matrix Remodeling, and the Healing Effects of H 2S. Biomolecules 2024; 14:1165. [PMID: 39334931 PMCID: PMC11429536 DOI: 10.3390/biom14091165] [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: 05/12/2024] [Revised: 09/12/2024] [Accepted: 09/14/2024] [Indexed: 09/30/2024] Open
Abstract
The kidney is an essential excretory organ that works as a filter of toxins and metabolic by-products of the human body and maintains osmotic pressure throughout life. The kidney undergoes several physiological, morphological, and structural changes with age. As life expectancy in humans increases, cell senescence in renal aging is a growing challenge. Identifying age-related kidney disorders and their cause is one of the contemporary public health challenges. While the structural abnormalities to the extracellular matrix (ECM) occur, in part, due to changes in MMPs, EMMPRIN, and Meprin-A, a variety of epigenetic modifiers, such as DNA methylation, histone alterations, changes in small non-coding RNA, and microRNA (miRNA) expressions are proven to play pivotal roles in renal pathology. An aged kidney is vulnerable to acute injury due to ischemia-reperfusion, toxic medications, altered matrix proteins, systemic hemodynamics, etc., non-coding RNA and miRNAs play an important role in renal homeostasis, and alterations of their expressions can be considered as a good marker for AKI. Other epigenetic changes, such as histone modifications and DNA methylation, are also evident in AKI pathophysiology. The endogenous production of gaseous molecule hydrogen sulfide (H2S) was documented in the early 1980s, but its ameliorative effects, especially on kidney injury, still need further research to understand its molecular mode of action in detail. H2S donors heal fibrotic kidney tissues, attenuate oxidative stress, apoptosis, inflammation, and GFR, and also modulate the renin-angiotensin-aldosterone system (RAAS). In this review, we discuss the complex pathophysiological interplay in AKI and its available treatments along with future perspectives. The basic role of H2S in the kidney has been summarized, and recent references and knowledge gaps are also addressed. Finally, the healing effects of H2S in AKI are described with special emphasis on epigenetic regulation and matrix remodeling.
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Affiliation(s)
- Shreyasi Gupta
- Department of Zoology, Trivenidevi Bhalotia College, College Para Rd, Raniganj 713347, West Bengal, India
| | - Subhadeep Mandal
- Department of Zoology, Trivenidevi Bhalotia College, College Para Rd, Raniganj 713347, West Bengal, India
| | - Kalyan Banerjee
- Department of Zoology, Trivenidevi Bhalotia College, College Para Rd, Raniganj 713347, West Bengal, India
| | - Hebah Almarshood
- Department of Physiology, University of Louisville School of Medicine, Louisville, KY 40202, USA
| | - Sathnur B Pushpakumar
- Department of Physiology, University of Louisville School of Medicine, Louisville, KY 40202, USA
| | - Utpal Sen
- Department of Physiology, University of Louisville School of Medicine, Louisville, KY 40202, USA
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Sabet Sarvestani F, Afshari A, Azarpira N. The role of non-protein-coding RNAs in ischemic acute kidney injury. Front Immunol 2024; 15:1230742. [PMID: 38390339 PMCID: PMC10881863 DOI: 10.3389/fimmu.2024.1230742] [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: 05/29/2023] [Accepted: 01/26/2024] [Indexed: 02/24/2024] Open
Abstract
Acute kidney injury (AKI) is a condition characterized by a rapid decline in kidney function within a span of 48 hours. It is influenced by various factors including inflammation, oxidative stress, excessive calcium levels within cells, activation of the renin-angiotensin system, and dysfunction in microcirculation. Ischemia-reperfusion injury (IRI) is recognized as a major cause of AKI; however, the precise mechanisms behind this process are not yet fully understood and effective treatments are still needed. To enhance the accuracy of diagnosing AKI during its early stages, the utilization of innovative markers is crucial. Numerous studies suggest that certain noncoding RNAs (ncRNAs), such as long noncoding RNAs (lncRNAs), microRNAs (miRNAs), and circular RNAs (circRNAs), play a central role in regulating gene expression and protein synthesis. These ncRNAs are closely associated with the development and recovery of AKI and have been detected in both kidney tissue and bodily fluids. Furthermore, specific ncRNAs may serve as diagnostic markers and potential targets for therapeutic interventions in AKI. This review aims to summarize the functional roles and changes observed in noncoding RNAs during ischemic AKI, as well as explore their therapeutic potential.
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Affiliation(s)
| | - Afsoon Afshari
- Shiraz Nephro-Urology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Negar Azarpira
- Shiraz Transplant Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
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Hagiwara S, Gohda T, Kantharidis P, Okabe J, Murakoshi M, Suzuki Y. Potential of Modulating Aldosterone Signaling and Mineralocorticoid Receptor with microRNAs to Attenuate Diabetic Kidney Disease. Int J Mol Sci 2024; 25:869. [PMID: 38255942 PMCID: PMC10815168 DOI: 10.3390/ijms25020869] [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: 11/18/2023] [Revised: 01/04/2024] [Accepted: 01/07/2024] [Indexed: 01/24/2024] Open
Abstract
Diabetic Kidney Disease (DKD) is a significant complication of diabetes and primary cause of end-stage renal disease globally. The exact mechanisms underlying DKD remain poorly understood, but multiple factors, including the renin-angiotensin-aldosterone system (RAAS), play a key role in its progression. Aldosterone, a mineralocorticoid steroid hormone, is one of the key components of RAAS and a potential mediator of renal damage and inflammation in DKD. miRNAs, small noncoding RNA molecules, have attracted interest due to their regulatory roles in numerous biological processes. These processes include aldosterone signaling and mineralocorticoid receptor (MR) expression. Numerous miRNAs have been recognized as crucial regulators of aldosterone signaling and MR expression. These miRNAs affect different aspects of the RAAS pathway and subsequent molecular processes, which impact sodium balance, ion transport, and fibrosis regulation. This review investigates the regulatory roles of particular miRNAs in modulating aldosterone signaling and MR activation, focusing on their impact on kidney injury, inflammation, and fibrosis. Understanding the complex interaction between miRNAs and the RAAS could lead to a new strategy to target aldosterone signaling and MR activation using miRNAs. This highlights the potential of miRNA-based interventions for DKD, with the aim of enhancing kidney outcomes in individuals with diabetes.
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Affiliation(s)
- Shinji Hagiwara
- Department of Nephrology, Juntendo University Faculty of Medicine, Tokyo 1138421, Japan; (M.M.); (Y.S.)
- Hagiwara Clinic, Tokyo 2030001, Japan
| | - Tomohito Gohda
- Department of Nephrology, Juntendo University Faculty of Medicine, Tokyo 1138421, Japan; (M.M.); (Y.S.)
| | - Phillip Kantharidis
- Department of Diabetes, Monash University, Melbourne, VIC 3004, Australia; (P.K.); (J.O.)
| | - Jun Okabe
- Department of Diabetes, Monash University, Melbourne, VIC 3004, Australia; (P.K.); (J.O.)
- Epigenetics in Human Health and Disease Program, Baker Heart & Diabetes Institute, Melbourne, VIC 3004, Australia
| | - Maki Murakoshi
- Department of Nephrology, Juntendo University Faculty of Medicine, Tokyo 1138421, Japan; (M.M.); (Y.S.)
| | - Yusuke Suzuki
- Department of Nephrology, Juntendo University Faculty of Medicine, Tokyo 1138421, Japan; (M.M.); (Y.S.)
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11
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Mahrous NN, Jamous YF, Almatrafi AM, Fallatah DI, Theyab A, Alanati BH, Alsagaby SA, Alenazi MK, Khan MI, Hawsawi YM. A Current Landscape on Alport Syndrome Cases: Characterization, Therapy and Management Perspectives. Biomedicines 2023; 11:2762. [PMID: 37893135 PMCID: PMC10604007 DOI: 10.3390/biomedicines11102762] [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: 09/09/2023] [Revised: 09/30/2023] [Accepted: 10/05/2023] [Indexed: 10/29/2023] Open
Abstract
Alport syndrome (AS) is a rare genetic disorder categorized by the progressive loss of kidney function, sensorineural hearing loss and eye abnormalities. It occurs due to mutations in three genes that encode for the alpha chains of type IV collagen. Globally, the disease is classified based on the pattern of inheritance into X-linked AS (XLAS), which is caused by pathogenic variants in COL4A5, representing 80% of AS. Autosomal recessive AS (ARAS), caused by mutations in either COL4A3 or COL4A4, represents 15% of AS. Autosomal dominant AS (ADAS) is rare and has been recorded in 5% of all cases due to mutations in COL4A3 or COL4A4. This review provides updated knowledge about AS including its clinical and genetic characteristics in addition to available therapies that only slow the progression of the disease. It also focuses on reported cases in Saudi Arabia and their prevalence. Moreover, we shed light on advances in genetic technologies like gene editing using CRISPR/Cas9 technology, the need for an early diagnosis of AS and managing the progression of the disease. Eventually, we provide a few recommendations for disease management, particularly in regions like Saudi Arabia where consanguineous marriages increase the risk.
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Affiliation(s)
- Nahed N. Mahrous
- Department of Biological Sciences, College of Science, University of Hafr Al-Batin, Hafr Al-Batin 39524, Saudi Arabia;
| | - Yahya F. Jamous
- The National Center of Vaccines and Bioprocessing, King Abdulaziz City for Science and Technology, Riyadh 12354, Saudi Arabia;
| | - Ahmad M. Almatrafi
- Department of Biological Sciences, College of Science, Taibah University, Madinah 42353, Saudi Arabia;
| | - Deema I. Fallatah
- Department of Medical Laboratory Sciences, College of Applied Medical Sciences, Prince Sattam Bin Abdulaziz University, Al-Kharj 11942, Saudi Arabia;
| | - Abdulrahman Theyab
- Department of Laboratory and Blood Bank, Security Forces Hospital, Makkah 11481, Saudi Arabia;
- Department of Biochemistry & Molecular Medicine, College of Medicine, Al-Faisal University, P.O. Box 50927, Riyadh 11533, Saudi Arabia
| | - Bayan H. Alanati
- Center for Synthetic Microbiology, Bioinformatics Core Facility, University of Marburg, 35032 Marburg, Germany;
| | - Suliman A. Alsagaby
- Department of Medicinal Laboratory Sciences, College of Applied Medical Sciences, Majmaah University, Al-Majmaah 11952, Saudi Arabia;
| | - Munifa K. Alenazi
- Research Center, King Faisal Specialist Hospital and Research Center, P.O. Box 40047, Jeddah 21499, Saudi Arabia; (M.K.A.); (M.I.K.)
| | - Mohammed I. Khan
- Research Center, King Faisal Specialist Hospital and Research Center, P.O. Box 40047, Jeddah 21499, Saudi Arabia; (M.K.A.); (M.I.K.)
| | - Yousef M. Hawsawi
- Department of Biochemistry & Molecular Medicine, College of Medicine, Al-Faisal University, P.O. Box 50927, Riyadh 11533, Saudi Arabia
- Research Center, King Faisal Specialist Hospital and Research Center, P.O. Box 40047, Jeddah 21499, Saudi Arabia; (M.K.A.); (M.I.K.)
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12
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Li C, Han S, Zhu J, Cheng F. MiR-132-3p activation aggravates renal ischemia-reperfusion injury by targeting Sirt1/PGC1alpha axis. Cell Signal 2023; 110:110801. [PMID: 37433399 DOI: 10.1016/j.cellsig.2023.110801] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2023] [Revised: 06/13/2023] [Accepted: 07/07/2023] [Indexed: 07/13/2023]
Abstract
The pathogenesis of renal ischemic diseases remains unclear. In this study, we demonstrate the induction of microRNA-132-3p (miR-132-3p) in ischemic acute kidney injury (AKI) and cultured renal tubular cells under oxidative stress. miR-132-3p mimic increased apoptosis in renal tubular cells and enhanced ischemic AKI in mice, whereas miR-132-3p inhibition offered protective effects. We analyzed miR-132-3p target genes through bioinformatic analysis and Sirt1 was predicted as the target gene of miR-132-3p. Luciferase microRNA target reporter assay further verified Sirt1 as a direct target of miR-132-3p. In cultured tubular cells and mouse kidneys, IRI and H2O2 treatment repressed Sirt1 and PGC-1α/NRF2/HO-1 expression, whereas anti-miR-132-3p preserved Sirt1 and PGC-1α/NRF2/HO-1 expression. In renal tubular, Sirt1 inhibitor suppressed PGC1-1α/NRF2/HO-1 expression and aggravated tubular apoptosis. Together, the results suggest that miR-132-3p induction aggravates ischemic AKI and oxidative stress by repressing Sirt1 expression, and miR-132-3p inhibition offers renal protection and may be a potential therapeutic target.
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Affiliation(s)
- Chenglong Li
- Department of Urology, Renmin Hospital of Wuhan University, Wuhan, Hubei Province, China
| | - Shangting Han
- Department of Urology, Renmin Hospital of Wuhan University, Wuhan, Hubei Province, China; Department of Organ Transplantation, Renmin Hospital of Wuhan University, Wuhan, Hubei Province, China
| | - Jiefu Zhu
- Department of Urology, Renmin Hospital of Wuhan University, Wuhan, Hubei Province, China; Department of Organ Transplantation, Renmin Hospital of Wuhan University, Wuhan, Hubei Province, China.
| | - Fan Cheng
- Department of Urology, Renmin Hospital of Wuhan University, Wuhan, Hubei Province, China.
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Zeng B, Liu Y, Xu J, Niu L, Wu Y, Zhang D, Tang X, Zhu Z, Chen Y, Hu L, Yu S, Yu P, Zhang J, Wang W. Future Directions in Optimizing Anesthesia to Reduce Perioperative Acute Kidney Injury. Am J Nephrol 2023; 54:434-450. [PMID: 37742618 DOI: 10.1159/000533534] [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: 05/05/2023] [Accepted: 08/01/2023] [Indexed: 09/26/2023]
Abstract
BACKGROUND Perioperative acute kidney injury (AKI) is common in surgical patients and is associated with high morbidity and mortality. There are currently few options for AKI prevention and treatment. Due to its complex pathophysiology, there is no efficient medication therapy to stop the onset of the injury or repair the damage already done. Certain anesthetics, however, have been demonstrated to affect the risk of perioperative AKI in some studies. The impact of anesthetics on renal function is particularly important as it is closely related to the prognosis of patients. Some anesthetics can induce anti-inflammatory, anti-necrotic, and anti-apoptotic effects. Propofol, sevoflurane, and dexmedetomidine are a few examples of anesthetics that have protective association with AKI in the perioperative period. SUMMARY In this study, we reviewed the clinical characteristics, risk factors, and pathogenesis of AKI. Subsequently, the protective effects of various anesthetic agents against perioperative AKI and the latest research are introduced. KEY MESSAGE This work demonstrates that a thorough understanding of the reciprocal effects of anesthetic drugs and AKI is crucial for safe perioperative care and prognosis of patients. However, more complete mechanisms and pathophysiological processes still need to be further studied.
