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Du X, Shen F, Yu C, Wang Y, Yu J, Yao L, Liu N, Zhuang S. SMYD3 as an Epigenetic Regulator of Renal Tubular Cell Survival and Regeneration Following Acute Kidney Injury in Mice. FASEB J 2025; 39:e70533. [PMID: 40317558 DOI: 10.1096/fj.202500089r] [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: 01/09/2025] [Revised: 03/25/2025] [Accepted: 03/31/2025] [Indexed: 05/07/2025]
Abstract
The protein SET and MYND-Domain Containing 3 (SMYD3) is a methyltransferase that modifies various non-histone and histone proteins, linking it to tumorigenesis and cyst formation. However, its role in acute kidney injury (AKI) remains unclear. This study investigates the role and mechanism of AKI using a murine model of ischemia-reperfusion (IR)-induced AKI. After IR injury, SMYD3 and H3K4me3 levels increased in the kidneys, correlating with renal dysfunction, tubular cell injury, and apoptosis. Administration of BCI-121, a selective SMYD3 inhibitor, exacerbated IR-induced tubular cell injury and apoptosis, leading to more severe renal dysfunction and pathological changes. Pharmacological inhibition of SMYD3 also impaired the dedifferentiation and proliferation of renal tubular cells, key regenerative processes in injured kidneys, as evidenced by decreased expression of vimentin, snail, proliferating cell nuclear antigen (PCNA), cyclin D1, and retinoblastoma protein (RB). Additionally, SMYD3 inhibition reduced phosphorylation of the epithelial growth factor receptor (EGFR) and AKT, as well as EGFR expression in damaged kidneys. Finally, both BCI-121 and SMYD3 siRNA reduced EGF-induced expression of vimentin, snail, cyclin D1, PCNA, and EGFR, along with phosphorylation of RB and AKT in cultured renal tubular cells. Chip assay indicated that SMYD3 and H3K4me3 are enriched at the promoter of EGFR and SMYD3 inhibition blocked this response. These data suggest that SMYD3 plays an important role as an epigenetic regulator of renal tubular cell survival and regenerative pathways following kidney injury. Targeting SMYD3 or its epigenetic effects could offer therapeutic potential for enhancing kidney regeneration in AKI and related renal diseases.
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Affiliation(s)
- Xinyu Du
- Department of Nephrology, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Fengchen Shen
- Department of Nephrology, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Chao Yu
- Department of Nephrology, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Yanjin Wang
- Department of Nephrology, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Jianjun Yu
- Department of Nephrology, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Liyuan Yao
- Department of Nephrology, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Na Liu
- Department of Nephrology, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Shougang Zhuang
- Department of Nephrology, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, China
- Department of Medicine, Rhode Island Hospital and Alpert Medical School, Brown University, Providence, Rhode Island, USA
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Li F, Lan Q, Wang Y, Xiong J, Xiao T, Gong S, Li Y, Wang S, Yao M, Lv L, Qin S, Xin W, Liu L, Zhang B, Zhao J. Single-cell analysis of proximal tubular cells with different DNA content reveals functional heterogeneity in the acute kidney injury to chronic kidney disease transition. Kidney Int 2025:S0085-2538(25)00332-1. [PMID: 40268163 DOI: 10.1016/j.kint.2025.03.025] [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: 08/07/2024] [Revised: 02/26/2025] [Accepted: 03/07/2025] [Indexed: 04/25/2025]
Abstract
INTRODUCTION Proximal tubular epithelial cells with different DNA contents emerge after acute kidney injury (AKI). However, their heterogeneity and roles in the acute kidney injury-to-chronic kidney disease (AKI-to-CKD) transition remain incompletely understood. METHODS Proximal tubular epithelial cells with different DNA contents were isolated at days 3 and 14 post-AKI following ischemia reperfusion injury for single-cell RNA sequencing. RESULTS Here, we found that proximal tubular epithelial cells with different DNA contents have existing and distinct bulk transcriptome profiles, especially those cells over 4N (polyploid cells with more than four chromosome sets) with upregulated profibrotic signatures. Heterogeneity existed within four distinct functional clusters. In particular, the polyploid cells demonstrated a preferential enrichment within specific proinflammatory and profibrotic clusters post-AKI. Polyploid cells within these specific clusters displayed the profibrotic trajectory, accompanied by increased fibrosis-driving regulon activity and very strong cell-cell interactions. This suggests polyploidy cells have an intrinsic role in promoting the AKI-to-CKD transition. Furthermore, we identified that secreted phosphoprotein 1 (SPP1) as the pivotal hub of polyploid cells and may be involved in various profibrotic signaling pathways. Genetic knockdown of SPP1 in the proximal tubule in vivo dramatically ameliorated kidney fibrosis. CONCLUSIONS Overall, our findings reveal the heterogeneity of proximal tubular epithelial cells with different DNA contents and identify intrinsic factors of polyploid cells such as SPP1 expression in promoting kidney fibrosis. Our study provides novel insights into potential therapeutic target of preventing the AKI-to-CKD transition.
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Affiliation(s)
- Fugang Li
- Department of Nephrology, Chongqing Key Laboratory of Prevention and Treatment of Kidney Disease, Chongqing Clinical Research Center of Kidney and Urology Diseases, Xinqiao Hospital, Army Medical University (Third Military Medical University), Chongqing, China
| | - Qigang Lan
- Department of Nephrology, Chongqing Key Laboratory of Prevention and Treatment of Kidney Disease, Chongqing Clinical Research Center of Kidney and Urology Diseases, Xinqiao Hospital, Army Medical University (Third Military Medical University), Chongqing, China
| | - Yaqin Wang
- Department of Nephrology, Chongqing Key Laboratory of Prevention and Treatment of Kidney Disease, Chongqing Clinical Research Center of Kidney and Urology Diseases, Xinqiao Hospital, Army Medical University (Third Military Medical University), Chongqing, China
| | - Jiachuan Xiong
- Department of Nephrology, Chongqing Key Laboratory of Prevention and Treatment of Kidney Disease, Chongqing Clinical Research Center of Kidney and Urology Diseases, Xinqiao Hospital, Army Medical University (Third Military Medical University), Chongqing, China
| | - Tangli Xiao
- Department of Nephrology, Chongqing Key Laboratory of Prevention and Treatment of Kidney Disease, Chongqing Clinical Research Center of Kidney and Urology Diseases, Xinqiao Hospital, Army Medical University (Third Military Medical University), Chongqing, China
| | - Shuiqin Gong
- Department of Nephrology, Chongqing Key Laboratory of Prevention and Treatment of Kidney Disease, Chongqing Clinical Research Center of Kidney and Urology Diseases, Xinqiao Hospital, Army Medical University (Third Military Medical University), Chongqing, China
| | - Yan Li
- Department of Nephrology, Chongqing Key Laboratory of Prevention and Treatment of Kidney Disease, Chongqing Clinical Research Center of Kidney and Urology Diseases, Xinqiao Hospital, Army Medical University (Third Military Medical University), Chongqing, China
| | - Shaobo Wang
- Department of Nephrology, Chongqing Key Laboratory of Prevention and Treatment of Kidney Disease, Chongqing Clinical Research Center of Kidney and Urology Diseases, Xinqiao Hospital, Army Medical University (Third Military Medical University), Chongqing, China
| | - Mengying Yao
- Department of Nephrology, Chongqing Key Laboratory of Prevention and Treatment of Kidney Disease, Chongqing Clinical Research Center of Kidney and Urology Diseases, Xinqiao Hospital, Army Medical University (Third Military Medical University), Chongqing, China
| | - Liangjing Lv
- Department of Nephrology, Chongqing Key Laboratory of Prevention and Treatment of Kidney Disease, Chongqing Clinical Research Center of Kidney and Urology Diseases, Xinqiao Hospital, Army Medical University (Third Military Medical University), Chongqing, China
| | - Shaozong Qin
- Department of Nephrology, Chongqing Key Laboratory of Prevention and Treatment of Kidney Disease, Chongqing Clinical Research Center of Kidney and Urology Diseases, Xinqiao Hospital, Army Medical University (Third Military Medical University), Chongqing, China
| | - Wang Xin
- Department of Nephrology, Chongqing Key Laboratory of Prevention and Treatment of Kidney Disease, Chongqing Clinical Research Center of Kidney and Urology Diseases, Xinqiao Hospital, Army Medical University (Third Military Medical University), Chongqing, China
| | - Li Liu
- Department of Nephrology, Chongqing Key Laboratory of Prevention and Treatment of Kidney Disease, Chongqing Clinical Research Center of Kidney and Urology Diseases, Xinqiao Hospital, Army Medical University (Third Military Medical University), Chongqing, China
| | - Bo Zhang
- Department of Nephrology, Chongqing Key Laboratory of Prevention and Treatment of Kidney Disease, Chongqing Clinical Research Center of Kidney and Urology Diseases, Xinqiao Hospital, Army Medical University (Third Military Medical University), Chongqing, China
| | - Jinghong Zhao
- Department of Nephrology, Chongqing Key Laboratory of Prevention and Treatment of Kidney Disease, Chongqing Clinical Research Center of Kidney and Urology Diseases, Xinqiao Hospital, Army Medical University (Third Military Medical University), Chongqing, China.
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Zheng Y, Zhang TN, Hao PH, Yang N, Du Y. Histone deacetylases and their inhibitors in kidney diseases. Mol Ther 2025:S1525-0016(25)00300-4. [PMID: 40263937 DOI: 10.1016/j.ymthe.2025.04.026] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2025] [Revised: 03/18/2025] [Accepted: 04/16/2025] [Indexed: 04/24/2025] Open
Abstract
Histone deacetylases (HDACs) have emerged as key regulators in the pathogenesis of various kidney diseases. This review explores recent advancements in HDAC research, focusing on their role in kidney development and their critical involvement in the progression of chronic kidney disease (CKD), acute kidney injury (AKI), autosomal dominant polycystic kidney disease (ADPKD), and diabetic kidney disease (DKD). It also discusses the therapeutic potential of HDAC inhibitors in treating these conditions. Various HDAC inhibitors have shown promise by targeting specific HDAC isoforms and modulating a range of biological pathways. Their protective effects include modulation of apoptosis, autophagy, inflammation, and fibrosis, underscoring their broad therapeutic potential for kidney diseases. However, further research is essential to improve the selectivity of HDAC inhibitors, minimize toxicity, overcome drug resistance, and enhance their pharmacokinetic properties. This review offers insights to guide future research and prevention strategies for kidney disease management.
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Affiliation(s)
- Yue Zheng
- Department of Pediatrics, Shengjing Hospital of China Medical University, Shenyang 110004, China
| | - Tie-Ning Zhang
- Department of Pediatrics, Shengjing Hospital of China Medical University, Shenyang 110004, China
| | - Peng-Hui Hao
- Department of Pediatrics, Shengjing Hospital of China Medical University, Shenyang 110004, China
| | - Ni Yang
- Department of Pediatrics, Shengjing Hospital of China Medical University, Shenyang 110004, China.
| | - Yue Du
- Department of Pediatrics, Shengjing Hospital of China Medical University, Shenyang 110004, China; Key Laboratory of Health Ministry for Congenital Malformation, Shengjing Hospital, China Medical University, Shenyang, China.
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Li J, Chen LT, Wang YL, Kang MX, Liang ST, Hong XZ, Hou FF, Zhang FJ. Inhibition of HIF-prolyl hydroxylase promotes renal tubule regeneration via the reprogramming of renal proximal tubular cells. Acta Pharmacol Sin 2025; 46:1002-1015. [PMID: 39775504 PMCID: PMC11950656 DOI: 10.1038/s41401-024-01445-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/06/2024] [Accepted: 11/24/2024] [Indexed: 01/11/2025]
Abstract
The ability of the mammalian kidney to repair or regenerate after acute kidney injury (AKI) is very limited. The maladaptive repair of AKI promotes progression to chronic kidney disease (CKD). Therefore, new strategies to promote the repair/regeneration of injured renal tubules after AKI are urgently needed. Hypoxia has been shown to induce heart regeneration in adult mice. However, it is unknown whether hypoxia can induce kidney regeneration after AKI. In this study, we used a prolyl hydroxylase domain inhibitor (PHDI), MK-8617, to mimic hypoxic conditions and found that MK-8617 significantly ameliorated ischemia reperfusion injury (IRI)-induced AKI. We also showed that MK-8617 dramatically facilitated renal tubule regeneration by promoting the proliferation of renal proximal tubular cells (RPTCs) after IRI-induced AKI. We then performed bulk mRNA sequencing and discovered that multiple nephrogenesis-related genes were significantly upregulated with MK-8617 pretreatment. We also showed that MK-8617 may alleviate proximal tubule injury by stabilizing the HIF-1α protein specifically in renal proximal tubular cells. Furthermore, we demonstrated that MK-8617 promotes the reprogramming of renal proximal tubular cells to Sox9+ renal progenitor cells and the regeneration of renal proximal tubules. In summary, we report that the inhibition of prolyl hydroxylase improves renal proximal tubule regeneration after IRI-induced AKI by promoting the reprogramming of renal proximal tubular cells to Sox9+ renal progenitor cells.