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Affiliation(s)
- Bin Zeng
- Department of Gastroenterology, First Affiliated Hospital of Gannan Medical University, Ganzhou, China
| | - Yinuo Liu
- Department of Metabolism and Endocrinology, The Second Affiliated Hospital of Nanchang University, Nanchang, China,
- The Second Clinical Medical College of Nanchang University, Nanchang, China,
| | - Jiawei Xu
- Department of Metabolism and Endocrinology, The Second Affiliated Hospital of Nanchang University, Nanchang, China
- The Second Clinical Medical College of Nanchang University, Nanchang, China
| | - Liyan Niu
- Department of Metabolism and Endocrinology, The Second Affiliated Hospital of Nanchang University, Nanchang, China
- The Second Clinical Medical College of Nanchang University, Nanchang, China
- Huan Kui College, Nanchang University, Nanchang, China
| | - Yuting Wu
- Huan Kui College, Nanchang University, Nanchang, China
- Department of Metabolism and Endocrinology, The Second Affiliated Hospital of Nanchang University, Nanchang, China
| | - Deju Zhang
- Huan Kui College, Nanchang University, Nanchang, China
- Food and Nutritional Sciences, School of Biological Sciences, The University of Hong Kong, Hong Kong, Hong Kong, China
| | - Xiaoyi Tang
- Department of Anesthesiology, The Second Affiliated Hospital of Nanchang University, Nanchang, China
| | - Zicheng Zhu
- Department of Anesthesiology, The Second Affiliated Hospital of Nanchang University, Nanchang, China
| | - Yixuan Chen
- Department of Anesthesiology, The Second Affiliated Hospital of Nanchang University, Nanchang, China
| | - Leilei Hu
- Department of Anesthesiology, The Second Affiliated Hospital of Nanchang University, Nanchang, China
| | - Shuchun Yu
- Department of Anesthesiology, The Second Affiliated Hospital of Nanchang University, Nanchang, China
| | - Peng Yu
- Department of Metabolism and Endocrinology, The Second Affiliated Hospital of Nanchang University, Nanchang, China
| | - Jing Zhang
- Department of Anesthesiology, The Second Affiliated Hospital of Nanchang University, Nanchang, China
| | - Wenting Wang
- Department of Anesthesiology, The Second Affiliated Hospital of Hainan Medical University, Haikou, China
- Department of Cardiopulmonary Bypass, State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
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Rahbar Saadat Y, Hosseiniyan Khatibi SM, Sani A, Zununi Vahed S, Ardalan M. Ischemic tubular injury: Oxygen-sensitive signals and metabolic reprogramming. Inflammopharmacology 2023; 31:1657-1669. [PMID: 37131045 DOI: 10.1007/s10787-023-01232-x] [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: 07/23/2022] [Accepted: 03/21/2023] [Indexed: 05/04/2023]
Abstract
The kidneys are the most vulnerable organs to severe ischemic insult that results in cellular hypoxia under pathophysiological conditions. Large amounts of oxygen are consumed by the kidneys, mainly to produce energy for tubular reabsorption. Beyond high oxygen demand and the low oxygen supply, different other factors make kidneys vulnerable to ischemia which is deemed to be a major cause of acute kidney injury (AKI). On the other hand, kidneys are capable of sensing and responding to oxygen alternations to evade harms resulting from inadequate oxygen. The hypoxia-inducible factor (HIF) is the main conserved oxygen-sensing mechanism that maintains homeostasis under hypoxia through direct/indirect regulation of several genes that contribute to metabolic adaptation, angiogenesis, energy conservation, erythropoiesis, and so on. In response to oxygen availability, prolyl-hydroxylases (PHDs) control the HIF stability. This review focuses on the oxygen-sensing mechanisms in kidneys, particularly in proximal tubular cells (PTCs) and discusses the molecules involved in ischemic response and metabolic reprogramming. Moreover, the possible roles of non-coding RNAs (microRNAs and long non-coding RNAs) in the development of ischemic AKI are put forward.
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Affiliation(s)
| | | | - Anis Sani
- Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran
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15
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Zhu J, Xiang X, Hu X, Li C, Song Z, Dong Z. miR-147 Represses NDUFA4, Inducing Mitochondrial Dysfunction and Tubular Damage in Cold Storage Kidney Transplantation. J Am Soc Nephrol 2023; 34:1381-1397. [PMID: 37211637 PMCID: PMC10400108 DOI: 10.1681/asn.0000000000000154] [Citation(s) in RCA: 22] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2022] [Accepted: 04/25/2023] [Indexed: 05/23/2023] Open
Abstract
SIGNIFICANCE STATEMENT Cold storage-associated transplantation (CST) injury occurs in renal transplant from deceased donors, the main organ source. The pathogenesis of CST injury remains poorly understood, and effective therapies are not available. This study has demonstrated an important role of microRNAs in CST injury and revealed the changes in microRNA expression profiles. Specifically, microRNA-147 (miR-147) is consistently elevated during CST injury in mice and in dysfunctional renal grafts in humans. Mechanistically, NDUFA4 (a key component of mitochondrial respiration complex) is identified as a direct target of miR-147. By repressing NDUFA4, miR-147 induces mitochondrial damage and renal tubular cell death. Blockade of miR-147 and overexpression of NDUFA4 reduce CST injury and improve graft function, unveiling miR-147 and NDUFA4 as new therapeutic targets in kidney transplantation. BACKGROUND Kidney injury due to cold storage-associated transplantation (CST) is a major factor determining the outcome of renal transplant, for which the role and regulation of microRNAs remain largely unclear. METHODS The kidneys of proximal tubule Dicer (an enzyme for microRNA biogenesis) knockout mice and their wild-type littermates were subjected to CST to determine the function of microRNAs. Small RNA sequencing then profiled microRNA expression in mouse kidneys after CST. Anti-microRNA-147 (miR-147) and miR-147 mimic were used to examine the role of miR-147 in CST injury in mouse and renal tubular cell models. RESULTS Knockout of Dicer from proximal tubules attenuated CST kidney injury in mice. RNA sequencing identified multiple microRNAs with differential expression in CST kidneys, among which miR-147 was induced consistently in mouse kidney transplants and in dysfunctional human kidney grafts. Anti-miR-147 protected against CST injury in mice and ameliorated mitochondrial dysfunction after ATP depletion injury in renal tubular cells in intro . Mechanistically, miR-147 was shown to target NDUFA4, a key component of the mitochondrial respiration complex. Silencing NDUFA4 aggravated renal tubular cell death, whereas overexpression of NDUFA4 prevented miR-147-induced cell death and mitochondrial dysfunction. Moreover, overexpression of NDUFA4 alleviated CST injury in mice. CONCLUSIONS microRNAs, as a class of molecules, are pathogenic in CST injury and graft dysfunction. Specifically, miR-147 induced during CST represses NDUFA4, leading to mitochondrial damage and renal tubular cell death. These results unveil miR-147 and NDUFA4 as new therapeutic targets in kidney transplantation.
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Affiliation(s)
- Jiefu Zhu
- Department of Urology, Renmin Hospital of Wuhan University, Wuhan, China
- Department of Organ Transplantation, Renmin Hospital of Wuhan University, Wuhan, China
- Department of Cellular Biology and Anatomy, Medical College of Georgia at Augusta University and Charlie Norwood VA Medical Center, Augusta, Georgia
| | - Xiaohong Xiang
- Department of Cellular Biology and Anatomy, Medical College of Georgia at Augusta University and Charlie Norwood VA Medical Center, Augusta, Georgia
- Department of Critical Care Medicine, The Second Xiangya Hospital at Central South University, Changsha, China
| | - Xiaoru Hu
- Department of Cellular Biology and Anatomy, Medical College of Georgia at Augusta University and Charlie Norwood VA Medical Center, Augusta, Georgia
- Department of Nephrology, The Second Xiangya Hospital at Central South University, Changsha, China
| | - Chenglong Li
- Department of Urology, Renmin Hospital of Wuhan University, Wuhan, China
- Department of Cellular Biology and Anatomy, Medical College of Georgia at Augusta University and Charlie Norwood VA Medical Center, Augusta, Georgia
| | - Zhixia Song
- Department of Cellular Biology and Anatomy, Medical College of Georgia at Augusta University and Charlie Norwood VA Medical Center, Augusta, Georgia
- Department of Nephrology, Yichang Central People's Hospital, The First Clinical Medical College of Three Gorges University, Yichang, China
| | - Zheng Dong
- Department of Cellular Biology and Anatomy, Medical College of Georgia at Augusta University and Charlie Norwood VA Medical Center, Augusta, Georgia
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Ejaz M, Usman SM, Amir S, Khan MJ. Holistic expression of miR-17-92 cluster in obesity, kidney diseases, cardiovascular diseases, and diabetes. Mol Biol Rep 2023; 50:6913-6925. [PMID: 37329480 DOI: 10.1007/s11033-023-08549-4] [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: 04/09/2023] [Accepted: 05/24/2023] [Indexed: 06/19/2023]
Abstract
miR-17-92 cluster encodes six micro RNAs (miRNAs) and plays a crucial role in the regulation of various cellular processes. Aberrant expression of this cluster may result in the onset of several diseases. Initially, the role of miR-17-92 cluster in tumorigenesis was discovered but recent research has also uncovered its role in other diseases. Members of the cluster may serve as potential biomarkers in the prognosis, diagnosis, and treatment of several diseases and their complications. In this article, we have reviewed the recent research carried out on the expression pattern of miR-17-92 cluster in non-communicable diseases i.e., obesity, cardiovascular diseases (CVD), kidney diseases (KD) and diabetes mellitus (DM). We examined miR-17-92 role in pathological processes and their potential importance as biomarkers. Each member of the cluster miR-17-92 was upregulated in obesity. miR-18a, miR-19b-3p, miR20a, and miR92a were significantly upregulated in CVD. An equal fraction of the cluster was dysregulated (upregulated and downregulated) in diabetes; however, miR-17-92 was downregulated in most studies on CKD.
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Affiliation(s)
- Maheen Ejaz
- Department of Biosciences, COMSATS University Islamabad, Park Road, Chak Shahzad Islamabad, Islamabad, 45550, Pakistan
| | - Syed Mohammad Usman
- Department of Biochemistry, McMaster University, Hamilton, ON, L8S 4L8, Canada
| | - Saira Amir
- Department of Biosciences, COMSATS University Islamabad, Park Road, Chak Shahzad Islamabad, Islamabad, 45550, Pakistan
| | - Muhammad Jawad Khan
- Department of Biosciences, COMSATS University Islamabad, Park Road, Chak Shahzad Islamabad, Islamabad, 45550, Pakistan.
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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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Williams AC, Singh V, Liu P, Kriegel AJ. Liquid Biopsies Poorly miRror Renal Ischemia-Reperfusion Injury. Noncoding RNA 2023; 9:ncrna9020024. [PMID: 37104006 PMCID: PMC10141369 DOI: 10.3390/ncrna9020024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2023] [Revised: 03/18/2023] [Accepted: 03/22/2023] [Indexed: 04/05/2023] Open
Abstract
Acute kidney injury (AKI) is the rapid reduction in renal function. It is often difficult to detect at an early stage. Biofluid microRNAs (miRs) have been proposed as novel biomarkers due to their regulatory role in renal pathophysiology. The goal of this study was to determine the overlap in AKI miRNA profiles in the renal cortex, urine, and plasma samples collected from a rat model of ischemia-reperfusion (IR)-induced AKI. Bilateral renal ischemia was induced by clamping the renal pedicles for 30 min, followed by reperfusion. Urine was then collected over 24 h, followed by terminal blood and tissue collection for small RNA profiling. Differentially expressed (IR vs. sham) miRs within the urine and renal cortex sample types demonstrated a strong correlation in normalized abundance regardless of injury (IR and sham: R2 = 0.8710 and 0.9716, respectively). Relatively few miRs were differentially expressed in multiple samples. Further, there were no differentially expressed miRs with clinically relevant sequence conservation common between renal cortex and urine samples. This project highlights the need for a comprehensive analysis of potential miR biomarkers, including analysis of pathological tissues and biofluids, with the goal of identifying the cellular origin of altered miRs. Analysis at earlier timepoints is needed to further evaluate clinical potential.
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Affiliation(s)
- Adaysha C. Williams
- Department of Physiology, Medical College of Wisconsin, Milwaukee, WI 53226, USA
| | - Vaishali Singh
- Department of Pediatrics, Medical College of Wisconsin, Milwaukee, WI 53226, USA
| | - Pengyuan Liu
- Department of Physiology, Medical College of Wisconsin, Milwaukee, WI 53226, USA
| | - Alison J. Kriegel
- Department of Physiology, Medical College of Wisconsin, Milwaukee, WI 53226, USA
- Department of Pediatrics, Medical College of Wisconsin, Milwaukee, WI 53226, USA
- Cardiovascular Center, Medical College of Wisconsin, Milwaukee, WI 53226, USA
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Ma M, Li H, Yin S, Lin T, Song T. Overexpression of miR-92a attenuates kidney ischemia-reperfusion injury and improves kidney preservation by inhibiting MEK4/JNK1-related autophagy. Cell Mol Biol Lett 2023; 28:20. [PMID: 36890442 PMCID: PMC9997008 DOI: 10.1186/s11658-023-00430-3] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2022] [Accepted: 02/07/2023] [Indexed: 03/10/2023] Open
Abstract
BACKGROUND Kidney ischemia-reperfusion injury is inevitable in kidney transplantation, and is essential for primary graft dysfunction and delayed graft function. Our previous study has proved that miR-92a could ameliorate kidney ischemia-reperfusion injury, but the mechanism has not been studied. METHODS This study conducted further research on the role of miR-92a in kidney ischemia-reperfusion injury and organ preservation. In vivo, mice models of bilateral kidney ischemia (30 min), cold preservation after ischemia (cold preservation time of 6, 12, and 24 h), and ischemia-reperfusion (reperfusion time of 24, 48, and 72 h) were established. Before or after modeling, the model mice were injected with miR-92a-agomir through the caudal vein. In vitro, the hypoxia-reoxygenation of HK-2 cells was used to simulate ischemia-reperfusion injury. RESULTS Kidney ischemia and ischemia-reperfusion significantly damaged kidney function, decreased the expression of miR-92a, and increased apoptosis and autophagy in kidneys. miR-92a agomir tail vein injection significantly increased the expression of miR-92a in kidneys, improved kidney function, and alleviated kidney injury, and the intervention before modeling achieved a better effect than after. Moreover, miR-92a agomir significantly reduced the apoptosis and autophagy in HK-2 cells induced by hypoxia, hypoxia-reoxygenation, and rapamycin, while miR-92a antagomir had opposite effects. Furthermore, mitogen-activated protein kinase, c-Jun NH (2) terminal kinase, caspase 3, Beclin 1, and microtubule-associated protein 1 light chain 3B were inhibited by overexpression of miR-92a both in vivo and in vitro, which in turn reduced apoptosis and autophagy. CONCLUSIONS Our results prove that overexpression of miR-92a attenuated kidney ischemia-reperfusion injury and improved kidney preservation, and intervention before ischemia-reperfusion provides better protection than after.