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Affiliation(s)
- Jing Li
- Division of Nephrology, Nanfang Hospital, Southern Medical University; National Clinical Research Center for Kidney Disease; State Key Laboratory of Organ Failure Research; Guangdong Provincial Institute of Nephrology; Guangdong Provincial Key Laboratory of Renal Failure Research, Guangzhou, 510515, China
- Department of Critical Care Medicine, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, 450008, China
| | - Li-Ting Chen
- Division of Nephrology, Nanfang Hospital, Southern Medical University; National Clinical Research Center for Kidney Disease; State Key Laboratory of Organ Failure Research; Guangdong Provincial Institute of Nephrology; Guangdong Provincial Key Laboratory of Renal Failure Research, Guangzhou, 510515, China
| | - You-Liang Wang
- Division of Nephrology, Nanfang Hospital, Southern Medical University; National Clinical Research Center for Kidney Disease; State Key Laboratory of Organ Failure Research; Guangdong Provincial Institute of Nephrology; Guangdong Provincial Key Laboratory of Renal Failure Research, Guangzhou, 510515, China
| | - Mei-Xia Kang
- Division of Nephrology, Nanfang Hospital, Southern Medical University; National Clinical Research Center for Kidney Disease; State Key Laboratory of Organ Failure Research; Guangdong Provincial Institute of Nephrology; Guangdong Provincial Key Laboratory of Renal Failure Research, Guangzhou, 510515, China
| | - Shi-Ting Liang
- Division of Nephrology, Nanfang Hospital, Southern Medical University; National Clinical Research Center for Kidney Disease; State Key Laboratory of Organ Failure Research; Guangdong Provincial Institute of Nephrology; Guangdong Provincial Key Laboratory of Renal Failure Research, Guangzhou, 510515, China
| | - Xi-Zhen Hong
- Division of Nephrology, Nanfang Hospital, Southern Medical University; National Clinical Research Center for Kidney Disease; State Key Laboratory of Organ Failure Research; Guangdong Provincial Institute of Nephrology; Guangdong Provincial Key Laboratory of Renal Failure Research, Guangzhou, 510515, China
| | - Fan Fan Hou
- Division of Nephrology, Nanfang Hospital, Southern Medical University; National Clinical Research Center for Kidney Disease; State Key Laboratory of Organ Failure Research; Guangdong Provincial Institute of Nephrology; Guangdong Provincial Key Laboratory of Renal Failure Research, Guangzhou, 510515, China
| | - Fu-Jian Zhang
- Division of Nephrology, Nanfang Hospital, Southern Medical University; National Clinical Research Center for Kidney Disease; State Key Laboratory of Organ Failure Research; Guangdong Provincial Institute of Nephrology; Guangdong Provincial Key Laboratory of Renal Failure Research, Guangzhou, 510515, China.
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Mboni-Johnston IM, Hartmann S, Kroll C, Berndt C, Adjaye J, Schupp N. Impact of nephrotoxins and oxidants on survival and transport function of hiPSC-derived renal proximal tubular cells. Arch Toxicol 2025:10.1007/s00204-025-04015-1. [PMID: 40119912 DOI: 10.1007/s00204-025-04015-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2024] [Accepted: 02/27/2025] [Indexed: 03/25/2025]
Abstract
Due to their role in excretion, renal proximal tubular cells are susceptible to damage by toxic metabolites and xenobiotics. The regenerative capacity of the kidney allows for the replacement of damaged cells, a process involving differentiation programs. However, kidney function tends to decline, suggesting that the replacement cells may not achieve full functionality. To understand possible causes of this decline, we investigated effects of nephrotoxins and oxidants on the differentiation of induced pluripotent stem cells (iPSC) into proximal tubular epithelial-like cells (PTELC). Proliferation, apoptosis, senescence, and expression of oxidative defense genes were analyzed in iPSC, differentiating and differentiated cells treated with cisplatin (CisPt, up to 45 µM), cyclosporin A (CycA, up to 12 µM), and the oxidants menadione (Mena, up to 50 µM) and tert-butylhydroquinone (tBHQ, up to 50 µM). We found that differentiating cells were most sensitive to oxidants and showed increased sensitivity to CisPt, whereas all differentiation stages showed similar sensitivity to CycA. Both oxidative stress and CisPt triggered apoptosis in all differentiation stages, whereas CycA mainly induced senescence. Treatment during differentiation resulted in long-term effects on gene expression in differentiated cells. While oxidants had no effect on transport function of differentiated cells, CisPt and CycA impaired albumin uptake. Our data suggest a substantial sensitivity of differentiating cells to nephrotoxins and oxidants, an aspect that could potentially interfere with regenerative processes.
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Affiliation(s)
- Isaac Musong Mboni-Johnston
- Institute of Toxicology, Medical Faculty, University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, Moorenstraße 5, 40225, Düsseldorf, Germany
| | - Sören Hartmann
- Institute of Toxicology, Medical Faculty, University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, Moorenstraße 5, 40225, Düsseldorf, Germany
| | - Christian Kroll
- Department of Neurology, Medical Faculty, University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, 40225, Düsseldorf, Germany
| | - Carsten Berndt
- Department of Neurology, Medical Faculty, University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, 40225, Düsseldorf, Germany
| | - James Adjaye
- Institute for Stem Cell Research and Regenerative Medicine, Medical Faculty, University Hospital Düsseldorf, University of Düsseldorf, 40225, Düsseldorf, Germany
- Zayed Centre for Research into Rare Diseases in Children (ZCR), EGA Institute for Women'S Health, University College London (UCL), 20 Guilford Street, London, WC1N 1DZ, UK
| | - Nicole Schupp
- Institute of Toxicology, Medical Faculty, University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, Moorenstraße 5, 40225, Düsseldorf, Germany.
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Janosevic D, De Luca T, Eadon MT. The Kidney Precision Medicine Project and Single-Cell Biology of the Injured Proximal Tubule. THE AMERICAN JOURNAL OF PATHOLOGY 2025; 195:7-22. [PMID: 39332674 PMCID: PMC11686451 DOI: 10.1016/j.ajpath.2024.09.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/26/2024] [Revised: 08/29/2024] [Accepted: 09/11/2024] [Indexed: 09/29/2024]
Abstract
Single-cell RNA sequencing (scRNA-seq) has led to major advances in our understanding of proximal tubule subtypes in health and disease. The proximal tubule serves essential functions in overall homeostasis, but pathologic or physiological perturbations can affect its transcriptomic signature and corresponding tasks. These alterations in proximal tubular cells are often described within a scRNA-seq atlas as cell states, which are pathophysiological subclassifications based on molecular and morphologic changes in a cell's response to that injury compared with its native state. This review describes the major cell states defined in the Kidney Precision Medicine Project's scRNA-seq atlas. It then identifies the overlap between the Kidney Precision Medicine Project and other seminal works that may use different nomenclature or cluster proximal tubule cells at different resolutions to define cell state subtypes. The goal is for the reader to understand the key transcriptomic markers of important cellular injury and regeneration processes across this highly dynamic and evolving field.
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Affiliation(s)
- Danielle Janosevic
- Division of Nephrology, Indiana University School of Medicine, Indianapolis, Indiana
| | - Thomas De Luca
- Division of Nephrology, Indiana University School of Medicine, Indianapolis, Indiana
| | - Michael T Eadon
- Division of Nephrology, Indiana University School of Medicine, Indianapolis, Indiana.
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Jeong K, Je J, Dusabimana T, Karekezi J, Nugroho TA, Ndahigwa EN, Kim HJ, Yun SP, Kim HJ, Kim H, Park SW. Deficiency of purinergic P2Y2 receptor impairs the recovery after renal ischemia-reperfusion injury and accelerates renal fibrosis and tubular senescence in mice. Sci Rep 2024; 14:31932. [PMID: 39738595 PMCID: PMC11686187 DOI: 10.1038/s41598-024-83411-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2024] [Accepted: 12/13/2024] [Indexed: 01/02/2025] Open
Abstract
Chronic kidney disease is defined as a progressive loss of kidney function associated with impaired recovery after acute kidney injury. Renal ischemia-reperfusion (IR) induces oxidative stress and inflammatory responses leading to severe tissue damage, where incomplete or maladaptive repair accelerates renal fibrosis and aging. To investigate the role of the purinergic P2Y2 receptor (P2Y2R) in these processes, we used P2Y2R knockout (KO) mice subjected to IR. KO mice showed severe kidney dysfunction and structural damage compared to WT mice. KO mice showed higher senescence-associated β-galactosidase expression and shorter telomere length than WT mice. Consistently, interstitial collagen accumulation and fibrogenic mediators were significantly upregulated in KO mice. Renal apoptosis and inflammation were highly elevated in KO mice. Interestingly, cell proliferation as shown by Ki-67 and PCNA expression, was increased for 3 days after IR in WT mice, whereas it maintained increased for 14 days in KO mice. Cell cycle inhibitors, p16 and p21, and regulators JunB and cyclin E were significantly increased after IR in KO mice, suggesting that cell cycle progression was impaired during recovery after IR. Proximal tubular cells treated with JunB siRNA showed a reduced expression of fibrogenic mediators and proinflammatory cytokines, consistent with the mice treated with MRS2768, a P2Y2 agonist that downregulated JunB levels. In conclusion, P2Y2R reduces kidney tissue damage after IR and repairs the tissue properly by regulating JunB-mediated signaling during the recovery process.
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Affiliation(s)
- Kyuho Jeong
- Department of Pharmacology, Institute of Health Sciences, Gyeongsang National University College of Medicine, 15, 816 Beon-gil, Jinjudaero, Jinju, 52727, Republic of Korea
- Department of Biochemistry, Dongguk University College of Medicine, Gyeongju, 38066, Republic of Korea
| | - Jihyun Je
- Department of Pharmacology, Institute of Health Sciences, Gyeongsang National University College of Medicine, 15, 816 Beon-gil, Jinjudaero, Jinju, 52727, Republic of Korea
| | - Theodomir Dusabimana
- Department of Pharmacology, Institute of Health Sciences, Gyeongsang National University College of Medicine, 15, 816 Beon-gil, Jinjudaero, Jinju, 52727, Republic of Korea
| | - Jacques Karekezi
- Department of Pharmacology, Institute of Health Sciences, Gyeongsang National University College of Medicine, 15, 816 Beon-gil, Jinjudaero, Jinju, 52727, Republic of Korea
- Department of Convergence Medical Science, Gyeongsang National University Graduate School, Jinju, 52727, Republic of Korea
| | - Tatang Aldi Nugroho
- Department of Pharmacology, Institute of Health Sciences, Gyeongsang National University College of Medicine, 15, 816 Beon-gil, Jinjudaero, Jinju, 52727, Republic of Korea
- Department of Convergence Medical Science, Gyeongsang National University Graduate School, Jinju, 52727, Republic of Korea
| | - Edvard Ntambara Ndahigwa
- Department of Pharmacology, Institute of Health Sciences, Gyeongsang National University College of Medicine, 15, 816 Beon-gil, Jinjudaero, Jinju, 52727, Republic of Korea
- Department of Convergence Medical Science, Gyeongsang National University Graduate School, Jinju, 52727, Republic of Korea
| | - Hyun Joon Kim
- Department of Anatomy, Institute of Health Sciences, Gyeongsang National University College of Medicine, Jinju, 52727, Republic of Korea
- Department of Convergence Medical Science, Gyeongsang National University Graduate School, Jinju, 52727, Republic of Korea
| | - Seung Pil Yun
- Department of Pharmacology, Institute of Health Sciences, Gyeongsang National University College of Medicine, 15, 816 Beon-gil, Jinjudaero, Jinju, 52727, Republic of Korea
- Department of Convergence Medical Science, Gyeongsang National University Graduate School, Jinju, 52727, Republic of Korea
| | - Hye Jung Kim
- Department of Pharmacology, Institute of Health Sciences, Gyeongsang National University College of Medicine, 15, 816 Beon-gil, Jinjudaero, Jinju, 52727, Republic of Korea
- Department of Convergence Medical Science, Gyeongsang National University Graduate School, Jinju, 52727, Republic of Korea
| | - Hwajin Kim
- Department of Pharmacology, Institute of Health Sciences, Gyeongsang National University College of Medicine, 15, 816 Beon-gil, Jinjudaero, Jinju, 52727, Republic of Korea.
| | - Sang Won Park
- Department of Pharmacology, Institute of Health Sciences, Gyeongsang National University College of Medicine, 15, 816 Beon-gil, Jinjudaero, Jinju, 52727, Republic of Korea.
- Department of Anatomy, Institute of Health Sciences, Gyeongsang National University College of Medicine, Jinju, 52727, Republic of Korea.