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Affiliation(s)
- Ming Ma
- Department of Urology, West China Hospital, Sichuan University, 37# Guoxue Alley, Chengdu, 610041, Sichuan, China.,Organ Transplantation Center, West China Hospital, Sichuan University, 37# Guoxue Alley, Chengdu, 610041, Sichuan, China
| | - Hui Li
- Department of Urology, West China Hospital, Sichuan University, 37# Guoxue Alley, Chengdu, 610041, Sichuan, China.,Organ Transplantation Center, West China Hospital, Sichuan University, 37# Guoxue Alley, Chengdu, 610041, Sichuan, China
| | - Saifu Yin
- Department of Urology, West China Hospital, Sichuan University, 37# Guoxue Alley, Chengdu, 610041, Sichuan, China.,Organ Transplantation Center, West China Hospital, Sichuan University, 37# Guoxue Alley, Chengdu, 610041, Sichuan, China
| | - Tao Lin
- Department of Urology, West China Hospital, Sichuan University, 37# Guoxue Alley, Chengdu, 610041, Sichuan, China. .,Organ Transplantation Center, West China Hospital, Sichuan University, 37# Guoxue Alley, Chengdu, 610041, Sichuan, China.
| | - Turun Song
- Department of Urology, West China Hospital, Sichuan University, 37# Guoxue Alley, Chengdu, 610041, Sichuan, China. .,Organ Transplantation Center, West China Hospital, Sichuan University, 37# Guoxue Alley, Chengdu, 610041, Sichuan, China.
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20
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Gregorio VD, Caparali B, Shojaei A, Ricardo S, Barua M. Alport Syndrome: Clinical Spectrum and Therapeutic Advances. Kidney Med 2023; 5:100631. [PMID: 37122389 PMCID: PMC10131117 DOI: 10.1016/j.xkme.2023.100631] [Citation(s) in RCA: 18] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/08/2023] Open
Abstract
Alport syndrome is a hereditary disorder characterized by kidney disease, ocular abnormalities, and sensorineural hearing loss. Work in understanding the cause of Alport syndrome and the molecular composition of the glomerular basement membrane ultimately led to the identification of COL4A3, COL4A4 (both on chromosome 2q36), and COL4A5 (chromosome Xq22), encoding the α3, α4, and α5 chains of type IV collagen, as the responsible genes. Subsequent studies suggested that autosomal recessive Alport syndrome and males with X-linked Alport syndrome have more severe disease, whereas autosomal dominant Alport syndrome and females with X-linked Alport syndrome have more variability. Variant type is also influential-protein-truncating variants in autosomal recessive Alport syndrome or males with X-linked Alport syndrome often present with severe symptoms, characterized by kidney failure, extrarenal manifestations, and lack of the α3-α4-α5(IV) network. By contrast, mild-moderate forms from missense variants display α3-α4-α5(IV) in the glomerular basement membrane and are associated with protracted kidney involvement without extrarenal manifestations. Regardless of type, therapeutic intervention for kidney involvement is focused on early initiation of angiotensin-converting enzyme inhibitors. There are several therapies under investigation including sodium/glucose cotransporter 2 inhibitors, aminoglycoside analogs, endothelin type A antagonists, lipid-modifying drugs, and hydroxychloroquine, although targeting the underlying defect through gene therapy remains in preclinical stages.
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21
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Nadeem RI, Aboutaleb AS, Younis NS, Ahmed HI. Diosmin Mitigates Gentamicin-Induced Nephrotoxicity in Rats: Insights on miR-21 and -155 Expression, Nrf2/HO-1 and p38-MAPK/NF-κB Pathways. TOXICS 2023; 11:48. [PMID: 36668774 PMCID: PMC9865818 DOI: 10.3390/toxics11010048] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 12/04/2022] [Revised: 12/26/2022] [Accepted: 12/29/2022] [Indexed: 06/17/2023]
Abstract
Gentamicin (GNT) is the most frequently used aminoglycoside. However, its therapeutic efficacy is limited due to nephrotoxicity. Thus, the potential anticipatory effect of Diosmin (DIOS) against GNT-prompted kidney damage in rats together with the putative nephroprotective pathways were scrutinized. Four groups of rats were used: (1) control; (2) GNT only; (3) GNT plus DIOS; and (4) DIOS only. Nephrotoxicity was elucidated, and the microRNA-21 (miR-21) and microRNA-155 (miR-155) expression and Nrf2/HO-1 and p38-MAPK/NF-κB pathways were assessed. GNT provoked an upsurge in the relative kidney weight and serum level of urea, creatinine, and KIM-1. The MDA level was markedly boosted, with a decline in the level of TAC, SOD, HO-1, and Nrf2 expression in the renal tissue. Additionally, GNT exhibited a notable amplification in TNF-α, IL-1β, NF-κB p65, and p38-MAPK kidney levels. Moreover, caspase-3 and BAX expression were elevated, whereas the Bcl-2 level was reduced. Furthermore, GNT resulted in the down-regulation of miR-21 expression along with an up-regulation of the miR-155 expression. Histological examination revealed inflammation, degradation, and necrosis. GNT-provoked pathological abnormalities were reversed by DIOS treatment, which restored normal kidney architecture. Hence, regulating miR-21 and -155 expression and modulating Nrf2/HO-1 and p38-MAPK/NF-κB pathways could take a vital part in mediating the reno-protective effect of DIOS.
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Affiliation(s)
- Rania I. Nadeem
- Pharmacology and Toxicology Department, Faculty of Pharmacy, Heliopolis University, Cairo 11785, Egypt
| | - Amany S. Aboutaleb
- Pharmacology and Toxicology Department, Faculty of Pharmacy (Girls), Al-Azhar University, Cairo 11754, Egypt
| | - Nancy S. Younis
- Pharmaceutical Sciences Department, Faculty of Clinical Pharmacy, King Faisal University, Al-Ahsa, Al-Hofuf 31982, Saudi Arabia
| | - Hebatalla I. Ahmed
- Pharmacology and Toxicology Department, Faculty of Pharmacy (Girls), Al-Azhar University, Cairo 11754, Egypt
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22
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Scalon MC, Martins CS, Ferreira GG, Schlemmer F, Titze de Almeida R, Paludo GR. miR-20a is upregulated in serum from domestic feline with PKD1 mutation. PLoS One 2022; 17:e0279337. [PMID: 36538546 PMCID: PMC9767353 DOI: 10.1371/journal.pone.0279337] [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: 06/03/2022] [Accepted: 12/05/2022] [Indexed: 12/24/2022] Open
Abstract
Polycystic kidney disease (PKD), also known as autosomal dominant polycystic kidney disease (ADPKD) is a genetically heterogeneous condition characterized by cysts in renal parenchyma. It is the most prevalent inherited disease of domestic cats. MicroRNAs (miRNAs or ncRNA) are short, noncoding, single-stranded RNAs that may induce PKD cytogenesis by affecting numerous targets genes as well as by directly regulating PKD gene expression. We compared the relative expression profile of miR-20a, -192, -365, -15b-5p, and -16-5p from plasma and serum samples of nine domestic cats with PKD1 mutation, detected by polymerase chain reaction (PCR), and a control group (n = 10). Blood samples from cats with PKD1 mutation provide similar concentrations of microRNAs either from plasma or serum. Serum miR-20a is upregulated in PKD group with p < 0.005; Roc curve analysis showed an AUC of 90,1% with a cut-off value sensitivity of 77.8% and specificity of 100%. This data provides important information regarding renal miRNA expression in peripheral blood sampling.
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Affiliation(s)
- Marcela Correa Scalon
- Veterinary Clinical Pathology Laboratory, College of Agronomy and Veterinary Medicine, University of Brasília, Brasília, Brazil
| | - Christine Souza Martins
- Veterinary Clinical Pathology Laboratory, College of Agronomy and Veterinary Medicine, University of Brasília, Brasília, Brazil
| | - Gabriel Ginani Ferreira
- Technology for Gene Therapy Laboratory, College of Agronomy and Veterinary Medicine, University of Brasília, Brasília, Brazil
| | - Franciele Schlemmer
- Technology for Gene Therapy Laboratory, College of Agronomy and Veterinary Medicine, University of Brasília, Brasília, Brazil
| | - Ricardo Titze de Almeida
- Technology for Gene Therapy Laboratory, College of Agronomy and Veterinary Medicine, University of Brasília, Brasília, Brazil
| | - Giane Regina Paludo
- Veterinary Clinical Pathology Laboratory, College of Agronomy and Veterinary Medicine, University of Brasília, Brasília, Brazil
- * E-mail:
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23
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He YL, Yang YL, Xu WX, Fang TY, Zeng M. Research hotspots and development trends of microRNA in ischemia-reperfusion: network analysis of academic journals oriented by bibliometric and visualization. ANNALS OF TRANSLATIONAL MEDICINE 2022; 10:1321. [PMID: 36660677 PMCID: PMC9843410 DOI: 10.21037/atm-22-5677] [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: 10/28/2022] [Accepted: 12/05/2022] [Indexed: 12/15/2022]
Abstract
Background Ischemia-reperfusion (IR) injury can occur in the heart, brain, liver, lung, kidney, and other important organs, and may greatly increase disease mortality. MicroRNAs (miRNAs) have a variety of functions, including regulating cell differentiation, proliferation, and apoptosis. In the past 10 years, many studies on miRNAs in IR have been conducted. This study involved a visual analysis of these studies, and a discussion of research hotspots, trends, and frontiers of this topic. Methods A total of 1,518 articles published between 2012 and 2022 on the topic of miRNA and IR and listed in the Web of Science database were analyzed visually using CiteSpace. Cooperative networks, literature citations, and keyword co-occurrence were analyzed. Results Of the 1,518 articles, most were published after 2018, and a rapid growth in numbers of publications was seen after 2019. Articles from China numbered the highest, followed by the United States and Canada. It has been found that many miRNAs are involved in the occurrence of IR, with various regulatory mechanisms and signaling pathways. The literature clustering generated by literature co-citation analysis and the keyword co-occurrence network showed that the previous miRNA research on IR had mainly focused on the following topics: myocardial infarction, ischemic stroke, acute kidney injury, oxidative stress, and inflammatory response. More attention has been paid to long noncoding RNA (lncRNA) and exosomes, with much exploration having been conducted in these areas. Conclusions Although miRNA is involved in the occurrence and development of IR, as a clinical intervention target for IR, further research is still needed.
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Affiliation(s)
- Yang-Li He
- Center of Geriatrics, Hainan Clinical Research Center for Cardiovascular Disease, Hainan General Hospital/Hainan Affiliated Hospital of Hainan Medical University, Haikou, China
| | - Ya-Li Yang
- Center of Geriatrics, Hainan Clinical Research Center for Cardiovascular Disease, Hainan General Hospital/Hainan Affiliated Hospital of Hainan Medical University, Haikou, China
| | - Wen-Xing Xu
- Center of Geriatrics, Hainan Clinical Research Center for Cardiovascular Disease, Hainan General Hospital/Hainan Affiliated Hospital of Hainan Medical University, Haikou, China
| | - Tuan-Yu Fang
- Department of Endocrinology, Hainan General Hospital/Hainan Affiliated Hospital of Hainan Medical University, Haikou, China
| | - Min Zeng
- Center of Geriatrics, Hainan Clinical Research Center for Cardiovascular Disease, Hainan General Hospital/Hainan Affiliated Hospital of Hainan Medical University, Haikou, China
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24
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Chen YL, Li HK, Wang L, Chen JW, Ma X. No safe renal warm ischemia time-The molecular network characteristics and pathological features of mild to severe ischemia reperfusion kidney injury. Front Mol Biosci 2022; 9:1006917. [PMID: 36465563 PMCID: PMC9709142 DOI: 10.3389/fmolb.2022.1006917] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2022] [Accepted: 11/03/2022] [Indexed: 07/25/2023] Open
Abstract
Ischemic acute kidney injury (AKI) has always been a hot and difficult research topic in the field of renal diseases. This study aims to illustrate the safe warm ischemia time of kidney and the molecular network characteristics and pathological features of mild to severe ischemia reperfusion kidney injury. We established varying degrees of renal injury due to different ischemia time (0 min, 16 min, 18 min, 20 min, 22 min, 24 min, 26 min, 28 min, and 30 min) on unilateral (left kidney) ischemia-reperfusion injury and contralateral (right kidney) resection (uIRIx) mouse model. Mice were sacrificed 24 h after uIRIx, blood samples were harvested to detect serum creatinine (Scr), and kidney tissue samples were harvested to perform Periodic Acid-Schiff (PAS) staining and RNA-Seq. Differentially expressed genes (DEGs) were identificated, time-dependent gene expression patterns and functional enrichment analysis were further performed. Finally, qPCR was performed to validated RNA-Seq results. Our results indicated that there was no absolute safe renal warm ischemia time, and every minute of ischemia increases kidney damage. Warm ischemia 26min or above in mice makes severe kidney injury, renal pathology and SCr were both significantly changed. Warm ischemia between 18 and 26 min makes mild kidney injury, with changes in pathology and renal molecular expression, while SCr did not change. No obvious pathological changes but significant differences in molecular expression were found less than 16min warm ischemia. There are two key time intervals in the process of renal ischemia injury, 0 min-16 min (short-term) and 26 min-28 min (long-term). Gene expression of immune-related pathways were most significantly down-regulated in short-term ischemia, while metabolism-related pathways were the mainly enriched pathway in long-term ischemia. Taken together, this study provides novel insights into safe renal artery occlusion time in partial nephrectomy, and is of great value for elucidating molecular network characteristics and pathological features of mild to severe ischemia reperfusion kidney injury, and key genes related to metabolism and immune found in this study also provide potential diagnostic and therapeutic biomarkers for AKI.
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Affiliation(s)
- Ya-Lei Chen
- Department of Critical Care Medicine, Capital Medical University Electric Power Teaching Hospital/State Grid Beijing Electric Power Hospital, Beijing, China
| | - Huai-Kang Li
- Senior Department of Urology, The Third Medical Centre of PLA General Hospital, Beijing, China
| | - Lei Wang
- Senior Department of Urology, The Third Medical Centre of PLA General Hospital, Beijing, China
| | - Jian-Wen Chen
- Senior Department of Urology, The Third Medical Centre of PLA General Hospital, Beijing, China
- Department of Nephrology, State Key Laboratory of Kidney Diseases, Beijing Key Laboratory of Kidney Disease Research, First Medical Center of Chinese PLA General Hospital, Nephrology Institute of the Chinese People’s Liberation Army, National Clinical Research Center for Kidney Diseases, Beijing, China
| | - Xin Ma
- Senior Department of Urology, The Third Medical Centre of PLA General Hospital, Beijing, China
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25
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Larrue R, Fellah S, Van der Hauwaert C, Hennino MF, Perrais M, Lionet A, Glowacki F, Pottier N, Cauffiez C. The Versatile Role of miR-21 in Renal Homeostasis and Diseases. Cells 2022; 11:cells11213525. [PMID: 36359921 PMCID: PMC9657972 DOI: 10.3390/cells11213525] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2022] [Revised: 11/03/2022] [Accepted: 11/04/2022] [Indexed: 11/09/2022] Open
Abstract
MicroRNAs (miRNAs) are small, non-coding RNA species that control gene expression and confer robustness to biological processes. Over the last two decades, their important roles during kidney development, homeostasis and the treatment of diseases have been established, in particular during the onset and progression of various forms of acute and chronic renal disorders. In recent years, miR-21, one of the best-characterized miRNAs to date, has received much attention in renal physiology in particular given its high degree of conservation and expression in kidneys, as well as its potent pathogenic role in various debilitating renal diseases. This review summarizes the current knowledge on miR-21’s involvement in both renal homeostasis and diseases, in particular its double-edged-sword role in acute versus chronic kidney injuries. Finally, we also discuss the potential of miR-21 as a biomarker and therapeutic target in renal diseases.