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Zhang T, Widdop RE, Ricardo SD. Transition from acute kidney injury to chronic kidney disease: mechanisms, models, and biomarkers. Am J Physiol Renal Physiol 2024; 327:F788-F805. [PMID: 39298548 DOI: 10.1152/ajprenal.00184.2024] [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: 06/26/2024] [Revised: 08/15/2024] [Accepted: 09/01/2024] [Indexed: 09/22/2024] Open
Abstract
Acute kidney injury (AKI) and chronic kidney disease (CKD) are increasingly recognized as interconnected conditions with overlapping pathophysiological mechanisms. This review examines the transition from AKI to CKD, focusing on the molecular mechanisms, animal models, and biomarkers essential for understanding and managing this progression. AKI often progresses to CKD due to maladaptive repair processes, persistent inflammation, and fibrosis, with both conditions sharing common pathways involving cell death, inflammation, and extracellular matrix (ECM) deposition. Current animal models, including ischemia-reperfusion injury (IRI) and nephrotoxic damage, help elucidate these mechanisms but have limitations in replicating the complexity of human disease. Emerging biomarkers such as kidney injury molecule-1 (KIM-1), neutrophil gelatinase-associated lipocalin (NGAL), and soluble tumor necrosis factor receptors (TNFRs) show promise in early detection and monitoring of disease progression. This review highlights the need for improved animal models and biomarker validation to better mimic human disease and enhance clinical translation. Advancing our understanding of the AKI-to-CKD transition through targeted therapies and refined research approaches holds the potential to significantly improve patient outcomes.
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Affiliation(s)
- Tingfang Zhang
- Department of Pharmacology, Biomedicine Discovery Institute, Monash University, Clayton, Victoria, Australia
| | - Robert E Widdop
- Department of Pharmacology, Biomedicine Discovery Institute, Monash University, Clayton, Victoria, Australia
| | - Sharon D Ricardo
- Department of Pharmacology, Biomedicine Discovery Institute, Monash University, Clayton, Victoria, Australia
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Li Y, Min X, Zhang X, Cao X, Kong Q, Mao Q, Cheng H, Gou L, Li Y, Li C, Liu L, Ding Z. HSPA12A promotes c-Myc lactylation-mediated proliferation of tubular epithelial cells to facilitate renal functional recovery from kidney ischemia/reperfusion injury. Cell Mol Life Sci 2024; 81:404. [PMID: 39277835 PMCID: PMC11402889 DOI: 10.1007/s00018-024-05427-5] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2024] [Revised: 08/08/2024] [Accepted: 08/27/2024] [Indexed: 09/17/2024]
Abstract
Proliferation of renal tubular epithelial cells (TEC) is essential for restoring tubular integrity and thereby to support renal functional recovery from kidney ischemia/reperfusion (KI/R) injury. Activation of transcriptional factor c-Myc promotes TEC proliferation following KI/R; however, the mechanism regarding c-Myc activation in TEC is incompletely known. Heat shock protein A12A (HSPA12A) is an atypic member of HSP70 family. In this study, we found that KI/R decreased HSPA12A expression in mouse kidneys and TEC, while ablation of HSPA12A in mice impaired TEC proliferation and renal functional recovery following KI/R. Gain-of-functional studies demonstrated that HSPA12A promoted TEC proliferation upon hypoxia/reoxygenation (H/R) through directly interacting with c-Myc and enhancing its nuclear localization to upregulate expression of its target genes related to TEC proliferation. Notably, c-Myc was lactylated in TEC after H/R, and this lactylation was enhanced by HSPA12A overexpression. Importantly, inhibition of c-Myc lactylation attenuated the HSPA12A-induced increases of c-Myc nuclear localization, proliferation-related gene expression, and TEC proliferation. Further experiments revealed that HSPA12A promoted c-Myc lactylation via increasing the glycolysis-derived lactate generation in a Hif1α-dependent manner. The results unraveled a role of HSPA12A in promoting TEC proliferation and facilitating renal recovery following KI/R, and this role of HSPA12A was achieved through increasing lactylation-mediated c-Myc activation. Therefore, targeting HSPA12A in TEC might be a viable strategy to promote renal functional recovery from KI/R injury in patients.
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Affiliation(s)
- Yunfan Li
- Department of Anesthesiology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China
| | - Xinxu Min
- Department of Anesthesiology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China
| | - Xiaojin Zhang
- Department of Geriatrics, Jiangsu Provincial Key Laboratory of Geriatrics, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China
| | - Xiaofei Cao
- Department of Anesthesiology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China
| | - Qiuyue Kong
- Department of Anesthesiology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China
| | - Qian Mao
- Department of Anesthesiology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China
| | - Hao Cheng
- Department of Anesthesiology, The First Affiliated Hospital With Wannan Medical College, Wuhu, 241001, China
| | - Liming Gou
- Core Laboratory, Sir Run Run Hospital, Nanjing Medical University, Nanjing, 211166, China
| | - Yuehua Li
- Key Laboratory of Targeted Intervention of Cardiovascular Disease, Collaborative Innovation Center for Cardiovascular Disease Translational Medicine, Nanjing Medical University, Nanjing, 210029, China
| | - Chuanfu Li
- Department of Surgery, East Tennessee State University, Johnson City, TN, 37614, USA
| | - Li Liu
- Department of Geriatrics, Jiangsu Provincial Key Laboratory of Geriatrics, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China
- Key Laboratory of Targeted Intervention of Cardiovascular Disease, Collaborative Innovation Center for Cardiovascular Disease Translational Medicine, Nanjing Medical University, Nanjing, 210029, China
| | - Zhengnian Ding
- Department of Anesthesiology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China.
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10
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Pasten C, Lozano M, Osorio LA, Cisterna M, Jara V, Sepúlveda C, Ramírez-Balaguera D, Moreno-Hidalgo V, Arévalo-Gil D, Soto P, Hurtado V, Morales A, Méndez GP, Busso D, Leon P, Michea L, Corvalán D, Luarte A, Irarrazabal CE. The protective effect of 1400W against ischaemia and reperfusion injury is countered by transient medullary kidney endothelial dysregulation. J Physiol 2024. [PMID: 39057844 DOI: 10.1113/jp285944] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2024] [Accepted: 06/12/2024] [Indexed: 07/28/2024] Open
Abstract
Renal ischaemia and reperfusion (I/R) is caused by a sudden temporary impairment of the blood flow. I/R is a prevalent cause of acute kidney injury. As nitric oxide generated by inducible nitric oxide synthase (iNOS) has detrimental effects during I/R, the pharmacological blockade of iNOS has been proposed as a potential strategy to prevent I/R injury. The aim of this study was to improve the understanding of 1400W (an iNOS inhibitor) on renal I/R as a pharmacological strategy against kidney disease. BALB/c mice received 30 min of bilateral ischaemia, followed by 48 h or 28 days of reperfusion. Vehicle or 1400W (10 mg/kg) was administered 30 min before inducing ischaemia. We found that after 48 h of reperfusion 1400W decreased the serum creatinine, blood urea nitrogen, neutrophil gelatinase-associated lipocalin and proliferating cell nuclear antigen 3 in the I/R animals. Unexpectedly, we observed mRNA upregulation of genes involved in kidney injury, cell-cycle arrest, inflammation, mesenchymal transition and endothelial activation in the renal medulla of sham animals treated with 1400W. We also explored if 1400W promoted chronic kidney dysfunction 28 days after I/R and did not find significant alterations in renal function, fibrosis, blood pressure or mortality. The results provide evidence that 1400W may have adverse effects in the renal medulla. Importantly, our data point to 1400W-induced endothelial dysfunction, establishing therapeutic limitations for its use. KEY POINTS: Acute kidney injury is a global health problem associated with high morbidity and mortality. The pharmacological blockade of inducible nitric oxide synthase (iNOS) has been proposed as a potential strategy to prevent AKI induced by ischaemia and reperfusion (I/R). Our main finding is that 1400W, a selective and irreversible iNOS inhibitor with low toxicity that is proposed as a therapeutic strategy to prevent kidney I/R injury, produces aberrant gene expression in the medulla associated to tissue injury, cell cycle arrest, inflammation, mesenchymal transition and endothelial activation. The negative effect of 1400W observed in the renal medulla at 48 h from drug administration, is transient as it did not translate into a chronic kidney disease condition.
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Affiliation(s)
- Consuelo Pasten
- Centro de Investigación e Innovación Biomédica (CiiB), Programa de Fisiología, Laboratorio de Fisiología Integrativa y Molecular, Universidad de los Andes, Chile
- Facultad de Medicina, Universidad de los Andes, Chile
| | - Mauricio Lozano
- Centro de Investigación e Innovación Biomédica (CiiB), Programa de Fisiología, Laboratorio de Fisiología Integrativa y Molecular, Universidad de los Andes, Chile
| | - Luis A Osorio
- Centro de Investigación e Innovación Biomédica (CiiB), Programa de Fisiología, Laboratorio de Fisiología Integrativa y Molecular, Universidad de los Andes, Chile
| | - Matías Cisterna
- Centro de Investigación e Innovación Biomédica (CiiB), Programa de Fisiología, Laboratorio de Fisiología Integrativa y Molecular, Universidad de los Andes, Chile
| | - Valeria Jara
- Centro de Investigación e Innovación Biomédica (CiiB), Programa de Fisiología, Laboratorio de Fisiología Integrativa y Molecular, Universidad de los Andes, Chile
| | - Catalina Sepúlveda
- Centro de Investigación e Innovación Biomédica (CiiB), Programa de Fisiología, Laboratorio de Fisiología Integrativa y Molecular, Universidad de los Andes, Chile
| | - Daniela Ramírez-Balaguera
- Centro de Investigación e Innovación Biomédica (CiiB), Programa de Fisiología, Laboratorio de Fisiología Integrativa y Molecular, Universidad de los Andes, Chile
| | - Viviana Moreno-Hidalgo
- Centro de Investigación e Innovación Biomédica (CiiB), Programa de Fisiología, Laboratorio de Fisiología Integrativa y Molecular, Universidad de los Andes, Chile
| | - Dayana Arévalo-Gil
- Centro de Investigación e Innovación Biomédica (CiiB), Programa de Fisiología, Laboratorio de Fisiología Integrativa y Molecular, Universidad de los Andes, Chile
| | - Paola Soto
- Centro de Investigación e Innovación Biomédica (CiiB), Programa de Fisiología, Laboratorio de Fisiología Integrativa y Molecular, Universidad de los Andes, Chile
| | - Valeria Hurtado
- Centro de Investigación e Innovación Biomédica (CiiB), Programa de Fisiología, Laboratorio de Fisiología Integrativa y Molecular, Universidad de los Andes, Chile
| | - Antonia Morales
- Centro de Investigación e Innovación Biomédica (CiiB), Programa de Fisiología, Laboratorio de Fisiología Integrativa y Molecular, Universidad de los Andes, Chile
| | | | - Dolores Busso
- Centro de Investigación e Innovación Biomédica (CiiB), Programa de Biología de la Reproducción, Universidad de los Andes, Chile
| | - Pablo Leon
- Programa de Fisiología y Biofísica, ICBM, Facultad de Medicina, Universidad de Chile, Santiago, Chile
| | - Luis Michea
- Programa de Fisiología y Biofísica, ICBM, Facultad de Medicina, Universidad de Chile, Santiago, Chile
| | - Daniela Corvalán
- Neuroscience Program, Center of Interventional Medicine for Precision and Advanced Cellular Therapy (IMPACT), Universidad de los Andes, Chile
| | - Alejandro Luarte
- Neuroscience Program, Center of Interventional Medicine for Precision and Advanced Cellular Therapy (IMPACT), Universidad de los Andes, Chile
| | - Carlos E Irarrazabal
- Centro de Investigación e Innovación Biomédica (CiiB), Programa de Fisiología, Laboratorio de Fisiología Integrativa y Molecular, Universidad de los Andes, Chile
- Facultad de Medicina, Universidad de los Andes, Chile
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11
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Pye K, Tasinato E, Shuttleworth S, Devlin C, Brown C. Comparison of the Impact of VRP-034 and Polymyxin B upon Markers of Kidney Injury in Human Proximal Tubule Monolayers In Vitro. Antibiotics (Basel) 2024; 13:530. [PMID: 38927196 PMCID: PMC11201133 DOI: 10.3390/antibiotics13060530] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2024] [Revised: 06/01/2024] [Accepted: 06/01/2024] [Indexed: 06/28/2024] Open
Abstract
In this study, we assessed the impact of commercially available polymyxin B against VRP-034 (novel formulation of polymyxin B) using a validated in vitro human renal model, aProximateTM. Freshly isolated primary proximal tubule cells (PTCs) were cultured in Transwell plates and treated with various concentrations of the formulations for up to 48 h. The functional expression of megalin-cubilin receptors in PTC monolayers was validated using FITC-conjugated albumin uptake assays. Polymyxin B and VRP-034 were evaluated at six concentrations (0.3, 1, 3, 10, 30, and 60 µM), and nephrotoxicity was assessed through measurements of transepithelial electrical resistance (TEER), intracellular adenosine triphosphate (ATP) levels, lactate dehydrogenase (LDH) release, and novel injury biomarkers [kidney injury molecule-1 (KIM-1), neutrophil gelatinase-associated lipocalin (NGAL), and clusterin]. Additionally, histological analysis using annexin V apoptosis staining was performed. Our results indicated a significant decrease in TEER with polymyxin B at concentrations ≥10 μM compared to VRP-034. Toxic effects were observed from ATP and LDH release only at concentrations ≥30 μM for both formulations. Furthermore, injury biomarker release was higher with polymyxin B compared to VRP-034, particularly at concentrations ≥10 µM. Histologically, polymyxin B-treated PTCs showed increased apoptosis compared to VRP-034-treated cells. Overall, VRP-034 demonstrated improved tolerance in the aProximateTM model compared to polymyxin B, suggesting its potential as a safer alternative for renal protection.