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Affiliation(s)
- Romain Larrue
- Univ. Lille, CNRS, Inserm, CHU Lille, UMR9020-U1277—CANTHER—Cancer Heterogeneity Plasticity and Resistance to Therapies, F-59000 Lille, France
| | - Sandy Fellah
- Univ. Lille, CNRS, Inserm, CHU Lille, UMR9020-U1277—CANTHER—Cancer Heterogeneity Plasticity and Resistance to Therapies, F-59000 Lille, France
| | - Cynthia Van der Hauwaert
- Univ. Lille, CNRS, Inserm, CHU Lille, UMR9020-U1277—CANTHER—Cancer Heterogeneity Plasticity and Resistance to Therapies, F-59000 Lille, France
- CHU Lille, Département de la Recherche en Santé, F-59000 Lille, France
| | | | - Michaël Perrais
- Univ. Lille, CNRS, Inserm, CHU Lille, UMR9020-U1277—CANTHER—Cancer Heterogeneity Plasticity and Resistance to Therapies, F-59000 Lille, France
| | - Arnaud Lionet
- CHU Lille, Service de Néphrologie, F-59000 Lille, France
| | - François Glowacki
- Univ. Lille, CNRS, Inserm, CHU Lille, UMR9020-U1277—CANTHER—Cancer Heterogeneity Plasticity and Resistance to Therapies, F-59000 Lille, France
- CHU Lille, Service de Néphrologie, F-59000 Lille, France
| | - Nicolas Pottier
- Univ. Lille, CNRS, Inserm, CHU Lille, UMR9020-U1277—CANTHER—Cancer Heterogeneity Plasticity and Resistance to Therapies, F-59000 Lille, France
| | - Christelle Cauffiez
- Univ. Lille, CNRS, Inserm, CHU Lille, UMR9020-U1277—CANTHER—Cancer Heterogeneity Plasticity and Resistance to Therapies, F-59000 Lille, France
- Correspondence:
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26
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Chen YJ, Hsu CT, Tsai SF, Chen CH. Association between Circulating MicroRNAs (miR-21-5p, miR-20a-5p, miR-29b-3p, miR-126-3p and miR-101-3p) and Chronic Allograft Dysfunction in Renal Transplant Recipients. Int J Mol Sci 2022; 23:ijms232012253. [PMID: 36293110 PMCID: PMC9603156 DOI: 10.3390/ijms232012253] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2022] [Revised: 09/30/2022] [Accepted: 10/12/2022] [Indexed: 01/24/2023] Open
Abstract
Chronic allograft dysfunction (CAD) is a major condition affecting long-term kidney graft survival. Serum microRNA (miRNA) has been reported as a biomarker for various conditions of allograft injuries. The upregulation of miR-21 is the best-known miRNA change in graft tissue, urine and plasma. However, the correlation of plasma miR-21 with the severity of CAD remains unclear. In our study, 40 kidney transplantation recipients with late graft survival for more than 10 years were enrolled. The CAD group (n = 20) had either an eGFR between 15 to 60 mL/min or a biopsy-proved chronic allograft nephropathy or rejection. The control group (n = 20) had an eGFR ≥ 60 mL/min without proteinuria and hematuria for a consecutive 3 months before the study. We performed RNA sequencing to profile the miRNAs expression. There were six differentially expressed miRNAs in the CAD group. Among them, miR-21-5p and miR-101-3p were decreased, and miR-20a-5p was increased. We found that miR-21-5p, miR-20a-5p and miR-101-3p all participated in the TGF-beta pathway. We demonstrated that decreased miR-21-5p and miR-101-3p, and increased miR-20a-5p were the novel CAD-associated miRNAs in the TGF-beta pathway. These findings may pave the way for developing early prediction miRNAs biomarkers for CAD, and possibly developing therapeutic tools in the field of kidney transplantation.
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Affiliation(s)
- Yu-Jen Chen
- Division of Nephrology, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung 407219, Taiwan
| | - Chia-Tien Hsu
- Division of Nephrology, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung 407219, Taiwan
| | - Shang-Feng Tsai
- Division of Nephrology, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung 407219, Taiwan
- Department of Life Science, Tunghai University, Taichung 407224, Taiwan
- Department of Post-Baccalaureate Medicine, College of Medicine, National Chung Hsing University, Taichung 40227, Taiwan
| | - Cheng-Hsu Chen
- Division of Nephrology, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung 407219, Taiwan
- Department of Life Science, Tunghai University, Taichung 407224, Taiwan
- Department of Post-Baccalaureate Medicine, College of Medicine, National Chung Hsing University, Taichung 40227, Taiwan
- School of Medicine, China Medical University, Taichung 651012, Taiwan
- Correspondence: ; Tel.: +886-4-23592525 (ext. 3040)
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27
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Seyahi NS, Ozcan SG. Application of New Acute Kidney Injury Biomarkers. Biomark Med 2022. [DOI: 10.2174/9789815040463122010021] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
Kidney-related biomarkers can provide structural and functional information
about different parts of the nephron. These biomarkers can be used to evaluate
glomerular, tubular, or interstitial injury, inflammation, or repair, and glomerular or
tubular function. Furthermore, biomarkers can improve the acute kidney injury
diagnosis in various clinical conditions, including acute interstitial nephritis, acute
tubular injury, hepatorenal and cardiorenal syndrome, ischemic and nephrotoxic acute
kidney injury, and drug-induced acute kidney injury. Biomarkers might be used as an
additional precision medicine tool in managing patients with acute kidney injury; they
can help with clinical decision-making and impact patient outcomes. In this chapter, we
reviewed the utility of biomarkers used in acute kidney injury.
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Affiliation(s)
- Nurhan Seyahi Seyahi
- Department of Nephrology, Cerrahpasa Medical Faculty, Istanbul University - Cerrahpasa,
Istanbul, Turkey
| | - Seyda Gul Ozcan
- Department of Internal Medicine, Cerrahpasa Medical Faculty, Istanbul University -
Cerrahpasa, Istanbul, Turkey
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28
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Protective Effects of PPARγ on Renal Ischemia-Reperfusion Injury by Regulating miR-21. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2022; 2022:7142314. [PMID: 36082081 PMCID: PMC9448582 DOI: 10.1155/2022/7142314] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/17/2022] [Accepted: 08/17/2022] [Indexed: 11/17/2022]
Abstract
Renal ischemia-reperfusion injury (RIRI) is a common pathological process that causes kidney injury. Previous studies have indicated that both peroxisome proliferator-activated receptor γ (PPARγ) and microRNA-21 (miR-21) exert protective effects against RIRI. However, their relationship is not well understood. In the present study, we investigated the role of the PPARγ/miR-21/programmed cell death 4 (PDCD4) axis in IRI, both in vivo and in vitro. In vitro cell hypoxia/reoxygenation (H/R) and in vivo RIRI models were established, and cell viability, cell apoptosis, and key molecule expression profiles were analyzed. Our results showed that both PPARγ and miR-21 had protective effects against RIRI to varying degrees, and there was an interaction between PPARγ and miR-21. PPARγ could promote the expression of miR-21 and partially protect against RIRI by reducing the level of the miR-21 target protein (PDCD4). Our findings underscore the potential utility of future clinical investigations of PPARγ activation and targeting of the underlying miR-21/PDCD4/caspase-3 pathway, which may participate in the pathogenesis of human IRI.
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29
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Mahtal N, Lenoir O, Tinel C, Anglicheau D, Tharaux PL. MicroRNAs in kidney injury and disease. Nat Rev Nephrol 2022; 18:643-662. [PMID: 35974169 DOI: 10.1038/s41581-022-00608-6] [Citation(s) in RCA: 100] [Impact Index Per Article: 33.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/11/2022] [Indexed: 11/09/2022]
Abstract
MicroRNAs (miRNAs) are small non-coding RNAs that regulate gene expression by degrading or repressing the translation of their target messenger RNAs. As miRNAs are critical regulators of cellular homeostasis, their dysregulation is a crucial component of cell and organ injury. A substantial body of evidence indicates that miRNAs are involved in the pathophysiology of acute kidney injury (AKI), chronic kidney disease and allograft damage. Different subsets of miRNAs are dysregulated during AKI, chronic kidney disease and allograft rejection, which could reflect differences in the physiopathology of these conditions. miRNAs that have been investigated in AKI include miR-21, which has an anti-apoptotic role, and miR-214 and miR-668, which regulate mitochondrial dynamics. Various miRNAs are downregulated in diabetic kidney disease, including the miR-30 family and miR-146a, which protect against inflammation and fibrosis. Other miRNAs such as miR-193 and miR-92a induce podocyte dedifferentiation in glomerulonephritis. In transplantation, miRNAs have been implicated in allograft rejection and injury. Further work is needed to identify and validate miRNAs as biomarkers of graft function and of kidney disease development and progression. Use of combinations of miRNAs together with other molecular markers could potentially improve diagnostic or predictive power and facilitate clinical translation. In addition, targeting specific miRNAs at different stages of disease could be a promising therapeutic strategy.
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Affiliation(s)
- Nassim Mahtal
- Paris Cardiovascular Research Center - PARCC, Inserm, Université Paris Cité, Paris, France
| | - Olivia Lenoir
- Paris Cardiovascular Research Center - PARCC, Inserm, Université Paris Cité, Paris, France.
| | - Claire Tinel
- Service de Néphrologie et Transplantation Adulte, Hôpital Necker-Enfants Malades, Université Paris Cité, Assistance Publique-Hôpitaux de Paris, Paris, France.,Institut Necker-Enfants Malades, Inserm, Université Paris Cité, Paris, France
| | - Dany Anglicheau
- Service de Néphrologie et Transplantation Adulte, Hôpital Necker-Enfants Malades, Université Paris Cité, Assistance Publique-Hôpitaux de Paris, Paris, France.,Institut Necker-Enfants Malades, Inserm, Université Paris Cité, Paris, France
| | - Pierre-Louis Tharaux
- Paris Cardiovascular Research Center - PARCC, Inserm, Université Paris Cité, Paris, France.
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30
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Fu Q, Yu W, Fu S, Xu Z, Zhang S. MicroRNA-449c-5p alleviates lipopolysaccharide-induced HUVECs injury via inhibiting the activation NF-κb signaling pathway by TAK1. Mol Immunol 2022; 146:18-26. [DOI: 10.1016/j.molimm.2022.03.123] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2021] [Revised: 11/23/2021] [Accepted: 03/27/2022] [Indexed: 12/01/2022]
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31
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Chen Y, He Y, Zhao S, He X, Xue D, Xia Y. Hypoxic/Ischemic Inflammation, MicroRNAs and δ-Opioid Receptors: Hypoxia/Ischemia-Sensitive Versus-Insensitive Organs. Front Aging Neurosci 2022; 14:847374. [PMID: 35615595 PMCID: PMC9124822 DOI: 10.3389/fnagi.2022.847374] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2022] [Accepted: 03/21/2022] [Indexed: 11/15/2022] Open
Abstract
Hypoxia and ischemia cause inflammatory injury and critically participate in the pathogenesis of various diseases in various organs. However, the protective strategies against hypoxic and ischemic insults are very limited in clinical settings up to date. It is of utmost importance to improve our understanding of hypoxic/ischemic (H/I) inflammation and find novel therapies for better prevention/treatment of H/I injury. Recent studies provide strong evidence that the expression of microRNAs (miRNAs), which regulate gene expression and affect H/I inflammation through post-transcriptional mechanisms, are differentially altered in response to H/I stress, while δ-opioid receptors (DOR) play a protective role against H/I insults in different organs, including both H/I-sensitive organs (e.g., brain, kidney, and heart) and H/I-insensitive organs (e.g., liver and muscle). Indeed, many studies have demonstrated the crucial role of the DOR-mediated cyto-protection against H/I injury by several molecular pathways, including NLRP3 inflammasome modulated by miRNAs. In this review, we summarize our recent studies along with those of others worldwide, and compare the effects of DOR on H/I expression of miRNAs in H/I-sensitive and -insensitive organs. The alternation in miRNA expression profiles upon DOR activation and the potential impact on inflammatory injury in different organs under normoxic and hypoxic conditions are discussed at molecular and cellular levels. More in-depth investigations into this field may provide novel clues for new protective strategies against H/I inflammation in different types of organs.
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Affiliation(s)
- Yimeng Chen
- Department of Urology, The Third Affiliated Hospital of Soochow University, Changzhou, China
| | - Yichen He
- Department of Urology, The Third Affiliated Hospital of Soochow University, Changzhou, China
| | - Shuchen Zhao
- Department of Urology, The Third Affiliated Hospital of Soochow University, Changzhou, China
| | - Xiaozhou He
- Department of Urology, The Third Affiliated Hospital of Soochow University, Changzhou, China
| | - Dong Xue
- Department of Urology, The Third Affiliated Hospital of Soochow University, Changzhou, China
- *Correspondence: Dong Xue,
| | - Ying Xia
- Shanghai Key Laboratory of Acupuncture Mechanism and Acupoint Function, Fudan University, Shanghai, China
- Ying Xia,
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Zaman A, Banday AA. Angiotensin1-7 Protects Against Renal Ischemia-Reperfusion Injury via Regulating the Expression of NRF2 and microRNAs in Fisher 344 Rats. Am J Physiol Renal Physiol 2022; 323:F33-F47. [PMID: 35532070 DOI: 10.1152/ajprenal.00283.2021] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
Ischemia/reperfusion (I/R) is considered the primary cause of acute kidney injury and is higher among older individuals. While ischemic episodes are hard to predict and prevent, detrimental ischemic effects could be mitigated by exogenous intervention. This study aims to identify the protective role of angiotensin (ANG)1-7 against I/R-induced renal injury in adult vs. aged rats. Adult and aged male Fisher 344 rats were subjected to 40-minute bilateral renal ischemia followed by 28-days reperfusion. ANG1-7 was administered intraperitoneally in ischemic rats for 28 days without or with Mas receptor antagonist A779. I/R increased blood pressure, plasma creatinine, urinary 8-isoprostane, and renal infiltration of pro and anti-inflammatory macrophages and reduced glomerular filtration rate in both adult and aged rats compared to shams. In addition to causing glomerular sclerosis and tubular damage, I/R increased the expression of pathogenic microRNAs (miRNAs): miR-20a-5p, miR-21-5p, miR-24-3p, and miR-194-5p in both the age groups. ANG1-7 treatment of ischemic rats mitigated oxidative stress and renal inflammation, restored renal structure and function, and reduced high blood pressure. Also, ANG1-7 suppressed the expression of pathogenic miRNAs. In addition, ANG1-7 treatment of I/R rats increased the expression of redox-sensitive transcription factor NRF2 and phase II antioxidant enzymes. The beneficial effects of ANG1-7 were sensitive to A779. Collectively, these data suggest that ANG1-7 associated with NRF2 activation could alleviate post-I/R-induced kidney injury and therefore serve as a potential therapeutic compound to protect against biochemical and morphological pathologies of I/R in both adults and aged populations.