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Affiliation(s)
- Keith Pye
- Newcells Biotech Ltd., The Biosphere, Newcastle-upon-Tyne NE4 5BX, UK
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12
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Matsushita K, Toyoda T, Akane H, Morikawa T, Ogawa K. CD44 expression in renal tubular epithelial cells in the kidneys of rats with cyclosporine-induced chronic kidney disease. J Toxicol Pathol 2024; 37:55-67. [PMID: 38584969 PMCID: PMC10995437 DOI: 10.1293/tox.2023-0111] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2023] [Accepted: 12/01/2023] [Indexed: 04/09/2024] Open
Abstract
Renal tubular epithelial cell (TEC) injury is the most common cause of drug-induced kidney injury (DIKI). Although TEC regeneration facilitates renal function and structural recovery following DIKI, maladaptive repair of TECs leads to irreversible fibrosis, resulting in chronic kidney disease (CKD). CD44 is specifically expressed in TECs during maladaptive repair in several types of rat CKD models. In this study, we investigated CD44 expression and its role in renal fibrogenesis in a cyclosporine (CyA) rat model of CKD. Seven-week-old male Sprague-Dawley rats fed a low-salt diet were subcutaneously administered CyA (0, 15, or 30 mg/kg) for 28 days. CD44 was expressed in atrophic, dilated, and hypertrophic TECs in the fibrotic lesions of the CyA groups. These TECs were collected by laser microdissection and evaluated by microarray analysis. Gene ontology analysis suggested that these TECs have a mesenchymal phenotype, and pathway analysis identified CD44 as an upstream regulator of fibrosis-related genes, including fibronectin 1 (Fn1). Immunohistochemistry revealed that epithelial and mesenchymal markers of TECs of fibrotic lesions were downregulated and upregulated, respectively, and that these TECs were surrounded by a thickened basement membrane. In situ hybridization revealed an increase in Fn1 mRNA in the cytoplasm of TECs of fibrotic lesions, whereas fibronectin protein was localized in the stroma surrounding these tubules. Enzyme-linked immunosorbent assay revealed increased serum CD44 levels in CyA-treated rats. Collectively, these findings suggest that CD44 contributes to renal fibrosis by inducing fibronectin secretion in TECs exhibiting partial epithelial-mesenchymal transition and highlight the potential of CD44 as a biomarker of renal fibrosis.
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Affiliation(s)
- Kohei Matsushita
- Division of Pathology, National Institute of Health
Sciences, 3-25-26 Tonomachi, Kawasaki-shi, Kanagawa 210-9501, Japan
| | - Takeshi Toyoda
- Division of Pathology, National Institute of Health
Sciences, 3-25-26 Tonomachi, Kawasaki-shi, Kanagawa 210-9501, Japan
| | - Hirotoshi Akane
- Division of Pathology, National Institute of Health
Sciences, 3-25-26 Tonomachi, Kawasaki-shi, Kanagawa 210-9501, Japan
| | - Tomomi Morikawa
- Division of Pathology, National Institute of Health
Sciences, 3-25-26 Tonomachi, Kawasaki-shi, Kanagawa 210-9501, Japan
| | - Kumiko Ogawa
- Division of Pathology, National Institute of Health
Sciences, 3-25-26 Tonomachi, Kawasaki-shi, Kanagawa 210-9501, Japan
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13
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Matsushita K, Toyoda T, Akane H, Morikawa T, Ogawa K. Role of CD44 expressed in renal tubules during maladaptive repair in renal fibrogenesis in an allopurinol-induced rat model of chronic kidney disease. J Appl Toxicol 2024; 44:455-469. [PMID: 37876353 DOI: 10.1002/jat.4554] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2023] [Revised: 09/30/2023] [Accepted: 10/01/2023] [Indexed: 10/26/2023]
Abstract
The kidney is a major target organ for the adverse effects of pharmaceuticals; renal tubular epithelial cells (TECs) are particularly vulnerable to drug-induced toxicity. TECs have regenerative capacity; however, maladaptive repair of TECs after injury leads to renal fibrosis, resulting in chronic kidney disease (CKD). We previously reported the specific expression of CD44 in failed-repair TECs of rat CKD model induced by ischemia reperfusion injury. Here, we investigated the pathophysiological role of CD44 in renal fibrogenesis in allopurinol-treated rat CKD model. Dilated or atrophic TECs expressing CD44 in fibrotic areas were collected by laser microdissection and subjected to microarray analysis. Gene ontology showed that extracellular matrix (ECM)-related genes were upregulated and differentiation-related genes were downregulated in dilated/atrophic TECs. Ingenuity Pathway Analysis identified CD44 as an upstream regulator of fibrosis-related genes, including Fn1, which encodes fibronectin. Immunohistochemistry demonstrated that dilated/atrophic TECs expressing CD44 showed decreases in differentiation markers of TECs and clear expression of mesenchymal markers during basement membrane attachment. In situ hybridization revealed an increase in Fn1 mRNA in the cytoplasm of dilated/atrophic TECs, whereas fibronectin was localized in the stroma around these TECs, supporting the production/secretion of ECM by dilated/atrophic TECs. Overall, these data indicated that dilated/atrophic TECs underwent a partial epithelial-mesenchymal transition (pEMT) and that CD44 promoted renal fibrogenesis via induction of ECM production in failed-repair TECs exhibiting pEMT. CD44 was detected in the urine and serum of APL-treated rats, which may reflect the expression of CD44 in the kidney.
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Affiliation(s)
- Kohei Matsushita
- Division of Pathology, National Institute of Health Sciences, Kawasaki, Kanagawa, Japan
| | - Takeshi Toyoda
- Division of Pathology, National Institute of Health Sciences, Kawasaki, Kanagawa, Japan
| | - Hirotoshi Akane
- Division of Pathology, National Institute of Health Sciences, Kawasaki, Kanagawa, Japan
| | - Tomomi Morikawa
- Division of Pathology, National Institute of Health Sciences, Kawasaki, Kanagawa, Japan
| | - Kumiko Ogawa
- Division of Pathology, National Institute of Health Sciences, Kawasaki, Kanagawa, Japan
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14
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Mao Y, Zhou Y, Chen Y, Xu R, Wu YQ, Zhu WW, Wang XF, Wang Q, Juan CX. Transcriptional mechanism of E2F1/TFAP2C/NRF1 in regulating KANK2 gene in nephrotic syndrome. Exp Cell Res 2024; 435:113931. [PMID: 38253280 DOI: 10.1016/j.yexcr.2024.113931] [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: 06/17/2023] [Revised: 01/06/2024] [Accepted: 01/12/2024] [Indexed: 01/24/2024]
Abstract
The mortality rate linked with nephrotic syndrome (NS) is quite high. The renal tubular injury influences the response of NS patients to steroid treatment. KN motif and ankyrin repeat domains 2 (KANK2) regulates actin polymerization, which is required for renal tubular cells to maintain their function. In this study, we found that the levels of KANK2 in patients with NS were considerably lower than those in healthy controls, especially in NS patients with acute kidney injury (AKI). To get a deeper understanding of the KANK2 transcriptional control mechanism, the core promoter region of the KANK2 gene was identified. KANK2 was further found to be positively regulated by E2F Transcription Factor 1 (E2F1), Transcription Factor AP-2 Gamma (TFAP2C), and Nuclear Respiratory Factor 1 (NRF1), both at mRNA and protein levels. Knocking down E2F1, TFAP2C, or NRF1 deformed the cytoskeleton of renal tubular cells and reduced F-actin content. EMSA and ChIP assays confirmed that all three transcription factors could bind to the upstream promoter transcription site of KANK2 to transactivate KANK2 in renal tubular epithelial cells. Our study suggests that E2F1, TFAP2C, and NRF1 play essential roles in regulating the KANK2 transcription, therefore shedding fresh light on the development of putative therapeutic options for the treatment of NS patients.
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Affiliation(s)
- Yan Mao
- Jiangsu Province Hospital of Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, Jiangsu, 210004, China.
| | - Yan Zhou
- Jiangsu Province Hospital of Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, Jiangsu, 210004, China.
| | - Yan Chen
- National Clinical Research Center for Kidney Diseases, Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, Jiangsu, 210018, China.
| | - Rong Xu
- Jiangsu Province Hospital of Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, Jiangsu, 210004, China.
| | - Yi-Qing Wu
- Jiangsu Province Hospital of Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, Jiangsu, 210004, China.
| | - Wei-Wei Zhu
- Jiangsu Province Hospital of Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, Jiangsu, 210004, China.
| | - Xu-Fang Wang
- Jiangsu Province Hospital of Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, Jiangsu, 210004, China.
| | - Qian Wang
- Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 201600, China.
| | - Chen-Xia Juan
- Jiangsu Province Hospital of Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, Jiangsu, 210004, China.
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15
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Yousef Yengej FA, Pou Casellas C, Ammerlaan CME, Olde Hanhof CJA, Dilmen E, Beumer J, Begthel H, Meeder EMG, Hoenderop JG, Rookmaaker MB, Verhaar MC, Clevers H. Tubuloid differentiation to model the human distal nephron and collecting duct in health and disease. Cell Rep 2024; 43:113614. [PMID: 38159278 DOI: 10.1016/j.celrep.2023.113614] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2023] [Revised: 11/09/2023] [Accepted: 12/06/2023] [Indexed: 01/03/2024] Open
Abstract
Organoid technology is rapidly gaining ground for studies on organ (patho)physiology. Tubuloids are long-term expanding organoids grown from adult kidney tissue or urine. The progenitor state of expanding tubuloids comes at the expense of differentiation. Here, we differentiate tubuloids to model the distal nephron and collecting ducts, essential functional parts of the kidney. Differentiation suppresses progenitor traits and upregulates genes required for function. A single-cell atlas reveals that differentiation predominantly generates thick ascending limb and principal cells. Differentiated human tubuloids express luminal NKCC2 and ENaC capable of diuretic-inhibitable electrolyte uptake and enable disease modeling as demonstrated by a lithium-induced tubulopathy model. Lithium causes hallmark AQP2 loss, induces proliferation, and upregulates inflammatory mediators, as seen in vivo. Lithium also suppresses electrolyte transport in multiple segments. In conclusion, this tubuloid model enables modeling of the human distal nephron and collecting duct in health and disease and provides opportunities to develop improved therapies.
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Affiliation(s)
- Fjodor A Yousef Yengej
- Hubrecht Institute for Developmental Biology and Stem Cell Research-KNAW & University Medical Center Utrecht, 3584 CT Utrecht, the Netherlands; Department of Nephrology and Hypertension, University Medical Center Utrecht, 3584 CX Utrecht, the Netherlands
| | - Carla Pou Casellas
- Hubrecht Institute for Developmental Biology and Stem Cell Research-KNAW & University Medical Center Utrecht, 3584 CT Utrecht, the Netherlands; Department of Nephrology and Hypertension, University Medical Center Utrecht, 3584 CX Utrecht, the Netherlands
| | - Carola M E Ammerlaan
- Hubrecht Institute for Developmental Biology and Stem Cell Research-KNAW & University Medical Center Utrecht, 3584 CT Utrecht, the Netherlands; Department of Nephrology and Hypertension, University Medical Center Utrecht, 3584 CX Utrecht, the Netherlands
| | - Charlotte J A Olde Hanhof
- Department of Medical BioSciences, Radboud Institute for Medical Innovation, 6525 GA Nijmegen, the Netherlands
| | - Emre Dilmen
- Department of Medical BioSciences, Radboud Institute for Medical Innovation, 6525 GA Nijmegen, the Netherlands
| | - Joep Beumer
- Hubrecht Institute for Developmental Biology and Stem Cell Research-KNAW, 3584 CT Utrecht, the Netherlands; Institute of Human Biology, Roche Pharma Research and Early Development, 4058 Basel, Switzerland
| | - Harry Begthel
- Hubrecht Institute for Developmental Biology and Stem Cell Research-KNAW, 3584 CT Utrecht, the Netherlands
| | - Elise M G Meeder
- Department of Psychiatry, Radboud University Medical Center, 6525 GA Nijmegen, the Netherlands
| | - Joost G Hoenderop
- Department of Medical BioSciences, Radboud Institute for Medical Innovation, 6525 GA Nijmegen, the Netherlands
| | - Maarten B Rookmaaker
- Department of Nephrology and Hypertension, University Medical Center Utrecht, 3584 CX Utrecht, the Netherlands
| | - Marianne C Verhaar
- Department of Nephrology and Hypertension, University Medical Center Utrecht, 3584 CX Utrecht, the Netherlands.
| | - Hans Clevers
- Hubrecht Institute for Developmental Biology and Stem Cell Research-KNAW & University Medical Center Utrecht, 3584 CT Utrecht, the Netherlands; Oncode Institute, Hubrecht Institute-KNAW, 3584 CT Utrecht, the Netherlands.
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16
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Arabul S, Melikoglu M, Kirimlioglu E, Boneval BC, Karaguzel G. Renal regenerative capacity related to stem cell reserve in nephrectomized rats. World J Urol 2024; 42:25. [PMID: 38206410 DOI: 10.1007/s00345-023-04702-7] [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: 04/01/2023] [Accepted: 11/17/2023] [Indexed: 01/12/2024] Open
Abstract
PURPOSE On the new era of stem cell therapy, the present experimental study was conducted to investigate renal regenerative capacity related to kidney stem cell reserve in different nephrectomy (Nx) models. METHODS Three- and eight-week-old rats (n = 168) were randomly divided into four groups to include control and three Nx subgroups (1/6 Nx, 1/2 Nx, and 5/6 Nx) (Fig. 1). On post-Nx days 15, 30 and 60, kidney specimens were obtained to determine renal regenerative capacity. The specimens were examined with immunofluorescence. CD90/CD105 and Ki-67 expressions were determined as stem cell and cellular proliferation markers, respectively. Fig. 1 Intraoperative photographs showing three different types of nephrectomies (unilateral total Nx has not been shown in 5/6 Nx group) RESULTS: CD90 and CD105 expressions were stronger in glomeruli, but Ki-67 expressions were present only in tubuli. When all Nx types and post-Nx days were considered, both 3- and 8-week-old rats undergone 5/6 Nx had the highest glomerular CD90 and CD105 double expressions. While the expressions gradually increased toward the day 60 in 3-weeks old rats, 8-week-old rats had almost stable double expressions. The strongest tubular Ki-67 expressions were seen in 5/6 Nx groups of both in 3- and 8-week-old rats. The expressions were strongest on day 15 and then gradually decreased. Ipsilateral 1/6 Nx groups had stronger Ki-67 expression than contralateral ones in both age groups. CONCLUSIONS Kidneys may pose a regenerative response to tissue/volume loss through its own CD90- and CD105-related stem cell reserve which mainly takes place in glomeruli and seems to have some interactions with Ki-67-related tubular proliferative process. This response supports that kidney stem cells may have a potential to overcome tissue/volume loss-related damage.
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Affiliation(s)
- Songul Arabul
- Department of Pediatric Surgery, Akdeniz University Faculty of Medicine, Antalya, Türkiye.
| | - Mustafa Melikoglu
- Department of Pediatric Surgery, Akdeniz University Faculty of Medicine, Antalya, Türkiye
| | - Esma Kirimlioglu
- Department of Histology and Embryology, Akdeniz University Faculty of Medicine, Antalya, Türkiye
| | - Bezmi Cem Boneval
- Department of Pediatric Surgery, Akdeniz University Faculty of Medicine, Antalya, Türkiye
| | - Gungor Karaguzel
- Department of Pediatric Surgery, Akdeniz University Faculty of Medicine, Antalya, Türkiye
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17
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Rossiter A, La A, Koyner JL, Forni LG. New biomarkers in acute kidney injury. Crit Rev Clin Lab Sci 2024; 61:23-44. [PMID: 37668397 DOI: 10.1080/10408363.2023.2242481] [Citation(s) in RCA: 12] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2023] [Revised: 05/14/2023] [Accepted: 07/26/2023] [Indexed: 09/06/2023]
Abstract
Acute kidney injury (AKI) is a commonly encountered clinical syndrome. Although it often complicates community acquired illness, it is more common in hospitalized patients, particularly those who are critically ill or who have undergone major surgery. Approximately 20% of hospitalized adult patients develop an AKI during their hospital care, and this rises to nearly 60% in the critically ill, depending on the population being considered. In general, AKI is more common in older adults, in those with preexisting chronic kidney disease and in those with known risk factors for AKI (including diabetes and hypertension). The development of AKI is associated with an increase in both mortality and morbidity, including the development of post-AKI chronic kidney disease. Currently, AKI is defined by a rise in serum creatinine from either a known or derived baseline value and/or oliguria or anuria. However, clinicians may fail to recognize the initial development of AKI because of a delay in the rise of serum creatinine or because of inaccurate urine output monitoring. This, in turn, delays any putative measures to treat AKI or to limit its degree. Consequently, efforts have focused on new biomarkers associated with AKI that may allow early recognition of this syndrome with the intent that this will translate into improved patient outcomes. Here we outline current biomarkers associated with AKI and explore their potential in aiding diagnosis, understanding the pathophysiology and directing therapy.
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Affiliation(s)
- Adam Rossiter
- Critical Care Unit, Royal Surrey Hospital, Guildford, Surry, UK
| | - Ashley La
- Department of Medicine, University of Chicago, Chicago, Illinois, USA
| | - Jay L Koyner
- Department of Medicine, University of Chicago, Chicago, Illinois, USA
| | - Lui G Forni
- Critical Care Unit, Royal Surrey Hospital, Guildford, Surry, UK
- School of Medicine, Department of Clinical & Experimental Medicine, Faculty of Health Sciences, University of Surrey, Surry, UK
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18
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Fischer Sigel LK, Sánchez DS, Sacerdoti F, Zotta E, Silberstein C. Progression of renal damage and tubular regeneration in pregnant and non-pregnant adult female rats inoculated with a sublethal dose of Shiga toxin 2. Microb Pathog 2024; 186:106482. [PMID: 38086442 DOI: 10.1016/j.micpath.2023.106482] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2023] [Revised: 11/13/2023] [Accepted: 11/29/2023] [Indexed: 12/17/2023]
Abstract
BACKGROUND Shiga toxin-producing Escherichia coli is the main cause of post-diarrheal hemolytic uremic syndrome (HUS) which produces acute kidney injury mainly in children, although it can also affect adults. The kidneys are the organs most affected by Shiga toxin type 2 (Stx2) in patients with HUS. However, previous studies in pregnant rats showed that a sublethal dose of Stx2 causes severe damage in the uteroplacental unit and induces abortion, whereas produces mild to moderate renal damage. The aim of the present work was to study the progression of renal injury caused by a sublethal dose of Stx2, as well as renal recovery, in pregnant and non-pregnant rats, and to investigate whether pregnancy physiology may affect renal damage progression mediated by Stx2. METHODS Renal function and histopathology was evaluated in pregnant rats intraperitoneally injected with a sublethal dose of Stx2 (0.5 ng/g bwt) at the early stage of gestation (day 8 of gestation), and results in these rats were compared over time with those observed in non-pregnant female rats injected with the same Stx2 dose. Hence, progression of cell proliferation and dedifferentiation in renal tubular epithelia was also investigated. RESULTS The sublethal dose of Stx2 induced abortion in pregnant rats as well as a significant more extended functional and histological renal injury in non-pregnant rats than in pregnant rats. Stx2 also caused decreased ability to concentrate urine in non-pregnant rats compared to their controls. However, renal water handling in pregnant rats was not altered by Stx2, and was significantly different than in non-pregnant rats. The greatest renal injury in both pregnant and non-pregnant rats was observed at 4 days post-Stx2 injection, and coincided with a significant increase in tubular epithelial proliferation. Expression of mesenchymal marker vimentin in tubular epithelia was consistent with the level of tubular damage, being higher in non-pregnant rats than in pregnant rats. Recovery from Stx2-induced kidney injury was faster in pregnant rats than in non-pregnant rats. CONCLUSIONS Adaptive mechanisms developed during pregnancy such as changes in water handle and renal hemodynamic may contribute to lessen the Stx2-induced renal injury, perhaps at the expense of fetal loss.
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Affiliation(s)
- Lilian K Fischer Sigel
- Universidad de Buenos Aires (UBA), Facultad de Ciencias Médicas, Departamento de Ciencias Fisiológicas, Laboratorio de Fisiología Renal, Buenos Aires, Argentina; Universidad de Buenos Aires - Consejo Nacional de Investigaciones Científicas y Tecnológicas (CONICET), Instituto de Fisiología y Biofísica Bernardo Houssay (IFIBIO Houssay), Buenos Aires, Argentina
| | - Daiana S Sánchez
- Universidad de Buenos Aires (UBA), Facultad de Ciencias Médicas, Departamento de Ciencias Fisiológicas, Laboratorio de Fisiología Renal, Buenos Aires, Argentina; Universidad de Buenos Aires - Consejo Nacional de Investigaciones Científicas y Tecnológicas (CONICET), Instituto de Fisiología y Biofísica Bernardo Houssay (IFIBIO Houssay), Buenos Aires, Argentina
| | - Flavia Sacerdoti
- Universidad de Buenos Aires - Consejo Nacional de Investigaciones Científicas y Tecnológicas (CONICET), Instituto de Fisiología y Biofísica Bernardo Houssay (IFIBIO Houssay), Buenos Aires, Argentina; Universidad de Buenos Aires, Facultad de Ciencias Médicas, Departamento de Ciencias Fisiológicas, Laboratorio de Fisiopatogenia, Buenos Aires, Argentina
| | - Elsa Zotta
- Universidad de Buenos Aires - Consejo Nacional de Investigaciones Científicas y Tecnológicas (CONICET), Instituto de Fisiología y Biofísica Bernardo Houssay (IFIBIO Houssay), Buenos Aires, Argentina; Universidad de Buenos Aires, Facultad de Ciencias Médicas, Departamento de Ciencias Fisiológicas, Laboratorio de Fisiopatogenia, Buenos Aires, Argentina; Universidad de Buenos Aires, Facultad de Ciencias Médicas, Departamento de Ciencias Fisiológicas. Laboratorio de Patología, and Facultad de Farmacia y Bioquímica, Cátedra de Fisiopatología, Buenos Aires, Argentina
| | - Claudia Silberstein
- Universidad de Buenos Aires (UBA), Facultad de Ciencias Médicas, Departamento de Ciencias Fisiológicas, Laboratorio de Fisiología Renal, Buenos Aires, Argentina; Universidad de Buenos Aires - Consejo Nacional de Investigaciones Científicas y Tecnológicas (CONICET), Instituto de Fisiología y Biofísica Bernardo Houssay (IFIBIO Houssay), Buenos Aires, Argentina.
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Hou X, Cui B, Qiu A, Liu N, Zhuang S. Pharmacological inhibition of the mixed lineage leukemia 1-menin interaction aggravates acute kidney injury induced by folic acid and ischemia-reperfusion in mice. Am J Physiol Renal Physiol 2023; 325:F669-F680. [PMID: 37733875 PMCID: PMC11905865 DOI: 10.1152/ajprenal.00287.2022] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2022] [Revised: 08/16/2023] [Accepted: 09/11/2023] [Indexed: 09/23/2023] Open
Abstract
Mixed lineage leukemia 1 (MLL1) is a methyltransferase that induces histone H3 lysine 4 trimethylation (H3K4me3) and partially exerts its untoward functional effects by interacting with multiple subunits including menin and WD repeat-containing protein 5 (WDR5). In this study, we investigated the role and mechanisms of MLL1 in murine models of acute kidney injury induced by folic acid (FA) and ischemia-reperfusion. Injury to the kidney elevated the expression of MLL1, menin, WDR5, and H3K4Me3, which was accompanied by increased serum creatinine and blood urea nitrogen, renal tubular injury, and apoptosis. Pharmacological inhibition of MLL1 activity with MI503 to disrupt the interaction between MLL1 with menin further increased serum creatinine and blood urea nitrogen levels, enhanced expression of neutrophil gelatinase-associated lipocalin and kidney injury molecule-1, and induced more apoptosis in the kidney following FA and ischemia-reperfusion injury. In contrast, MI503 treatment decreased the expression of vimentin and proliferating cell nuclear antigens. Similarly, treatment with MM102 to disrupt the interaction between MLL1 and WDR5 also worsened renal dysfunction, aggravated tubular cell injury, increased apoptosis, and inhibited cellular dedifferentiation and proliferation in mice following FA injection. Moreover, MI503 inhibited FA-induced phosphorylation of epidermal growth factor receptor, signal transducer and activator of transcription 3, and extracellular signal-regulated kinase-1/2 in injured kidneys. Collectively, these data suggest that MLL1 contributes to renal protection and functional recovery and promotes renal regeneration through a mechanism associated with activation of the epidermal growth factor receptor signaling pathway.NEW & NOTEWORTHY Mixed lineage leukemia 1 (MLL1) is a methyltransferase that induces histone H3 lysine 4 trimethylation and exerts its functional roles by interacting with multiple subunits. In this study, we demonstrated that inhibition of MLL1 activity by MI503 or MM102 aggravated renal injury and apoptosis and suppressed renal tubular cell dedifferentiation and proliferation, suggesting that MLL1 activation during acute kidney injury acts as an intrinsic protective mechanism to mediate renal tubular cell survival and regeneration.