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Affiliation(s)
- Asif Zaman
- Heart and Kidney Institute, College of Pharmacy, University of Houston, Houston, Texas, United States
| | - Anees Ahmad Banday
- Heart and Kidney Institute, College of Pharmacy, University of Houston, Houston, Texas, United States
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Rutman AK, Negi S, Saberi N, Khan K, Tchervenkov J, Paraskevas S. Extracellular Vesicles From Kidney Allografts Express miR-218-5p and Alter Th17/Treg Ratios. Front Immunol 2022; 13:784374. [PMID: 35281056 PMCID: PMC8906931 DOI: 10.3389/fimmu.2022.784374] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2021] [Accepted: 02/03/2022] [Indexed: 01/18/2023] Open
Abstract
Delayed graft function (DGF) in kidney transplantation is associated with ischemic injury and carries long term functional and immunological risks. Extracellular vesicles (EV) released from allografts may signal a degree of ischemic stress, and are thought to play an important role in the development of anti-donor immunity. Here, we show that kidney perfusate-derived extracellular vesicles (KP-EV) express donor-specific human leukocyte antigen. KP-EV from kidneys that experience DGF increase the T-helper 17 (Th17) to T-regulatory (Treg) ratio in third party peripheral blood mononuclear cells to a greater degree than those from kidneys with immediate function. We report miR-218-5p upregulation in KP-EV of kidney transplant recipients with DGF. Levels of miR-218-5p in KP-EV inversely correlated with recipient eGFR at multiple time points following transplantation. Additionally, the degree of increase in Th17/Treg ratio by KP-EV positively correlated with miR-218-5p expression in KP-EV samples. Taken together, these data provide evidence that KP-EV may contribute to modulating immune responses in transplant recipients. This could lead to novel intervention strategies to inhibit DGF in order to improve graft function and survival.
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Affiliation(s)
- Alissa K Rutman
- Department of Surgery, McGill University, Montréal, QC, Canada.,Transplantation Immunology Laboratory, Research Institute of the McGill University Health Centre, Montréal, QC, Canada
| | - Sarita Negi
- Department of Surgery, McGill University, Montréal, QC, Canada.,Transplantation Immunology Laboratory, Research Institute of the McGill University Health Centre, Montréal, QC, Canada
| | - Nasim Saberi
- Department of Surgery, McGill University, Montréal, QC, Canada
| | - Kashif Khan
- Division of Cardiology and Cardiac Surgery, McGill University Health Centre, Montréal, QC, Canada
| | - Jean Tchervenkov
- Department of Surgery, McGill University, Montréal, QC, Canada.,Transplantation Immunology Laboratory, Research Institute of the McGill University Health Centre, Montréal, QC, Canada
| | - Steven Paraskevas
- Department of Surgery, McGill University, Montréal, QC, Canada.,Transplantation Immunology Laboratory, Research Institute of the McGill University Health Centre, Montréal, QC, Canada
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Lim SW, Kim KW, Kim BM, Shin YJ, Luo K, Quan Y, Cui S, Ko EJ, Chung BH, Yang CW. Alleviation of renal ischemia/reperfusion injury by exosomes from induced pluripotent stem cell-derived mesenchymal stem cells. Korean J Intern Med 2022; 37:411-424. [PMID: 34521186 PMCID: PMC8925954 DOI: 10.3904/kjim.2020.438] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/19/2020] [Accepted: 11/20/2020] [Indexed: 11/27/2022] Open
Abstract
BACKGROUND/AIMS Renal ischemia followed by reperfusion (I/R) is a leading cause of acute kidney injury (AKI), which is closely associated with high morbidity and mortality. Studies have shown that induced pluripotent stem cell (iPSC)-derived mesenchymal stem cells (iMSCs) exert powerful therapeutic effects in renal ischemia. However, the efficacy of iMSC-derived exosomes (iExo) on I/R injuries remains largely unknown. METHODS Human iPSCs were differentiated into iMSCs using a modified one-step method. Ultrafiltration, combined with purification, was used to isolate iExo from iMSCs. iExo was administered following I/R injury in a mouse model. The effect of iExo on I/R injury was assessed through changes in renal function, histology, and expression of oxidative stress, inflammation, and apoptosis markers. Further, we evaluated its association with the extracellular signal-regulated kinase (ERK) 1/2 signaling pathway. RESULTS Mice subjected to I/R injury exhibited typical AKI patterns; serum creatinine level, tubular necrosis, apoptosis, inflammatory cytokine production, and oxidative stress were markedly increased compared to sham mice. However, treatment with iExo attenuated these changes, significantly improving renal function and tissue damage, similar to the renoprotective effects of iMSCs on I/R injury. Significant induction of activated ERK 1/2 signaling molecules was observed in mice treated with iExo compared to those in the I/R injury group. CONCLUSION The present study demonstrates that iExo administration ameliorated renal damage following I/R, suggesting that iMSC-derived exosomes may provide a novel therapeutic approach for AKI treatment.
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Affiliation(s)
- Sun Woo Lim
- Transplant Research Center, College of Medicine, The Catholic University of Korea, Seoul, Korea
- Convergent Research Consortium for Immunologic disease, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Kyung Woon Kim
- Convergent Research Consortium for Immunologic disease, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea
- R&D Center, OncoInsight Co. Ltd., Seoul, Korea
| | - Bo Mi Kim
- Convergent Research Consortium for Immunologic disease, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Yoo Jin Shin
- Transplant Research Center, College of Medicine, The Catholic University of Korea, Seoul, Korea
- Convergent Research Consortium for Immunologic disease, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Kang Luo
- Transplant Research Center, College of Medicine, The Catholic University of Korea, Seoul, Korea
- Convergent Research Consortium for Immunologic disease, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Yi Quan
- Transplant Research Center, College of Medicine, The Catholic University of Korea, Seoul, Korea
- Convergent Research Consortium for Immunologic disease, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Sheng Cui
- Transplant Research Center, College of Medicine, The Catholic University of Korea, Seoul, Korea
- Convergent Research Consortium for Immunologic disease, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Eun Jeong Ko
- Transplant Research Center, College of Medicine, The Catholic University of Korea, Seoul, Korea
- Convergent Research Consortium for Immunologic disease, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea
- Division of Nephrology, Department of Internal Medicine, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Byung Ha Chung
- Transplant Research Center, College of Medicine, The Catholic University of Korea, Seoul, Korea
- Convergent Research Consortium for Immunologic disease, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea
- Division of Nephrology, Department of Internal Medicine, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Chul Woo Yang
- Transplant Research Center, College of Medicine, The Catholic University of Korea, Seoul, Korea
- Convergent Research Consortium for Immunologic disease, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea
- Division of Nephrology, Department of Internal Medicine, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea
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Rubel D, Boulanger J, Craciun F, Xu EY, Zhang Y, Phillips L, Callahan M, Weber W, Song W, Ngai N, Bukanov NO, Shi X, Hariri A, Husson H, Ibraghimov-Beskrovnaya O, Liu S, Gross O. Anti-microRNA-21 Therapy on Top of ACE Inhibition Delays Renal Failure in Alport Syndrome Mouse Models. Cells 2022; 11:cells11040594. [PMID: 35203245 PMCID: PMC8869926 DOI: 10.3390/cells11040594] [Citation(s) in RCA: 30] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2021] [Revised: 01/28/2022] [Accepted: 02/03/2022] [Indexed: 02/01/2023] Open
Abstract
Col4a3−/− Alport mice serve as an animal model for renal fibrosis. MicroRNA-21 (miR-21) expression has been shown to be increased in the kidneys of Alport syndrome patients. Here, we investigated the nephroprotective effects of Lademirsen anti-miR-21 therapy. We used a fast-progressing Col4a3−/− mouse model with a 129/SvJ background and an intermediate-progressing F1 hybrid mouse model with a mixed genetic background, with angiotensin-converting enzyme inhibitor (ACEi) monotherapy in combination with anti-miR-21 therapy. In the fast-progressing model, the anti miR-21 and ACEi therapies showed an additive effect in the reduction in fibrosis, the decline of proteinuria, the preservation of kidney function and increased survival. In the intermediate-progressing F1 model, the anti-miR-21 and ACEi therapies individually improved kidney pathology. Both also improved kidney function and survival; however, the combination showed a significant additive effect, particularly for survival. RNA sequencing (RNA-seq) gene expression profiling revealed that the anti-miR-21 and ACEi therapies modulate several common pathways. However, anti-miR-21 was particularly effective at normalizing the expression profiles of the genes involved in renal tubulointerstitial injury pathways. In conclusion, significant additive effects were detected for the combination of anti-miR-21 and ACEi therapies on kidney function, pathology and survival in Alport mouse models, as well as a strong differential effect of anti-miR-21 on the renal expression of fibrotic factors. These results support the addition of anti-miR-21 to the current standard of care (ACEi) in ongoing clinical trials in patients with Alport syndrome.
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Affiliation(s)
- Diana Rubel
- Clinic for Nephrology and Rheumatology, University Medical Center Goettingen, 37075 Goettingen, Germany; (D.R.); (Y.Z.)
| | | | - Florin Craciun
- Sanofi-Genzyme Research and Development, Framingham, MA 02118, USA; (F.C.); (E.Y.X.); (L.P.); (M.C.); (W.W.); (W.S.); (N.N.); (N.O.B.); (X.S.); (H.H.); (O.I.-B.)
| | - Ethan Y. Xu
- Sanofi-Genzyme Research and Development, Framingham, MA 02118, USA; (F.C.); (E.Y.X.); (L.P.); (M.C.); (W.W.); (W.S.); (N.N.); (N.O.B.); (X.S.); (H.H.); (O.I.-B.)
- Excision BioTherapeutics, San Francisco, CA 94111, USA
| | - Yanqin Zhang
- Clinic for Nephrology and Rheumatology, University Medical Center Goettingen, 37075 Goettingen, Germany; (D.R.); (Y.Z.)
- Department of Pediatrics, Peking University First Hospital, Beijing 100034, China
| | - Lucy Phillips
- Sanofi-Genzyme Research and Development, Framingham, MA 02118, USA; (F.C.); (E.Y.X.); (L.P.); (M.C.); (W.W.); (W.S.); (N.N.); (N.O.B.); (X.S.); (H.H.); (O.I.-B.)
- Abbvie Bioresearch Center, Worcester, MA 01605, USA
| | - Michelle Callahan
- Sanofi-Genzyme Research and Development, Framingham, MA 02118, USA; (F.C.); (E.Y.X.); (L.P.); (M.C.); (W.W.); (W.S.); (N.N.); (N.O.B.); (X.S.); (H.H.); (O.I.-B.)
| | - William Weber
- Sanofi-Genzyme Research and Development, Framingham, MA 02118, USA; (F.C.); (E.Y.X.); (L.P.); (M.C.); (W.W.); (W.S.); (N.N.); (N.O.B.); (X.S.); (H.H.); (O.I.-B.)
- Takeda Pharmaceuticals, Cambridge, MA 02139, USA
| | - Wenping Song
- Sanofi-Genzyme Research and Development, Framingham, MA 02118, USA; (F.C.); (E.Y.X.); (L.P.); (M.C.); (W.W.); (W.S.); (N.N.); (N.O.B.); (X.S.); (H.H.); (O.I.-B.)
| | - Nicholas Ngai
- Sanofi-Genzyme Research and Development, Framingham, MA 02118, USA; (F.C.); (E.Y.X.); (L.P.); (M.C.); (W.W.); (W.S.); (N.N.); (N.O.B.); (X.S.); (H.H.); (O.I.-B.)
| | - Nikolay O. Bukanov
- Sanofi-Genzyme Research and Development, Framingham, MA 02118, USA; (F.C.); (E.Y.X.); (L.P.); (M.C.); (W.W.); (W.S.); (N.N.); (N.O.B.); (X.S.); (H.H.); (O.I.-B.)
- Janssen Pharmaceuticals, Boston, MA 02115, USA
| | - Xingyi Shi
- Sanofi-Genzyme Research and Development, Framingham, MA 02118, USA; (F.C.); (E.Y.X.); (L.P.); (M.C.); (W.W.); (W.S.); (N.N.); (N.O.B.); (X.S.); (H.H.); (O.I.-B.)
- Novartis Institute for BioMedical Research, Boston, MA 02139, USA
| | - Ali Hariri
- Sanofi-Genzyme, Clinical Development, Cambridge, MA 02142, USA; (A.H.); (S.L.)
- Eloxx Pharmaceuticals, Watertown, MA 02140, USA
| | - Hervé Husson
- Sanofi-Genzyme Research and Development, Framingham, MA 02118, USA; (F.C.); (E.Y.X.); (L.P.); (M.C.); (W.W.); (W.S.); (N.N.); (N.O.B.); (X.S.); (H.H.); (O.I.-B.)
| | - Oxana Ibraghimov-Beskrovnaya
- Sanofi-Genzyme Research and Development, Framingham, MA 02118, USA; (F.C.); (E.Y.X.); (L.P.); (M.C.); (W.W.); (W.S.); (N.N.); (N.O.B.); (X.S.); (H.H.); (O.I.-B.)
- Dyne Therapeutics, Waltham, MA 02451, USA
| | - Shiguang Liu
- Sanofi-Genzyme, Clinical Development, Cambridge, MA 02142, USA; (A.H.); (S.L.)
| | - Oliver Gross
- Clinic for Nephrology and Rheumatology, University Medical Center Goettingen, 37075 Goettingen, Germany; (D.R.); (Y.Z.)
- Correspondence: ; Tel.: +49-551-39-60488
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Abstract
Almost 200 years ago, the first evidence described by Robert Bright (1836) showed the strong interaction between the kidneys and heart and, since then, the scientific community has dedicated itself to better understanding the mechanisms involved in the kidney-heart relationship, known in recent decades as cardiorenal syndrome (CRS). This syndrome includes a wide clinical variety that affects the kidneys and heart, in an acute or chronic manner. Moreover, it is well established in the literature that the immune system, the sympathetic nervous system, the renin-angiotensin-aldosterone, and the oxidative stress actively play a strong role in the cellular and molecular processes present in CRS. More recently, uremic molecules and epigenetic factors have been also shown to be key mediators in the development of syndrome. The present review intends to present the state of the art regarding CRS and to show the paths known, until now, in the long road between the kidneys and heart.