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Affiliation(s)
- Xiying Hou
- Department of Nephrology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China
| | - Binbin Cui
- Department of Nephrology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China
| | - Andong Qiu
- School of Life Science and Technology, Advanced Institute of Translational Medicine, Tongji University, Shanghai, China
| | - Na Liu
- Department of Nephrology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China
| | - Shougang Zhuang
- Department of Nephrology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China
- Department of Medicine, Rhode Island Hospital and Alpert Medical School, Brown University, Providence, Rhode Island, United States
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20
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Ibi Y, Nishinakamura R. Kidney Bioengineering for Transplantation. Transplantation 2023; 107:1883-1894. [PMID: 36717963 DOI: 10.1097/tp.0000000000004526] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]
Abstract
The kidney is an important organ for maintenance of homeostasis in the human body. As renal failure progresses, renal replacement therapy becomes necessary. However, there is a chronic shortage of kidney donors, creating a major problem for transplantation. To solve this problem, many strategies for the generation of transplantable kidneys are under investigation. Since the first reports describing that nephron progenitors could be induced from human induced pluripotent stem cells, kidney organoids have been attracting attention as tools for studying human kidney development and diseases. Because the kidney is formed through the interactions of multiple renal progenitors, current studies are investigating ways to combine these progenitors derived from human induced pluripotent stem cells for the generation of transplantable kidney organoids. Other bioengineering strategies, such as decellularization and recellularization of scaffolds, 3-dimensional bioprinting, interspecies blastocyst complementation and progenitor replacement, and xenotransplantation, also have the potential to generate whole kidneys, although each of these strategies has its own challenges. Combinations of these approaches will lead to the generation of bioengineered kidneys that are transplantable into humans.
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Affiliation(s)
- Yutaro Ibi
- Department of Kidney Development, Institute of Molecular Embryology and Genetics, Kumamoto University, Kumamoto, Japan
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21
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Yu Z, Zhou Y, Zhang Y, Ning X, Li T, Wei L, Wang Y, Bai X, Sun S. Cell Profiling of Acute Kidney Injury to Chronic Kidney Disease Reveals Novel Oxidative Stress Characteristics in the Failed Repair of Proximal Tubule Cells. Int J Mol Sci 2023; 24:11617. [PMID: 37511374 PMCID: PMC10380716 DOI: 10.3390/ijms241411617] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2023] [Revised: 06/16/2023] [Accepted: 06/27/2023] [Indexed: 07/30/2023] Open
Abstract
Chronic kidney disease (CKD) is a major public health issue around the world. A significant number of CKD patients originates from acute kidney injury (AKI) patients, namely "AKI-CKD". CKD is significantly related to the consequences of AKI. Damaged renal proximal tubular (PT) cell repair has been widely confirmed to indicate the renal prognosis of AKI. Oxidative stress is a key damage-associated factor and plays a significant role throughout the development of AKI and CKD. However, the relationships between AKI-CKD progression and oxidative stress are not totally clear and the underlying mechanisms in "AKI-CKD" remain indistinct. In this research, we constructed unilateral ischemia-reperfusion injury (UIRI)-model mice and performed single-nucleus RNA sequencing (snRNA-seq) of the kidney samples from UIRI and sham mice. We obtained our snRNA-seq data and validated the findings based on the joint analysis of public databases, as well as a series of fundamental experiments. Proximal tubular cells associated with failed repair express more complete senescence and oxidative stress characteristics compared to other subgroups. Furthermore, oxidative stress-related transcription factors, including Stat3 and Dnmt3a, are significantly more active under the circumstance of failed repair. What is more, we identified abnormally active intercellular communication between PT cells associated with failed repair and macrophages through the APP-CD74 pathway. More notably, we observed that the significantly increased expression of CD74 in hypoxia-treated TECs (tubular epithelial cells) was dependent on adjacently infiltrated macrophages, which was essential for the further deterioration of failed repair in PT cells. This research provides a novel understanding of the process of AKI to CKD progression, and the oxidative stress-related characteristics that we identified might represent a potentially novel therapeutic strategy against AKI.
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Affiliation(s)
- Zhixiang Yu
- Department of Nephrology, Xijing Hospital, Fourth Military Medical University, Xi’an 710032, China
| | - Ying Zhou
- Department of Nephrology, Xijing Hospital, Fourth Military Medical University, Xi’an 710032, China
| | - Yuzhan Zhang
- Department of Nephrology, Xijing Hospital, Fourth Military Medical University, Xi’an 710032, China
| | - Xiaoxuan Ning
- Department of Geriatrics, Xijing Hospital, Fourth Military Medical University, Xi’an 710032, China
| | - Tian Li
- School of Basic Medicine, Fourth Military Medical University, Xi’an 710032, China
| | - Lei Wei
- Department of Nephrology, Xijing Hospital, Fourth Military Medical University, Xi’an 710032, China
| | - Yingxue Wang
- National Local Joint Engineering Research Center for Precision Surgery & Regenerative Medicine, Shaanxi Provincial Center for Regenerative Medicine and Surgical Engineering, Center for Regenerative and Reconstructive Medicine, Med-X Institute, First Affiliated Hospital of Xi’an Jiaotong University, 124, 76 West Yanta Road, Xi’an 710061, China;
| | - Xiao Bai
- Department of Nephrology, Xijing Hospital, Fourth Military Medical University, Xi’an 710032, China
| | - Shiren Sun
- Department of Nephrology, Xijing Hospital, Fourth Military Medical University, Xi’an 710032, China
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22
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Harris AS, Aratani S, Johmura Y, Suzuki N, Dan L, Nakanishi M. In vivo dynamics of senescence in rhabdomyolysis-induced acute kidney injury. Biochem Biophys Res Commun 2023; 673:121-130. [PMID: 37385006 DOI: 10.1016/j.bbrc.2023.06.046] [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: 05/22/2023] [Accepted: 06/14/2023] [Indexed: 07/01/2023]
Abstract
Cellular senescence is involved in the pathogenesis of various diseases, including acute kidney injury (AKI). AKI is defined as a sudden loss of kidney function. In severe AKI, irreversible loss of kidney cells can occur. Cellular senescence might contribute to this maladaptive tubular repair, though, its pathophysiological role in vivo is incompletely understood. In this study, we used p16-CreERT2-tdTomato mice in which cells with high p16 expression, a prototypical senescent marker, are labeled with tdTomato fluorescence. Then, we induced AKI by rhabdomyolysis and traced the cells with high p16 expression following AKI. We proved that the induction of senescence was observed predominantly in proximal tubular epithelial cells (PTECs) and occurred in a relatively acute phase within 1-3 days after AKI. These acute senescent PTECs were spontaneously eliminated by day 15. On the contrary, the generation of senescence in PTECs persisted during the chronic recovery phase. We also confirmed that the kidney function did not fully recover on day 15. These results suggest that the chronic generation of senescent PTECs might contribute to maladaptive recovery from AKI and lead to chronic kidney disease progression.
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Affiliation(s)
- Alexander S Harris
- Division of Cancer Cell Biology, Institute of Medical Science, University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo, 108-8639, Japan
| | - Sae Aratani
- Division of Cancer Cell Biology, Institute of Medical Science, University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo, 108-8639, Japan; Department of Endocrinology, Metabolism and Nephrology, Graduate School of Medicine, Nippon Medical School, 1-1-5 Sendagi, Bunkyo-ku, Tokyo, 113-8603, Japan.
| | - Yoshikazu Johmura
- Division of Cancer and Senescence Biology, Cancer Research Institute, Institute for Frontier Science Initiative, Kanazawa University, Kakuma-machi, Kanazawa, 920-1192, Japan
| | - Narumi Suzuki
- Division of Cancer Cell Biology, Institute of Medical Science, University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo, 108-8639, Japan
| | - Li Dan
- Division of Cancer Cell Biology, Institute of Medical Science, University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo, 108-8639, Japan
| | - Makoto Nakanishi
- Division of Cancer Cell Biology, Institute of Medical Science, University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo, 108-8639, Japan.
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23
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Prem PN, Chellappan DR, Kurian GA. Impaired renal ischemia reperfusion recovery after bilateral renal artery ligation in rats treated with adenine: role of renal mitochondria. J Bioenerg Biomembr 2023; 55:219-232. [PMID: 37392294 DOI: 10.1007/s10863-023-09974-7] [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: 04/17/2023] [Accepted: 06/24/2023] [Indexed: 07/03/2023]
Abstract
Vascular calcification (VC) and ischemia reperfusion (IR) injury is characterised to have mitochondrial dysfunction. However, the impact of dysfunctional mitochondria associated with vascular calcified rat kidney challenged to IR is not explored and is addressed in the present study. Male Wistar rats were treated with adenine for 20 days to induce chronic kidney dysfunction and VC. After 63 days, renal IR protocol was performed with subsequent recovery for 24 h and 7 days. Various mitochondrial parameters and biochemical assays were performed to assess kidney function, IR injury and its recovery. Adenine-induced rats with VC, decreased creatinine clearance (CrCl), and severe tissue injury demonstrated an increase in renal tissue damage and decreased CrCl after 24 h of IR (CrCl in ml: IR-0.220.02, VC-IR-0.050.01). Incidentally, the 24 h IR pathology in kidney was similar in both VC-IR and normal rat IR. But, the magnitude of dysfunction was higher with VC-IR due to pre-existing basal tissue alterations. We found severed deterioration in mitochondrial quantity and quality supported by low bioenergetic function in both VC basal tissue and IR challenged sample. However, post 7 days of IR, unlike normal rat IR, VC rat IR did not improve CrCl and corresponding mitochondrial damage in terms of quantity and its function were observed. Based on the above findings, we conclude that IR in VC rat adversely affect the post-surgical recovery, mainly due to the ineffective renal mitochondrial functional restoration from the surgery.
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Affiliation(s)
- Priyanka N Prem
- School of Chemical and Biotechnology, SASTRA Deemed University, Tirumalaisamudram, Thanjavur, Tamil Nadu, India
- Vascular Biology lab, School of Chemical and Biotechnology, SASTRA Deemed University, Tirumalaisamudram, Thanjavur, Tamil Nadu, India
| | - David Raj Chellappan
- School of Chemical and Biotechnology, SASTRA Deemed University, Tirumalaisamudram, Thanjavur, Tamil Nadu, India
| | - Gino A Kurian
- School of Chemical and Biotechnology, SASTRA Deemed University, Tirumalaisamudram, Thanjavur, Tamil Nadu, India.
- Vascular Biology lab, School of Chemical and Biotechnology, SASTRA Deemed University, Tirumalaisamudram, Thanjavur, Tamil Nadu, India.
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24
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Nakai K, Umehara M, Minamida A, Yamauchi-Sawada H, Sunahara Y, Matoba Y, Okuno-Ozeki N, Nakamura I, Nakata T, Yagi-Tomita A, Uehara-Watanabe N, Ida T, Yamashita N, Kamezaki M, Kirita Y, Konishi E, Yasuda H, Matoba S, Tamagaki K, Kusaba T. Streptozotocin induces renal proximal tubular injury through p53 signaling activation. Sci Rep 2023; 13:8705. [PMID: 37248327 DOI: 10.1038/s41598-023-35850-w] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2022] [Accepted: 05/24/2023] [Indexed: 05/31/2023] Open
Abstract
Streptozotocin (STZ), an anti-cancer drug that is primarily used to treat neuroendocrine tumors (NETs) in clinical settings, is incorporated into pancreatic β-cells or proximal tubular epithelial cells through the glucose transporter, GLUT2. However, its cytotoxic effects on kidney cells have been underestimated and the underlying mechanisms remain unclear. We herein demonstrated that DNA damage and subsequent p53 signaling were responsible for the development of STZ-induced tubular epithelial injury. We detected tubular epithelial DNA damage in NET patients treated with STZ. Unbiased transcriptomics of STZ-treated tubular epithelial cells in vitro showed the activation of the p53 signaling pathway. STZ induced DNA damage and activated p53 signaling in vivo in a dose-dependent manner, resulting in reduced membrane transporters. The pharmacological inhibition of p53 and sodium-glucose transporter 2 (SGLT2) mitigated STZ-induced epithelial injury. However, the cytotoxic effects of STZ on pancreatic β-cells were preserved in SGLT2 inhibitor-treated mice. The present results demonstrate the proximal tubular-specific cytotoxicity of STZ and the underlying mechanisms in vivo. Since the cytotoxic effects of STZ against β-cells were not impaired by dapagliflozin, pretreatment with an SGLT2 inhibitor has potential as a preventative remedy for kidney injury in NET patients treated with STZ.