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Li J, Ma L, Yu H, Yao Y, Xu Z, Lin W, Wang L, Wang X, Yang H. MicroRNAs as Potential Biomarkers for the Diagnosis of Chronic Kidney Disease: A Systematic Review and Meta-Analysis. Front Med (Lausanne) 2022; 8:782561. [PMID: 35198569 PMCID: PMC8860181 DOI: 10.3389/fmed.2021.782561] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2021] [Accepted: 12/29/2021] [Indexed: 12/19/2022] Open
Abstract
For Chronic Kidney Disease (CKD), the study of microRNA as a biomarker has become an exciting area, so we carried out a meta-analysis to investigate the potential diagnostic values of miRNAs in CKD. We searched Pubmed, Cochrane Library, Embase, and Web of science databases to identify relevant publications published from the establishment of the database to April 30, 2021. We included a total of 26 articles containing 56 studies. There were 4,098 patients with CKD and 2,450 patients without CKD. We found that the overall sensitivity and specificity of miRNAs in CKD diagnosis were 0.86 (95% CI: 0.83–0.89) and 0.79 (95% CI: 0.75–0.83), respectively. In addition, we plotted the summary receiver operator characteristic (SROC) curve to assess diagnostic accuracy, with the area under the curve (AUC) of 0.90 (95% CI: 0.87–0.92). Subgroup analysis showed that sensitivity, specificity, and AUC of miRNAs in plasma and serum were 0.84, 0.78, 0.88; and 0.79, 0.76, 0.83, respectively, while miRNAs in urine were 0.89 for sensitivity, 0.82 for specificity, and 0.92 for AUC. Moreover, we found that the panel of microRNAs (miRNAs) could improve the pooled sensitivity (0.88, 0.81, and 0.91 for sensitivity, specificity, and AUC, respectively). We believe that miRNAs have great potential to become an effective diagnostic biomarker for CKD. Panels of miRNA have higher accuracy than single miRNAs. Additionally, miRNAs in both blood and urine have significant accuracy in the diagnosis of CKD; nevertheless, urine is superior.
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de Godoy Torso N, Pereira JKN, Visacri MB, Vasconcelos PENS, Loren P, Saavedra K, Saavedra N, Salazar LA, Moriel P. Dysregulated MicroRNAs as Biomarkers or Therapeutic Targets in Cisplatin-Induced Nephrotoxicity: A Systematic Review. Int J Mol Sci 2021; 22:12765. [PMID: 34884570 PMCID: PMC8657822 DOI: 10.3390/ijms222312765] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2021] [Revised: 10/07/2021] [Accepted: 10/15/2021] [Indexed: 12/14/2022] Open
Abstract
The purpose of this systematic review was to map out and summarize scientific evidence on dysregulated microRNAs (miRNAs) that can be possible biomarkers or therapeutic targets for cisplatin nephrotoxicity and have already been tested in humans, animals, or cells. In addition, an in silico analysis of the two miRNAs found to be dysregulated in the majority of studies was performed. A literature search was performed using eight databases for studies published up to 4 July 2021. Two independent reviewers selected the studies and extracted the data; disagreements were resolved by a third and fourth reviewers. A total of 1002 records were identified, of which 30 met the eligibility criteria. All studies were published in English and reported between 2010 and 2021. The main findings were as follows: (a) miR-34a and miR-21 were the main miRNAs identified by the studies as possible biomarkers and therapeutic targets of cisplatin nephrotoxicity; (b) the in silico analysis revealed 124 and 131 different strongly validated targets for miR-34a and miR-21, respectively; and (c) studies in humans remain scarce.
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Affiliation(s)
- Nadine de Godoy Torso
- School of Medical Sciences, University of Campinas, Campinas 13083894, Brazil; (N.d.G.T.); (J.K.N.P.); (M.B.V.); (P.E.N.S.V.)
| | - João Kleber Novais Pereira
- School of Medical Sciences, University of Campinas, Campinas 13083894, Brazil; (N.d.G.T.); (J.K.N.P.); (M.B.V.); (P.E.N.S.V.)
| | - Marília Berlofa Visacri
- School of Medical Sciences, University of Campinas, Campinas 13083894, Brazil; (N.d.G.T.); (J.K.N.P.); (M.B.V.); (P.E.N.S.V.)
| | | | - Pía Loren
- Center of Molecular Biology and Pharmacogenetics, Scientific and Technological Bioresource Nucleus, Universidad de La Frontera, Temuco 4811230, Chile; (P.L.); (K.S.); (N.S.); (L.A.S.)
| | - Kathleen Saavedra
- Center of Molecular Biology and Pharmacogenetics, Scientific and Technological Bioresource Nucleus, Universidad de La Frontera, Temuco 4811230, Chile; (P.L.); (K.S.); (N.S.); (L.A.S.)
| | - Nicolás Saavedra
- Center of Molecular Biology and Pharmacogenetics, Scientific and Technological Bioresource Nucleus, Universidad de La Frontera, Temuco 4811230, Chile; (P.L.); (K.S.); (N.S.); (L.A.S.)
| | - Luis A. Salazar
- Center of Molecular Biology and Pharmacogenetics, Scientific and Technological Bioresource Nucleus, Universidad de La Frontera, Temuco 4811230, Chile; (P.L.); (K.S.); (N.S.); (L.A.S.)
| | - Patricia Moriel
- Faculty of Pharmaceutical Sciences, University of Campinas, Campinas 13083970, Brazil
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Ke P, Qian L, Zhou Y, Feng L, Zhang Z, Zheng C, Chen M, Huang X, Wu X. Identification of hub genes and transcription factor-miRNA-mRNA pathways in mice and human renal ischemia-reperfusion injury. PeerJ 2021; 9:e12375. [PMID: 34754625 PMCID: PMC8555504 DOI: 10.7717/peerj.12375] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2021] [Accepted: 10/03/2021] [Indexed: 12/13/2022] Open
Abstract
Background Renal ischemia-reperfusion injury (IRI) is a disease with high incidence rate in kidney related surgery. Micro RNA (miRNA) and transcription factors (TFs) are widely involved in the process of renal IRI through regulation of their target genes. However, the regulatory relationships and functional roles of TFs, miRNAs and mRNAs in the progression of renal IRI are insufficiently understood. The present study aimed to clarify the underlying mechanism of regulatory relationships in renal IRI. Methods Six gene expression profiles were downloaded from Gene Expression Omnibus (GEO). Differently expressed genes (DEGs) and differently expressed miRNAs (DEMs) were identified through RRA integrated analysis of mRNA datasets (GSE39548, GSE87025, GSE52004, GSE71647, and GSE131288) and miRNA datasets (GSE29495). miRDB and TransmiR v2.0 database were applied to predict target genes of miRNA and TFs, respectively. DEGs were applied for Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis, followed with construction of protein-protein interaction (PPI) network. Then, the TF-miRNA-mRNA network was constructed. Correlation coefficient and ROC analysis were used to verify regulatory relationship between genes and their diagnostic value in GSE52004. Furthermore, in independent mouse RNA-seq datasets GSE98622, human RNA-seq GSE134386 and in vitro, the expression of hub genes and genes from the network were observed and correlation coefficient and ROC analysis were validated. Results A total of 21 DEMs and 187 DEGs were identified in renal IRI group compared to control group. The results of PPI analysis showed 15 hub genes. The TF-miRNA-mRNA regulatory network was constructed and several important pathways were identified and further verified, including Junb-miR-223-Ranbp3l, Cebpb-miR-223-Ranbp3l, Cebpb-miR-21-Ranbp3l and Cebpb-miR-181b-Bsnd. Four regulatory loops were identified, including Fosl2-miR-155, Fosl2-miR-146a, Cebpb-miR-155 and Mafk-miR-25. The hub genes and genes in the network showed good diagnostic value in mice and human. Conclusions In this study, we found 15 hub genes and several TF-miRNA-mRNA pathways, which are helpful for understanding the molecular and regulatory mechanisms in renal IRI. Junb-miR-223-Ranbp3l, Cebpb-miR-223-Ranbp3l, Cebpb-miR-21-Ranbp3l and Cebpb-miR-181b-Bsnd were the most important pathways, while Spp1, Fos, Timp1, Tnc, Fosl2 and Junb were the most important hub genes. Fosl2-miR-155, Fosl2-miR-146a, Cebpb-miR-155 and Mafk-miR-25 might be the negative feedback loops in renal IRI.
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Affiliation(s)
- Peng Ke
- Department of Anesthesiology, Shengli Clinical Medical College, Fujian Medical University, Fuzhou, Fujian, China
| | - Lin Qian
- Department of Anesthesiology, Shengli Clinical Medical College, Fujian Medical University, Fuzhou, Fujian, China
| | - Yi Zhou
- Institute of Pharmaceutics, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang, China
| | - Liu Feng
- Department of Anesthesiology, Shengli Clinical Medical College, Fujian Medical University, Fuzhou, Fujian, China
| | - Zhentao Zhang
- Institute of Pharmaceutics, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang, China
| | - Chengjie Zheng
- Department of Anesthesiology, Shengli Clinical Medical College, Fujian Medical University, Fuzhou, Fujian, China
| | - Mengnan Chen
- Department of Anesthesiology, Shengli Clinical Medical College, Fujian Medical University, Fuzhou, Fujian, China
| | - Xinlei Huang
- Department of Anesthesiology, Shengli Clinical Medical College, Fujian Medical University, Fuzhou, Fujian, China
| | - Xiaodan Wu
- Department of Anesthesiology, Shengli Clinical Medical College, Fujian Medical University, Fuzhou, Fujian, China
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Lee SI, Park H, Kim SJ, Lee KW, Shin DY, Son JK, Hong JH, Kim SH, Cho HJ, Park JB, Kim TM. Circulating RNA Profiling in Postreperfusion Plasma From Kidney Transplant Recipients. Transplant Proc 2021; 53:2853-2865. [PMID: 34772491 DOI: 10.1016/j.transproceed.2021.09.044] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2021] [Accepted: 09/30/2021] [Indexed: 12/29/2022]
Abstract
BACKGROUND Ischemia/reperfusion injury (IRI) is inevitable in kidney transplantation (KT) and may lead to impaired tubular epithelial cell function and reduce graft function and survival. Renal IRI is a complex cellular and molecular event; therefore, investigating the genetic or molecular pathways associated with the early phase of KT would improve our understanding of IRI in KT. MicroRNAs (miRNAs) play a critical role in various pathologic events associated with IRI. METHODS We compared the expression profile of miRNAs extracted from 2 blood plasma samples, 1 from periphery and the other form gonadal veins immediately after reperfusion, in a total 5 cases of KT. RESULTS We observed that the total RNA yield was higher in postreperfusion plasma and that a subset of miRNAs was upregulated (miR-let-7a-3p, miR-143-3p, and miR-214-3p) or downregulated (let-7d-3p, let-7d-3p, miR-1246, miR-1260b, miR-1290, and miR-130b-3p) in postreperfusion plasma. Gene ontology analyses revealed that these subsets target different biological functions. Twenty-four predicted genes were commonly targeted by the upregulated miRNAs, and gene ontology enrichment and pathway analyses revealed that these were associated with various cellular activities such as signal transduction or with components such as exosomes and membranous organelles. CONCLUSION We present 2 subsets of miRNAs that were differentially upregulated or downregulated in postreperfusion plasma. Our findings may enhance our understanding of miRNA-mediated early molecular events related to IRI in KT.
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Affiliation(s)
- Sang In Lee
- Department of Animal Biotechnology, Kyungpook National University, Sangju, Gyeongsangbuk-do, Republic of Korea
| | - Hyojun Park
- School of Medicine, Sungkyunkwan University, Gangnam-gu, Seoul, Republic of Korea
| | - Sung Joo Kim
- School of Medicine, Sungkyunkwan University, Gangnam-gu, Seoul, Republic of Korea; Gennbio Co Ltd, Gangnam-gu, Seoul, Republic of Korea
| | - Kyo Won Lee
- Department of Surgery, Samsung Medical Center, Seoul, Republic of Korea
| | - Du Yeon Shin
- Transplantation Research Center, Stem Cell & Regenerative Medicine Institute, Samsung Medical Center, Seoul, Republic of Korea
| | - Jin Kyung Son
- Department of Surgery, Samsung Medical Center, Seoul, Republic of Korea
| | - Ju Hee Hong
- Department of Health Sciences & Technology, Samsung Advanced Institute for Health Sciences & Technology, Graduate School, Sungkyunkwan University, Seoul, Republic of Korea
| | - Seung Han Kim
- Gennbio Co Ltd, Gangnam-gu, Seoul, Republic of Korea
| | - Hye Jin Cho
- Graduate School of International Agricultural Technology, Seoul National University, Gangwon-do, Republic of Korea
| | - Jae Berm Park
- Department of Surgery, Samsung Medical Center, Seoul, Republic of Korea
| | - Tae Min Kim
- Graduate School of International Agricultural Technology, Seoul National University, Gangwon-do, Republic of Korea.
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Ciccarelli M, Dawson D, Falcao-Pires I, Giacca M, Hamdani N, Heymans S, Hooghiemstra A, Leeuwis A, Hermkens D, Tocchetti CG, van der Velden J, Zacchigna S, Thum T. Reciprocal organ interactions during heart failure: a position paper from the ESC Working Group on Myocardial Function. Cardiovasc Res 2021; 117:2416-2433. [PMID: 33483724 PMCID: PMC8562335 DOI: 10.1093/cvr/cvab009] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/10/2020] [Revised: 11/20/2021] [Accepted: 01/08/2021] [Indexed: 12/13/2022] Open
Abstract
Heart failure-either with reduced or preserved ejection fraction (HFrEF/HFpEF)-is a clinical syndrome of multifactorial and gender-dependent aetiology, indicating the insufficiency of the heart to pump blood adequately to maintain blood flow to meet the body's needs. Typical symptoms commonly include shortness of breath, excessive fatigue with impaired exercise capacity, and peripheral oedema, thereby alluding to the fact that heart failure is a syndrome that affects multiple organ systems. Patients suffering from progressed heart failure have a very limited life expectancy, lower than that of numerous cancer types. In this position paper, we provide an overview regarding interactions between the heart and other organ systems, the clinical evidence, underlying mechanisms, potential available or yet-to-establish animal models to study such interactions and finally discuss potential new drug interventions to be developed in the future. Our working group suggests that more experimental research is required to understand the individual molecular mechanisms underlying heart failure and reinforces the urgency for tailored therapeutic interventions that target not only the heart but also other related affected organ systems to effectively treat heart failure as a clinical syndrome that affects and involves multiple organs.