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Affiliation(s)
- Kunihiro Nakai
- Department of Nephrology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kamigyo-ku, Kyoto, 602-8566, Japan
| | - Minato Umehara
- Department of Nephrology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kamigyo-ku, Kyoto, 602-8566, Japan
| | - Atsushi Minamida
- Department of Nephrology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kamigyo-ku, Kyoto, 602-8566, Japan
| | - Hiroko Yamauchi-Sawada
- Department of Nephrology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kamigyo-ku, Kyoto, 602-8566, Japan
| | - Yasuto Sunahara
- Department of Nephrology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kamigyo-ku, Kyoto, 602-8566, Japan
| | - Yayoi Matoba
- Department of Nephrology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kamigyo-ku, Kyoto, 602-8566, Japan
| | - Natsuko Okuno-Ozeki
- Department of Nephrology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kamigyo-ku, Kyoto, 602-8566, Japan
| | - Itaru Nakamura
- Department of Nephrology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kamigyo-ku, Kyoto, 602-8566, Japan
| | - Tomohiro Nakata
- Department of Nephrology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kamigyo-ku, Kyoto, 602-8566, Japan
| | - Aya Yagi-Tomita
- Department of Nephrology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kamigyo-ku, Kyoto, 602-8566, Japan
| | - Noriko Uehara-Watanabe
- Department of Nephrology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kamigyo-ku, Kyoto, 602-8566, Japan
| | - Tomoharu Ida
- Department of Nephrology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kamigyo-ku, Kyoto, 602-8566, Japan
| | - Noriyuki Yamashita
- Department of Nephrology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kamigyo-ku, Kyoto, 602-8566, Japan
| | - Michitsugu Kamezaki
- Department of Nephrology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kamigyo-ku, Kyoto, 602-8566, Japan
| | - Yuhei Kirita
- Department of Nephrology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kamigyo-ku, Kyoto, 602-8566, Japan
| | - Eiichi Konishi
- Department of Surgical Pathology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Hiroaki Yasuda
- Department of Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Satoaki Matoba
- Department of Cardiovascular Medicine, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Keiichi Tamagaki
- Department of Nephrology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kamigyo-ku, Kyoto, 602-8566, Japan
| | - Tetsuro Kusaba
- Department of Nephrology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kamigyo-ku, Kyoto, 602-8566, Japan.
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Gerhardt LM, Koppitch K, van Gestel J, Guo J, Cho S, Wu H, Kirita Y, Humphreys BD, McMahon AP. Lineage Tracing and Single-Nucleus Multiomics Reveal Novel Features of Adaptive and Maladaptive Repair after Acute Kidney Injury. J Am Soc Nephrol 2023; 34:554-571. [PMID: 36735940 PMCID: PMC10103206 DOI: 10.1681/asn.0000000000000057] [Citation(s) in RCA: 54] [Impact Index Per Article: 27.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2022] [Accepted: 11/17/2022] [Indexed: 01/22/2023] Open
Abstract
SIGNIFICANCE STATEMENT Understanding the mechanisms underlying adaptive and maladaptive renal repair after AKI and their long-term consequences is critical to kidney health. The authors used lineage tracing of cycling cells and single-nucleus multiomics (profiling transcriptome and chromatin accessibility) after AKI. They demonstrated that AKI triggers a cell-cycle response in most epithelial and nonepithelial kidney cell types. They also showed that maladaptive proinflammatory proximal tubule cells (PTCs) persist until 6 months post-AKI, although they decreased in abundance over time, in part, through cell death. Single-nucleus multiomics of lineage-traced cells revealed regulatory features of adaptive and maladaptive repair. These included activation of cell state-specific transcription factors and cis-regulatory elements, and effects in PTCs even after adaptive repair, weeks after the injury event. BACKGROUND AKI triggers a proliferative response as part of an intrinsic cellular repair program, which can lead to adaptive renal repair, restoring kidney structure and function, or maladaptive repair with the persistence of injured proximal tubule cells (PTCs) and an altered kidney structure. However, the cellular and molecular understanding of these repair programs is limited. METHODS To examine chromatin and transcriptional responses in the same cell upon ischemia-reperfusion injury (IRI), we combined genetic fate mapping of cycling ( Ki67+ ) cells labeled early after IRI with single-nucleus multiomics-profiling transcriptome and chromatin accessibility in the same nucleus-and generated a dataset of 83,315 nuclei. RESULTS AKI triggered a broad cell cycle response preceded by cell type-specific and global transcriptional changes in the nephron, the collecting and vascular systems, and stromal and immune cell types. We observed a heterogeneous population of maladaptive PTCs throughout proximal tubule segments 6 months post-AKI, with a marked loss of maladaptive cells from 4 weeks to 6 months. Gene expression and chromatin accessibility profiling in the same nuclei highlighted differences between adaptive and maladaptive PTCs in the activity of cis-regulatory elements and transcription factors, accompanied by corresponding changes in target gene expression. Adaptive repair was associated with reduced expression of genes encoding transmembrane transport proteins essential to kidney function. CONCLUSIONS Analysis of genome organization and gene activity with single-cell resolution using lineage tracing and single-nucleus multiomics offers new insight into the regulation of renal injury repair. Weeks to months after mild-to-moderate IRI, maladaptive PTCs persist with an aberrant epigenetic landscape, and PTCs exhibit an altered transcriptional profile even following adaptive repair.
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Affiliation(s)
- Louisa M.S. Gerhardt
- Department of Stem Cell Biology and Regenerative Medicine, Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research, Keck School of Medicine of the University of Southern California, Los Angeles, California
| | - Kari Koppitch
- Department of Stem Cell Biology and Regenerative Medicine, Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research, Keck School of Medicine of the University of Southern California, Los Angeles, California
| | - Jordi van Gestel
- Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, California
- Developmental Biology Unit, European Molecular Biology Laboratory, Heidelberg, Germany
| | - Jinjin Guo
- Department of Stem Cell Biology and Regenerative Medicine, Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research, Keck School of Medicine of the University of Southern California, Los Angeles, California
| | - Sam Cho
- Department of Stem Cell Biology and Regenerative Medicine, Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research, Keck School of Medicine of the University of Southern California, Los Angeles, California
| | - Haojia Wu
- Division of Nephrology, Department of Medicine, Washington University in St. Louis, St. Louis, Missouri
| | - Yuhei Kirita
- Department of Nephrology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Benjamin D. Humphreys
- Division of Nephrology, Department of Medicine, Washington University in St. Louis, St. Louis, Missouri
- Department of Developmental Biology, Washington University in St. Louis, St. Louis, Missouri
| | - Andrew P. McMahon
- Department of Stem Cell Biology and Regenerative Medicine, Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research, Keck School of Medicine of the University of Southern California, Los Angeles, California
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Zhang T, Li Y, Wise AF, Kulkarni K, Aguilar MI, Samuel CS, Del Borgo M, Widdop RE, Ricardo SD. The protective effects of a novel AT 2 receptor agonist, β-Pro 7Ang III in ischemia-reperfusion kidney injury. Biomed Pharmacother 2023; 161:114556. [PMID: 36948137 DOI: 10.1016/j.biopha.2023.114556] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2023] [Revised: 03/14/2023] [Accepted: 03/15/2023] [Indexed: 03/24/2023] Open
Abstract
BACKGROUND AND PURPOSE This study investigated the reno-protective effects of a highly selective AT2R agonist peptide, β-Pro7Ang III in a mouse model of acute kidney injury (AKI). METHODS C57BL/6 J mice underwent either sham surgery or unilateral kidney ischemia-reperfusion injury (IRI) for 40 min. IRI mice were treated with either β-Pro7Ang III or perindopril and at 7 days post-surgery the kidneys analysed for histopathology and the development of fibrosis and matrix metalloproteinase (MMP)-2 and -9 activity. The association of the therapeutic effects of β-Pro7Ang III with macrophage number and phenotype was determined in vivo and in vitro. KEY RESULTS Decreased kidney tubular injury, interstitial matrix expansion and reduced interstitial immune cell infiltration in IRI mice receiving β-Pro7Ang III treatment was observed at day 7, compared to IRI mice without treatment. This correlated to reduced collagen accumulation and MMP-2 activity in IRI mice following β-Pro7Ang III treatment. FACS analysis showed a reduced number and proportion of CD45+CD11b+F4/80+ macrophages in IRI kidneys in response to β-Pro7Ang III, correlating with a significant increase in M2 macrophage markers and decreased M1 markers at day 3 and 7 post-IR injury, respectively. In vitro analysis of cultured THP-1 cells showed that β-Pro7Ang III attenuated lipopolysaccharide (LPS)-induced tumour necrosis factor-α (TNF-α) and interleukin (IL)- 6 production but increased IL-10 secretion, compared to LPS alone. CONCLUSION Administration of β-Pro7Ang III via mini-pump improved kidney structure and reduced interstitial collagen accumulation, in parallel with an alteration of macrophage phenotype and anti-inflammatory cytokine release, therefore mitigating the downstream progression of ischemic AKI.
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Affiliation(s)
- Tingfang Zhang
- Department of Pharmacology, Monash Biomedicine Discovery Institute, Monash University, Clayton, Victoria 3800, Australia
| | - Yifang Li
- Department of Pharmacology, Monash Biomedicine Discovery Institute, Monash University, Clayton, Victoria 3800, Australia
| | - Andrea F Wise
- Department of Pharmacology, Monash Biomedicine Discovery Institute, Monash University, Clayton, Victoria 3800, Australia
| | - Ketav Kulkarni
- Department of Biochemistry and Molecular Biology, Monash Biomedicine Discovery Institute, Monash University, Clayton, Victoria 3800, Australia
| | - Marie-Isabel Aguilar
- Department of Biochemistry and Molecular Biology, Monash Biomedicine Discovery Institute, Monash University, Clayton, Victoria 3800, Australia
| | - Chrishan S Samuel
- Department of Pharmacology, Monash Biomedicine Discovery Institute, Monash University, Clayton, Victoria 3800, Australia
| | - Mark Del Borgo
- Department of Pharmacology, Monash Biomedicine Discovery Institute, Monash University, Clayton, Victoria 3800, Australia
| | - Robert E Widdop
- Department of Pharmacology, Monash Biomedicine Discovery Institute, Monash University, Clayton, Victoria 3800, Australia
| | - Sharon D Ricardo
- Department of Pharmacology, Monash Biomedicine Discovery Institute, Monash University, Clayton, Victoria 3800, Australia.
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Zhang Y, Bao S, Wang D, Lu W, Xu S, Zhou W, Wang X, Xu X, Ding X, Zhao S. Downregulation of KLF10 contributes to the regeneration of survived renal tubular cells in cisplatin-induced acute kidney injury via ZBTB7A-KLF10-PTEN axis. Cell Death Discov 2023; 9:82. [PMID: 36878898 PMCID: PMC9988960 DOI: 10.1038/s41420-023-01381-6] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2022] [Revised: 02/22/2023] [Accepted: 02/24/2023] [Indexed: 03/08/2023] Open
Abstract
Acute kidney injury (AKI) is a common clinical dysfunction with complicated pathophysiology and limited therapeutic methods. Renal tubular injury and the following regeneration process play a vital role in the course of AKI, but the underlining molecular mechanism remains unclear. In this study, network-based analysis of online transcriptional data of human kidney found that KLF10 was closely related to renal function, tubular injury and regeneration in various renal diseases. Three classical mouse models confirmed the downregulation of KLF10 in AKI and its correlation with tubular regeneration and AKI outcome. The 3D renal tubular model in vitro and fluorescent visualization system of cellular proliferation were constructed to show that KLF10 declined in survived cells but increased during tubular formation or conquering proliferative impediment. Furthermore, overexpression of KLF10 significantly inhibited, whereas knockdown of KLF10 extremely promoted the capacity of proliferation, injury repairing and lumen-formation of renal tubular cells. In mechanism, PTEN/AKT pathway were validated as the downstream of KLF10 and participated in its regulation of tubular regeneration. By adopting proteomic mass spectrum and dual-luciferase reporter assay, ZBTB7A were found to be the upstream transcription factor of KLF10. Our findings suggest that downregulation of KLF10 positively contributed to tubular regeneration in cisplatin induced acute kidney injury via ZBTB7A-KLF10-PTEN axis, which gives insight into the novel therapeutic and diagnostical target of AKI.