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Affiliation(s)
- Michele Ciccarelli
- University of Salerno, Department of Medicine, Surgery and Dentistry, Via S. Allende 1, 84081, Baronissi(Salerno), Italy
| | - Dana Dawson
- School of Medicine and Dentistry, University of Aberdeen, Aberdeen AB25 2DZ, UK
| | - Inês Falcao-Pires
- Department of Surgery and Physiology, Cardiovascular Research and Development Center, Faculty of Medicine of the University of Porto, Alameda Prof. Hernâni Monteiro, 4200-319, Porto, Portugal
| | - Mauro Giacca
- King’s College London, Molecular Medicine Laboratory, 125 Caldharbour Lane, London WC2R2LS, United Kingdom
- International Centre for Genetic Engineering and Biotechnology (ICGEB), Padriciano, 99, 34149 Trieste, Italy
- Department of Medicine, Surgery and Health Sciences, University of Trieste, Strada di Fiume, 447, 34129 Trieste, Italy
| | - Nazha Hamdani
- Department of Clinical Pharmacology and Molecular Cardiology, Institute of Physiology, Ruhr University Bochum, Universitätsstraße 150, D-44801 Bochum, Germany
- Department of Cardiology, St. Josef-Hospital, Ruhr University Bochum, Universitätsstraße 150, D-44801 Bochum, Germany
| | - Stéphane Heymans
- Centre for Molecular and Vascular Biology, KU Leuven, Herestraat 49, Bus 911, 3000 Leuven, Belgium
- Department of Cardiology, Maastricht University, CARIM School for Cardiovascular Diseases, Universiteitssingel 50, 6229 ER Maastricht, the Netherlands
- ICIN-Netherlands Heart Institute, Holland Heart House, Moreelsepark 1, 3511 EP Utrecht, the Netherlands
| | - Astrid Hooghiemstra
- Department of Neurology, Alzheimer Center Amsterdam, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, Amsterdam UMC, De Boelelaan 1118, 1081HZ, Amsterdam, The Netherlands
- Department of Medical Humanities, Amsterdam Public Health Research Institute, Amsterdam UMC, Location VUmc, De Boelelaan 1089a, 1081HV, Amsterdam, The Netherlands
| | - Annebet Leeuwis
- Department of Neurology, Alzheimer Center Amsterdam, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, Amsterdam UMC, De Boelelaan 1118, 1081HZ, Amsterdam, The Netherlands
| | - Dorien Hermkens
- Department of Pathology, Amsterdam Cardiovascular Sciences, Amsterdam UMC, University of Amsterdam, Meibergdreef 9, 1105AZ, Amsterdam, the Netherlands
| | - Carlo Gabriele Tocchetti
- Department of Translational Medical Sciences and Interdepartmental Center of Clinical and Translational Research (CIRCET), Federico II University, Naples, Italy
| | - Jolanda van der Velden
- Amsterdam UMC, Vrije Universiteit Amsterdam, Department of Physiology, Amsterdam Cardiovascular Sciences, De Boelelaan 1118, 1081HZ Amsterdam, the Netherlands
| | - Serena Zacchigna
- Department of Medicine, Surgery and Health Sciences, University of Trieste, Strada di Fiume, 447, 34129 Trieste, Italy
- Cardiovascular Biology Laboratory, International Centre for Genetic Engineering and Biotechnology (ICGEB), Padriciano, 99, 34149 Trieste, Italy
| | - Thomas Thum
- Institute of Molecular and Translational Therapeutic Strategies (IMTTS), Hannover Medical School, Carl-Neuberg-Str. 1, D-30625 Hannover, Germany
- REBIRTH Center for Translational Regenerative Medicine, Hannover Medical School, Carl-Neuberg-Str. 1, D-30625 Hannover, Germany
- Fraunhofer Institute of Toxicology and Experimental Medicine, Nicolai-Fuchs-Str. 1, D-30625 Hannover, Germany
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Usuelli V, Ben Nasr M, D'Addio F, Liu K, Vergani A, El Essawy B, Yang J, Assi E, Uehara M, Rossi C, Solini A, Capobianco A, Rigamonti E, Potena L, Venturini M, Sabatino M, Bottarelli L, Ammirati E, Frigerio M, Castillo‐Leon E, Maestroni A, Azzoni C, Loretelli C, Joe Seelam A, Tai AK, Pastore I, Becchi G, Corradi D, Visner GA, Zuccotti GV, Chau NB, Abdi R, Pezzolesi MG, Fiorina P. miR-21 antagonism reprograms macrophage metabolism and abrogates chronic allograft vasculopathy. Am J Transplant 2021; 21:3280-3295. [PMID: 33764625 PMCID: PMC8518036 DOI: 10.1111/ajt.16581] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2020] [Revised: 02/19/2021] [Accepted: 03/09/2021] [Indexed: 01/25/2023]
Abstract
Despite much progress in improving graft outcome during cardiac transplantation, chronic allograft vasculopathy (CAV) remains an impediment to long-term graft survival. MicroRNAs (miRNAs) emerged as regulators of the immune response. Here, we aimed to examine the miRNA network involved in CAV. miRNA profiling of heart samples obtained from a murine model of CAV and from cardiac-transplanted patients with CAV demonstrated that miR-21 was most significantly expressed and was primarily localized to macrophages. Interestingly, macrophage depletion with clodronate did not significantly prolong allograft survival in mice, while conditional deletion of miR-21 in macrophages or the use of a specific miR-21 antagomir resulted in indefinite cardiac allograft survival and abrogated CAV. The immunophenotype, secretome, ability to phagocytose, migration, and antigen presentation of macrophages were unaffected by miR-21 targeting, while macrophage metabolism was reprogrammed, with a shift toward oxidative phosphorylation in naïve macrophages and with an inhibition of glycolysis in pro-inflammatory macrophages. The aforementioned effects resulted in an increase in M2-like macrophages, which could be reverted by the addition of L-arginine. RNA-seq analysis confirmed alterations in arginase-associated pathways associated with miR-21 antagonism. In conclusion, miR-21 is overexpressed in murine and human CAV, and its targeting delays CAV onset by reprogramming macrophages metabolism.
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Affiliation(s)
- Vera Usuelli
- International Center for T1DPediatric Clinical Research Center “Romeo ed Enrica Invernizzi”Department of Biomedical and Clinical Science L. SaccoUniversita Degli Studi di MilanoMilanItaly
| | - Moufida Ben Nasr
- International Center for T1DPediatric Clinical Research Center “Romeo ed Enrica Invernizzi”Department of Biomedical and Clinical Science L. SaccoUniversita Degli Studi di MilanoMilanItaly,Nephrology DivisionBoston Children's HospitalHarvard Medical SchoolBostonMassachusetts
| | - Francesca D'Addio
- International Center for T1DPediatric Clinical Research Center “Romeo ed Enrica Invernizzi”Department of Biomedical and Clinical Science L. SaccoUniversita Degli Studi di MilanoMilanItaly
| | - Kaifeng Liu
- Division of Pulmonary and Respiratory DiseasesBoston Children's HospitalHarvard Medical SchoolBostonMassachusetts
| | - Andrea Vergani
- Nephrology DivisionBoston Children's HospitalHarvard Medical SchoolBostonMassachusetts
| | - Basset El Essawy
- Department of MedicineAl‐Azhar UniversityCairoEgypt,Renal DivisionTransplantation Research CenterBrigham and Women's HospitalHarvard Medical SchoolBostonMassachusetts
| | - Jun Yang
- Institute of Organ TransplantationTongji Hospital and Medical CollegeHuazhong University of Science and TechnologyWuhanChina
| | - Emma Assi
- International Center for T1DPediatric Clinical Research Center “Romeo ed Enrica Invernizzi”Department of Biomedical and Clinical Science L. SaccoUniversita Degli Studi di MilanoMilanItaly
| | - Mayuko Uehara
- Renal DivisionTransplantation Research CenterBrigham and Women's HospitalHarvard Medical SchoolBostonMassachusetts
| | - Chiara Rossi
- Department of Clinical and Experimental MedicineUniversity of PisaPisaItaly
| | - Anna Solini
- Department of SurgicalMedical, Molecular and Critical Area PathologyUniversity of PisaPisaItaly
| | - Annalisa Capobianco
- Division of Immunology, Transplantation and Infectious DiseaseSan Raffaele Scientific InstituteMilanItaly
| | - Elena Rigamonti
- Division of Immunology, Transplantation and Infectious DiseaseSan Raffaele Scientific InstituteMilanItaly
| | - Luciano Potena
- Heart Failure and Heart Transplant ProgramS. Orsola‐Malpighi HospitalAlma‐Mater University of BolognaBolognaItaly
| | | | - Mario Sabatino
- Department of Cardiothoracic, Transplantation and Vascular SurgeryS. Orsola‐Malpighi HospitalAlma Mater‐University of BolognaBolognaItaly
| | | | - Enrico Ammirati
- De Gasperis Cardio Center and Transplant CenterNiguarda HospitalMilanItaly
| | - Maria Frigerio
- De Gasperis Cardio Center and Transplant CenterNiguarda HospitalMilanItaly
| | - Eduardo Castillo‐Leon
- Nephrology DivisionBoston Children's HospitalHarvard Medical SchoolBostonMassachusetts
| | - Anna Maestroni
- International Center for T1DPediatric Clinical Research Center “Romeo ed Enrica Invernizzi”Department of Biomedical and Clinical Science L. SaccoUniversita Degli Studi di MilanoMilanItaly
| | - Cinzia Azzoni
- Department of Medicine and SurgeryUniversity of ParmaParmaItaly
| | - Cristian Loretelli
- International Center for T1DPediatric Clinical Research Center “Romeo ed Enrica Invernizzi”Department of Biomedical and Clinical Science L. SaccoUniversita Degli Studi di MilanoMilanItaly
| | - Andy Joe Seelam
- International Center for T1DPediatric Clinical Research Center “Romeo ed Enrica Invernizzi”Department of Biomedical and Clinical Science L. SaccoUniversita Degli Studi di MilanoMilanItaly
| | - Albert K. Tai
- Tufts University Core Facility (TUCF) Genomics CoreTufts University School of MedicineBostonMassachusetts
| | - Ida Pastore
- Division of EndocrinologyASST Fatebenefratelli‐SaccoMilanItaly
| | | | | | - Gary A. Visner
- Division of Pulmonary and Respiratory DiseasesBoston Children's HospitalHarvard Medical SchoolBostonMassachusetts
| | - Gian V. Zuccotti
- International Center for T1DPediatric Clinical Research Center “Romeo ed Enrica Invernizzi”Department of Biomedical and Clinical Science L. SaccoUniversita Degli Studi di MilanoMilanItaly,Department of PediatricsBuzzi Children's HospitalMilanItaly
| | | | - Reza Abdi
- Renal DivisionTransplantation Research CenterBrigham and Women's HospitalHarvard Medical SchoolBostonMassachusetts
| | - Marcus G. Pezzolesi
- Division of Nephrology and Hypertension, Diabetes and Metabolism CenterUniversity of UtahSalt Lake CityUtah
| | - Paolo Fiorina
- International Center for T1DPediatric Clinical Research Center “Romeo ed Enrica Invernizzi”Department of Biomedical and Clinical Science L. SaccoUniversita Degli Studi di MilanoMilanItaly,Nephrology DivisionBoston Children's HospitalHarvard Medical SchoolBostonMassachusetts,Division of EndocrinologyASST Fatebenefratelli‐SaccoMilanItaly
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Novel Role of miR-18a-5p and Galanin in Rat Lung Ischemia Reperfusion-Mediated Response. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2021; 2021:6621921. [PMID: 34497682 PMCID: PMC8420977 DOI: 10.1155/2021/6621921] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/27/2020] [Revised: 07/05/2021] [Accepted: 07/25/2021] [Indexed: 12/12/2022]
Abstract
Lung ischemia reperfusion (IR) is known to occur after lung transplantation or cardiac bypass. IR leads to tissue inflammation and damage and is also associated with increased morbidity and mortality. Various receptors are known to partake in activation of the innate immune system, but the downstream mechanism of tissue damage and inflammation is yet unknown. MicroRNAs (miRNAs) are in the forefront in regulating ischemia reperfusion injury and are involved in inflammatory response. Here, we have identified by high-throughput approach and evaluated a distinct set of miRNAs that may play a role in response to IR in rat lung tissue. The top three differentially expressed miRNAs were validated through quantitative PCRs in the IR rat lung model and an in vitro model of IR of hypoxia and reoxygenation exposed type II alveolar cells. Among the miRNAs, miR-18a-5p showed consistent downregulation in both the model systems on IR. Cellular and molecular analysis brought to light a crucial role of this miRNA in ischemia reperfusion. miR-18a-5p plays a role in IR-mediated apoptosis and ROS production and regulates the expression of neuropeptide Galanin. It also influences the nuclear localization of transcription factor: nuclear factor-erythroid 2-related factor (Nrf2) which in turn may regulate the expression of the miR-18a gene. Thus, we have not only established a rat model for lung IR and enumerated the important miRNAs involved in IR but have also extensively characterized the role of miR-18a-5p. This study will have important clinical and therapeutic implications for and during transplantation procedures.
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Abstract
Epigenetics examines heritable changes in DNA and its associated proteins except mutations in gene sequence. Epigenetic regulation plays fundamental roles in kidney cell biology through the action of DNA methylation, chromatin modification via epigenetic regulators and non-coding RNA species. Kidney diseases, including acute kidney injury, chronic kidney disease, diabetic kidney disease and renal fibrosis are multistep processes associated with numerous molecular alterations even in individual kidney cells. Epigenetic alterations, including anomalous DNA methylation, aberrant histone alterations and changes of microRNA expression all contribute to kidney pathogenesis. These changes alter the genome-wide epigenetic signatures and disrupt essential pathways that protect renal cells from uncontrolled growth, apoptosis and development of other renal associated syndromes. Molecular changes impact cellular function within kidney cells and its microenvironment to drive and maintain disease phenotype. In this chapter, we briefly summarize epigenetic mechanisms in four kidney diseases including acute kidney injury, chronic kidney disease, diabetic kidney disease and renal fibrosis. We primarily focus on current knowledge about the genome-wide profiling of DNA methylation and histone modification, and epigenetic regulation on specific gene(s) in the pathophysiology of these diseases and the translational potential of identifying new biomarkers and treatment for prevention and therapy. Incorporating epigenomic testing into clinical research is essential to elucidate novel epigenetic biomarkers and develop precision medicine using emerging therapies.
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45
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Scalon MC, Martins CS, Ferreira GG, Schlemmer F, Titze-de-Almeida R, Paludo GR. RT-rtPCR quantification of circulating microRNAs in plasma and serum samples from healthy domestic cats. J Vet Diagn Invest 2021; 33:1151-1155. [PMID: 34301168 DOI: 10.1177/10406387211034843] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
Abstract
MicroRNAs (miRNAs) are small non-coding RNAs that regulate gene expression at a post-transcriptional level by silencing targeted messenger RNA (mRNA). Most studies concerning miRNA expression use solid tissue samples. However, circulating miRNAs from different body fluids have recently emerged as diagnostic and prognostic molecules, given that they hold informative value and have increased stability in cell-free form. Blood sampling of cats can be challenging given their small body size and because they often experience distress when handled. We quantified miR-20a, -192, -365, -15b-5p, and -16-5p from plasma and serum samples of 10 healthy domestic cats. Our RT-rtPCR procedure used 100 µL of either plasma or serum samples as sources of biomarker molecules. However, serum provided higher amounts of miRNA than plasma samples, with a p < 0.0001 for miR-20a and p < 0.0002 for miR-16-5p.
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Affiliation(s)
- Marcela C Scalon
- Veterinary Clinical Pathology Laboratory, College of Agronomy and Veterinary Medicine, University of Brasilia, Brasilia, Brazil
| | - Christine S Martins
- Veterinary Clinical Pathology Laboratory, College of Agronomy and Veterinary Medicine, University of Brasilia, Brasilia, Brazil
| | - Gabriel G Ferreira
- Technology for Gene Therapy Laboratory, College of Agronomy and Veterinary Medicine, University of Brasilia, Brasilia, Brazil
| | - Franciele Schlemmer
- Technology for Gene Therapy Laboratory, College of Agronomy and Veterinary Medicine, University of Brasilia, Brasilia, Brazil
| | - Ricardo Titze-de-Almeida
- Technology for Gene Therapy Laboratory, College of Agronomy and Veterinary Medicine, University of Brasilia, Brasilia, Brazil
| | - Giane R Paludo
- Veterinary Clinical Pathology Laboratory, College of Agronomy and Veterinary Medicine, University of Brasilia, Brasilia, Brazil
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Róka B, Tod P, Kaucsár T, Bukosza ÉN, Vörös I, Varga ZV, Petrovich B, Ágg B, Ferdinandy P, Szénási G, Hamar P. Delayed Contralateral Nephrectomy Halted Post-Ischemic Renal Fibrosis Progression and Inhibited the Ischemia-Induced Fibromir Upregulation in Mice. Biomedicines 2021; 9:biomedicines9070815. [PMID: 34356879 PMCID: PMC8301422 DOI: 10.3390/biomedicines9070815] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2020] [Revised: 07/06/2021] [Accepted: 07/08/2021] [Indexed: 12/12/2022] Open
Abstract
(1) Background: Ischemia reperfusion (IR) is the leading cause of acute kidney injury (AKI) and results in predisposition to chronic kidney disease. We demonstrated that delayed contralateral nephrectomy (Nx) greatly improved the function of the IR-injured kidney and decelerated fibrosis progression. Our aim was to identify microRNAs (miRNA/miR) involved in this process. (2) Methods: NMRI mice were subjected to 30 min of renal IR and one week later to Nx/sham surgery. The experiments were conducted for 7-28 days after IR. On day 8, multiplex renal miRNA profiling was performed. Expression of nine miRNAs was determined with qPCR at all time points. Based on the target prediction, plexin-A2 and Cd2AP were measured by Western blot. (3) Results: On day 8 after IR, the expression of 20/1195 miRNAs doubled, and 9/13 selected miRNAs were upregulated at all time points. Nx reduced the expression of several ischemia-induced pro-fibrotic miRNAs (fibromirs), such as miR-142a-duplex, miR-146a-5p, miR-199a-duplex, miR-214-3p and miR-223-3p, in the injured kidneys at various time points. Plexin-A2 was upregulated by IR on day 10, while Cd2AP was unchanged. (4) Conclusion: Nx delayed fibrosis progression and decreased the expression of ischemia-induced fibromirs. The protein expression of plexin-A2 and Cd2AP is mainly regulated by factors other than miRNAs.
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Affiliation(s)
- Beáta Róka
- Institute of Translational Medicine, Semmelweis University, 1094 Budapest, Hungary; (B.R.); (P.T.); (T.K.); (É.N.B.); (G.S.)
| | - Pál Tod
- Institute of Translational Medicine, Semmelweis University, 1094 Budapest, Hungary; (B.R.); (P.T.); (T.K.); (É.N.B.); (G.S.)
- Institute for Translational Medicine, Medical School, University of Pécs, 7624 Pécs, Hungary
| | - Tamás Kaucsár
- Institute of Translational Medicine, Semmelweis University, 1094 Budapest, Hungary; (B.R.); (P.T.); (T.K.); (É.N.B.); (G.S.)
| | - Éva Nóra Bukosza
- Institute of Translational Medicine, Semmelweis University, 1094 Budapest, Hungary; (B.R.); (P.T.); (T.K.); (É.N.B.); (G.S.)
| | - Imre Vörös
- Department of Pharmacology and Pharmacotherapy, Semmelweis University, 1089 Budapest, Hungary; (I.V.); (Z.V.V.); (B.P.); (B.Á.); (P.F.)
- HCEMM-SU Cardiometabolic Immunology Research Group, Semmelweis University, 1089 Budapest, Hungary
| | - Zoltán V. Varga
- Department of Pharmacology and Pharmacotherapy, Semmelweis University, 1089 Budapest, Hungary; (I.V.); (Z.V.V.); (B.P.); (B.Á.); (P.F.)
- HCEMM-SU Cardiometabolic Immunology Research Group, Semmelweis University, 1089 Budapest, Hungary
| | - Balázs Petrovich
- Department of Pharmacology and Pharmacotherapy, Semmelweis University, 1089 Budapest, Hungary; (I.V.); (Z.V.V.); (B.P.); (B.Á.); (P.F.)
| | - Bence Ágg
- Department of Pharmacology and Pharmacotherapy, Semmelweis University, 1089 Budapest, Hungary; (I.V.); (Z.V.V.); (B.P.); (B.Á.); (P.F.)
- Pharmahungary Group, 6722 Szeged, Hungary
| | - Péter Ferdinandy
- Department of Pharmacology and Pharmacotherapy, Semmelweis University, 1089 Budapest, Hungary; (I.V.); (Z.V.V.); (B.P.); (B.Á.); (P.F.)
- Pharmahungary Group, 6722 Szeged, Hungary
| | - Gábor Szénási
- Institute of Translational Medicine, Semmelweis University, 1094 Budapest, Hungary; (B.R.); (P.T.); (T.K.); (É.N.B.); (G.S.)
| | - Péter Hamar
- Institute of Translational Medicine, Semmelweis University, 1094 Budapest, Hungary; (B.R.); (P.T.); (T.K.); (É.N.B.); (G.S.)
- Institute for Translational Medicine, Medical School, University of Pécs, 7624 Pécs, Hungary
- Correspondence: ; Tel.: +36-20-825-9751
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Abstract
Chronic kidney disease (CKD), which is characterized by the gradual loss of kidney function, is a growing worldwide problem due to CKD-related morbidity and mortality. There are no reliable and early biomarkers enabling the monitoring, the stratification of CKD progression and the estimation of the risk of CKD-related complications, and therefore, the search for such molecules is still going on. Numerous studies have provided evidence that miRNAs are potentially important particles in the CKD field. Studies indicate that some miRNA levels can be increased in patients with CKD stages III–V and hemodialysis and decreased in renal transplant recipients (miR-143, miR-145 and miR-223) as well as elevated in patients with CKD stages III–V, decreased in hemodialysis patients and even more markedly decreased in renal transplant recipients (miR-126 and miR-155). miRNA have great potential of being sensitive and specific biomarkers in kidney diseases as they are tissue specific and stable in various biological materials. Some promising non-invasive miRNA biomarkers have already been recognized in renal disease with the potential to enhance diagnostic accuracy, predict prognosis and monitor the course of disease. However, large-scale clinical trials enrolling heterogeneous patients are required to evaluate the clinical value of miRNAs.
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Luo YH, Huang ZT, Zong KZ, Cao ZR, Peng DD, Zhou BY, Shen A, Yan P, Wu ZJ. miR-194 ameliorates hepatic ischemia/reperfusion injury via targeting PHLDA1 in a TRAF6-dependent manner. Int Immunopharmacol 2021; 96:107604. [PMID: 33839577 DOI: 10.1016/j.intimp.2021.107604] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2021] [Revised: 03/09/2021] [Accepted: 03/18/2021] [Indexed: 02/07/2023]
Abstract
Hepatic ischemia/reperfusion injury (IRI) is an inevitable pathological process in liver resection, shock and transplantation. However, the internal mechanism of hepatic IRI, including inflammatory transduction of multiple signaling pathways, is not fully understood. In the present study, we identified pleckstrin homology-like domain family member 1 (PHLDA1), suppressed by microRNA (miR)-194, as a critical intersection of dual inflammatory signals in hepatic IRI. PHLDA1 was upregulated in hepatic IRI with a concomitant downregulation of miR-194. Overexpression of miR-194 diminished PHLDA1 and inhibitors of the nuclear factor kappa-B kinase (IKK) pathway, thus leading to remission of hepatic pathological injury, apoptosis and release of cytokines. Further enrichment of PHLDA1 reversed the function of miR-194 both in vivo and in vitro. For an in-depth query, we verified PHLDA1 as a direct target of miR-194. Notably, inflammatory signal transduction of PHLDA1 was induced by activating TNF receptor-associated factor 6 (TRAF6), sequentially initiating IKK and mitogen-activated protein kinase (MAPK), both of which aggravate stress and inflammation in hepatic IRI. In conclusion, the miR-194/PHLDA1 axis was a key upstream regulator of IKK and MAPK in hepatic IRI. Targeting PHLDA1 might be a potential strategy for hepatic IRI therapy.
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Affiliation(s)
- Yun-Hai Luo
- The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China
| | - Zuo-Tian Huang
- The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China
| | - Ke-Zhen Zong
- The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China
| | - Zhen-Rui Cao
- The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China
| | - Da-Di Peng
- The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China
| | - Bao-Yong Zhou
- The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China
| | - Ai Shen
- Hepatobiliary Pancreatic Tumor Center, Chongqing University Cancer Hospital, Chongqing 400030, China
| | - Ping Yan
- The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China
| | - Zhong-Jun Wu
- The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China.
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Pushpakumar S, Kundu S, Weber G, Sen U. Exogenous hydrogen sulfide and miR-21 antagonism attenuates macrophage-mediated inflammation in ischemia reperfusion injury of the aged kidney. GeroScience 2021; 43:1349-1367. [PMID: 33433751 PMCID: PMC8190249 DOI: 10.1007/s11357-020-00299-6] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2020] [Accepted: 11/16/2020] [Indexed: 12/17/2022] Open
Abstract
Ischemia reperfusion injury (IRI) is a common cause of acute kidney injury (AKI) in the aging population. A reduction of hydrogen sulfide (H2S) production in the old kidney and renal IRI contribute to renal pathology and injury. Recent studies suggest that microRNAs (miRs) play an important role in the pathophysiology of AKI and a significant crosstalk exists between H2S and miRs. Among the miRs, miR-21 is highly expressed in AKI and is reported to have both pathological and protective role. In the present study, we sought to determine the effects of age-induced reduction in H2S and mir-21 antagonism in AKI. Wild type (WT, C57BL/6J) mice aged 12-14 weeks and 75-78 weeks underwent bilateral renal ischemia (27 min) and reperfusion for 7 days and were treated with H2S donor, GYY4137 (GYY, 0.25 mg/kg/day, ip) or locked nucleic acid anti-miR-21 (20 mg/kg b.w., ip) for 7 days. Following IRI, old kidney showed increased macrophage polarization toward M1 inflammatory phenotype, cytokine upregulation, endothelial-mesenchymal transition, and fibrosis compared to young kidney. Treatment with GYY or anti-miR-21 reversed the changes and improved renal vascular density, blood flow, and renal function in the old kidney. Anti-miR-21 treatment in mouse glomerular endothelial cells showed upregulation of H2S-producing enzymes, cystathionine β-synthase (CBS), and cystathionineγ-lyase (CSE), and reduction of matrix metalloproteinase-9 and collagen IV expression. In conclusion, exogenous H2S and inhibition of miR-21 rescued the old kidney dysfunction due to IRI by increasing H2S levels, reduction of macrophage-mediated injury, and promoting reparative process suggesting a viable approach for aged patients sustaining AKI.
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Affiliation(s)
- Sathnur Pushpakumar
- Department of Physiology, University of Louisville School of Medicine, 500 S Preston St. HSC-A, Room 1115, Louisville, KY, 40202, USA.
| | - Sourav Kundu
- NMCG Laboratory ICAR-Central Inland Fisheries Research Institute, Barrackpore, Kolkata, West Bengal, 700120, India
| | - Gregory Weber
- Department of Physiology, University of Louisville School of Medicine, 500 S Preston St. HSC-A, Room 1115, Louisville, KY, 40202, USA
| | - Utpal Sen
- Department of Physiology, University of Louisville School of Medicine, 500 S Preston St. HSC-A, Room 1115, Louisville, KY, 40202, USA.
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50
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Ke J, Zhao F, Luo Y, Deng F, Wu X. MiR-124 Negatively Regulated PARP1 to Alleviate Renal Ischemia-reperfusion Injury by Inhibiting TNFα/RIP1/RIP3 Pathway. Int J Biol Sci 2021; 17:2099-2111. [PMID: 34131409 PMCID: PMC8193263 DOI: 10.7150/ijbs.58163] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2021] [Accepted: 04/28/2021] [Indexed: 12/01/2022] Open
Abstract
Renal ischemia-reperfusion injury (IRI) is one of the underlying causes of acute kidney injury and also an unavoidable problem in renal transplantation. Lots of miRNAs and targets have been found to participate in some post-transcriptional processes in renal IRI, however, the detailed knowledge of miRNA targets and mechanism is unknown. In this study, miR-124 was found inhibited and PARP1 was overexpressed in renal IRI cells and mouse models. Dual-luciferase reporter assay revealed that miR-124 post-transcriptionally regulated PAPR1 3′UTR activity. Our results also demonstrated miR-124 negatively regulated PARP1 which played a role in necroptosis of renal ischemia-reperfusion injury by activating TNFα. TNFα induced the RIP1/RIP3 necroptosis signaling pathway to aggravate the renal injury. Collectively, these studies identified PARP1 as a direct target of miR-124 and activated RIP1/RIP3 necroptosis signaling pathway through TNFα. It elucidated the protective effect of miR-124 in renal ischemia-reperfusion injury, which demonstrated the regulatory mechanism of miR-124/PARP1 in renal injury and exhibited the potential as a novel therapeutic for the treatment of renal IRI.
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Affiliation(s)
- Jing Ke
- Department of Nephrology, Renmin Hospital of Wuhan University, Wuhan, China.,Department of Endocrinology, Ezhou Central Hospital, Ezhou, Hubei, China
| | - Fan Zhao
- Department of Nephrology, Renmin Hospital of Wuhan University, Wuhan, China
| | - Yanwen Luo
- Department of Nephrology, Renmin Hospital of Wuhan University, Wuhan, China
| | - Fangjing Deng
- Department of Nephrology, Renmin Hospital of Wuhan University, Wuhan, China
| | - Xiongfei Wu
- Department of Nephrology, Renmin Hospital of Wuhan University, Wuhan, China
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