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Affiliation(s)
- Yang Zhang
- Department of Nephrology, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Siyu Bao
- Department of Nephrology, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Daxi Wang
- Department of Nephrology, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Wei Lu
- Department of Nephrology, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Sujuan Xu
- Department of Nephrology, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Weiran Zhou
- Department of Nephrology, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Xiaoyan Wang
- Department of Nephrology, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Xialian Xu
- Department of Nephrology, Zhongshan Hospital, Fudan University, Shanghai, China. .,Shanghai Medical Center of Kidney Disease, Shanghai, China. .,Kidney and Dialysis Institute of Shanghai, Shanghai, China. .,Kidney and Blood Purification Key Laboratory of Shanghai, Shanghai, China.
| | - Xiaoqiang Ding
- Department of Nephrology, Zhongshan Hospital, Fudan University, Shanghai, China. .,Shanghai Medical Center of Kidney Disease, Shanghai, China. .,Kidney and Dialysis Institute of Shanghai, Shanghai, China. .,Kidney and Blood Purification Key Laboratory of Shanghai, Shanghai, China.
| | - Shuan Zhao
- Department of Nephrology, Zhongshan Hospital, Fudan University, Shanghai, China. .,Shanghai Medical Center of Kidney Disease, Shanghai, China. .,Kidney and Dialysis Institute of Shanghai, Shanghai, China. .,Kidney and Blood Purification Key Laboratory of Shanghai, Shanghai, China.
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28
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Wang D, Sant S, Lawless C, Ferrell N. A kidney proximal tubule model to evaluate effects of basement membrane stiffening on renal tubular epithelial cells. Integr Biol (Camb) 2022; 14:171-183. [PMID: 36573280 DOI: 10.1093/intbio/zyac016] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2022] [Revised: 09/21/2022] [Accepted: 11/06/2022] [Indexed: 12/28/2022]
Abstract
The kidney tubule consists of a single layer of epithelial cells supported by the tubular basement membrane (TBM), a thin layer of specialized extracellular matrix (ECM). The mechanical properties of the ECM are important for regulating a wide range of cell functions including proliferation, differentiation and cell survival. Increased ECM stiffness plays a role in promoting multiple pathological conditions including cancer, fibrosis and heart disease. How changes in TBM mechanics regulate tubular epithelial cell behavior is not fully understood. Here we introduce a cell culture system that utilizes in vivo-derived TBM to investigate cell-matrix interactions in kidney proximal tubule cells. Basement membrane mechanics was controlled using genipin, a biocompatibility crosslinker. Genipin modification resulted in a dose-dependent increase in matrix stiffness. Crosslinking had a marginal but statistically significant impact on the diffusive molecular transport properties of the TBM, likely due to a reduction in pore size. Both native and genipin-modified TBM substrates supported tubular epithelial cell growth. Cells were able to attach and proliferate to form confluent monolayers. Tubular epithelial cells polarized and assembled organized cell-cell junctions. Genipin modification had minimal impact on cell viability and proliferation. Genipin stiffened TBM increased gene expression of pro-fibrotic cytokines and altered gene expression for N-cadherin, a proximal tubular epithelial specific cell-cell junction marker. This work introduces a new cell culture model for cell-basement membrane mechanobiology studies that utilizes in vivo-derived basement membrane. We also demonstrate that TBM stiffening affects tubular epithelial cell function through altered gene expression of cell-specific differentiation markers and induced increased expression of pro-fibrotic growth factors.
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Affiliation(s)
- Dan Wang
- Department of Internal Medicine, Division of Nephrology, The Ohio State University Wexner Medical Center, Columbus, OH, USA
| | - Snehal Sant
- Department of Medicine, Division of Nephrology, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Craig Lawless
- Wellcome Trust Centre for Cell-Matrix Research, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, University of Manchester, Manchester, UK
| | - Nicholas Ferrell
- Department of Internal Medicine, Division of Nephrology, The Ohio State University Wexner Medical Center, Columbus, OH, USA
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29
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Taguchi K, Elias BC, Sugahara S, Sant S, Freedman BS, Waikar SS, Pozzi A, Zent R, Harris RC, Parikh SM, Brooks CR. Cyclin G1 induces maladaptive proximal tubule cell dedifferentiation and renal fibrosis through CDK5 activation. J Clin Invest 2022; 132:e158096. [PMID: 36453545 PMCID: PMC9711881 DOI: 10.1172/jci158096] [Citation(s) in RCA: 28] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2022] [Accepted: 10/05/2022] [Indexed: 12/02/2022] Open
Abstract
Acute kidney injury (AKI) occurs in approximately 13% of hospitalized patients and predisposes patients to chronic kidney disease (CKD) through the AKI-to-CKD transition. Studies from our laboratory and others have demonstrated that maladaptive repair of proximal tubule cells (PTCs), including induction of dedifferentiation, G2/M cell cycle arrest, senescence, and profibrotic cytokine secretion, is a key process promoting AKI-to-CKD transition, kidney fibrosis, and CKD progression. The molecular mechanisms governing maladaptive repair and the relative contribution of dedifferentiation, G2/M arrest, and senescence to CKD remain to be resolved. We identified cyclin G1 (CG1) as a factor upregulated in chronically injured and maladaptively repaired PTCs. We demonstrated that global deletion of CG1 inhibits G2/M arrest and fibrosis. Pharmacological induction of G2/M arrest in CG1-knockout mice, however, did not fully reverse the antifibrotic phenotype. Knockout of CG1 did not alter dedifferentiation and proliferation in the adaptive repair response following AKI. Instead, CG1 specifically promoted the prolonged dedifferentiation of kidney tubule epithelial cells observed in CKD. Mechanistically, CG1 promotes dedifferentiation through activation of cyclin-dependent kinase 5 (CDK5). Deletion of CDK5 in kidney tubule cells did not prevent G2/M arrest but did inhibit dedifferentiation and fibrosis. Thus, CG1 and CDK5 represent a unique pathway that regulates maladaptive, but not adaptive, dedifferentiation, suggesting they could be therapeutic targets for CKD.
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Affiliation(s)
- Kensei Taguchi
- Division of Nephrology and Hypertension, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Bertha C. Elias
- Division of Nephrology and Hypertension, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Sho Sugahara
- Division of Nephrology and Hypertension, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Snehal Sant
- Division of Nephrology and Hypertension, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Benjamin S. Freedman
- Kidney Research Institute, Institute for Stem Cell and Regenerative Medicine, and Department of Medicine, Division of Nephrology, University of Washington, Seattle, Washington, USA
| | - Sushrut S. Waikar
- Section of Nephrology, Boston University School of Medicine and Boston Medical Center, Boston, Massachusetts, USA
| | - Ambra Pozzi
- Division of Nephrology and Hypertension, Vanderbilt University Medical Center, Nashville, Tennessee, USA
- Veterans Affairs Hospital, Nashville, Tennessee, USA
| | - Roy Zent
- Division of Nephrology and Hypertension, Vanderbilt University Medical Center, Nashville, Tennessee, USA
- Veterans Affairs Hospital, Nashville, Tennessee, USA
- Department of Cell and Developmental Biology, Vanderbilt University, Nashville, Tennessee, USA
| | - Raymond C. Harris
- Division of Nephrology and Hypertension, Vanderbilt University Medical Center, Nashville, Tennessee, USA
- Veterans Affairs Hospital, Nashville, Tennessee, USA
| | - Samir M. Parikh
- Division of Nephrology, Department of Internal Medicine, Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, Texas, USA
| | - Craig R. Brooks
- Division of Nephrology and Hypertension, Vanderbilt University Medical Center, Nashville, Tennessee, USA
- Department of Cell and Developmental Biology, Vanderbilt University, Nashville, Tennessee, USA
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30
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Wang P, Huang Z, Peng Y, Li H, Lin T, Zhao Y, Hu Z, Zhou Z, Zhou W, Liu Y, Hou FF. Circular RNA circBNC2 inhibits epithelial cell G2-M arrest to prevent fibrotic maladaptive repair. Nat Commun 2022; 13:6502. [PMID: 36316334 PMCID: PMC9622807 DOI: 10.1038/s41467-022-34287-5] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2021] [Accepted: 10/20/2022] [Indexed: 11/17/2022] Open
Abstract
The mechanisms underlying fibrogenic responses after injury are not well understood. Epithelial cell cycle arrest in G2/M after injury is a key checkpoint for determining wound-healing leading to either normal cell proliferation or fibrosis. Here, we identify a kidney- and liver-enriched circular RNA, circBNC2, which is abundantly expressed in normal renal tubular cells and hepatocytes but significantly downregulated after acute ischemic or toxic insult. Loss of circBNC2 is at least partially mediated by upregulation of DHX9. Gain- and loss-of-function studies, both in vitro and in vivo, demonstrate that circBNC2 acts as a negative regulator of cell G2/M arrest by encoding a protein that promotes formation of CDK1/cyclin B1 complexes. Restoring circBNC2 in experimentally-induced male mouse models of fibrotic kidney and liver, decreases G2/M arrested cell numbers with secretion of fibrotic factors, thereby mitigating extracellular matrix deposition and fibrosis. Decreased expression of circBNC2 and increased G2/M arrest of epithelial cells are recapitulated in human ischemic reperfusion injury (IRI)-induced chronic kidney disease and inflammation-induced liver fibrosis, highlighting the clinical relevance. These findings suggest that restoring circBNC2 might represent a potential strategy for therapeutic intervention in epithelial organ fibrosis.
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Affiliation(s)
- Peng Wang
- Division of Nephrology, Nanfang Hospital, Southern Medical University, State Key Laboratory of Organ Failure Research, National Clinical Research Center of Kidney Disease, Guangdong Provincial Key Laboratory of Renal Failure Research, Guangzhou, 510515, China
| | - Zhitao Huang
- Division of Nephrology, Nanfang Hospital, Southern Medical University, State Key Laboratory of Organ Failure Research, National Clinical Research Center of Kidney Disease, Guangdong Provincial Key Laboratory of Renal Failure Research, Guangzhou, 510515, China
| | - Yili Peng
- Division of Nephrology, Nanfang Hospital, Southern Medical University, State Key Laboratory of Organ Failure Research, National Clinical Research Center of Kidney Disease, Guangdong Provincial Key Laboratory of Renal Failure Research, Guangzhou, 510515, China
| | - Hongwei Li
- Division of Nephrology, Nanfang Hospital, Southern Medical University, State Key Laboratory of Organ Failure Research, National Clinical Research Center of Kidney Disease, Guangdong Provincial Key Laboratory of Renal Failure Research, Guangzhou, 510515, China
| | - Tong Lin
- Division of Nephrology, Nanfang Hospital, Southern Medical University, State Key Laboratory of Organ Failure Research, National Clinical Research Center of Kidney Disease, Guangdong Provincial Key Laboratory of Renal Failure Research, Guangzhou, 510515, China
| | - Yingyu Zhao
- Division of Nephrology, Nanfang Hospital, Southern Medical University, State Key Laboratory of Organ Failure Research, National Clinical Research Center of Kidney Disease, Guangdong Provincial Key Laboratory of Renal Failure Research, Guangzhou, 510515, China
| | - Zheng Hu
- Division of Nephrology, Nanfang Hospital, Southern Medical University, State Key Laboratory of Organ Failure Research, National Clinical Research Center of Kidney Disease, Guangdong Provincial Key Laboratory of Renal Failure Research, Guangzhou, 510515, China
| | - Zhanmei Zhou
- Division of Nephrology, Nanfang Hospital, Southern Medical University, State Key Laboratory of Organ Failure Research, National Clinical Research Center of Kidney Disease, Guangdong Provincial Key Laboratory of Renal Failure Research, Guangzhou, 510515, China
| | - Weijie Zhou
- Division of Nephrology, Nanfang Hospital, Southern Medical University, State Key Laboratory of Organ Failure Research, National Clinical Research Center of Kidney Disease, Guangdong Provincial Key Laboratory of Renal Failure Research, Guangzhou, 510515, China
| | - Youhua Liu
- Division of Nephrology, Nanfang Hospital, Southern Medical University, State Key Laboratory of Organ Failure Research, National Clinical Research Center of Kidney Disease, Guangdong Provincial Key Laboratory of Renal Failure Research, Guangzhou, 510515, China
| | - Fan Fan Hou
- Division of Nephrology, Nanfang Hospital, Southern Medical University, State Key Laboratory of Organ Failure Research, National Clinical Research Center of Kidney Disease, Guangdong Provincial Key Laboratory of Renal Failure Research, Guangzhou, 510515, China.
- Guangzhou Regenerative Medicine and Health Guangdong Laboratory, Guangzhou, 510515, China.
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31
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Hinze C, Kocks C, Leiz J, Karaiskos N, Boltengagen A, Cao S, Skopnik CM, Klocke J, Hardenberg JH, Stockmann H, Gotthardt I, Obermayer B, Haghverdi L, Wyler E, Landthaler M, Bachmann S, Hocke AC, Corman V, Busch J, Schneider W, Himmerkus N, Bleich M, Eckardt KU, Enghard P, Rajewsky N, Schmidt-Ott KM. Single-cell transcriptomics reveals common epithelial response patterns in human acute kidney injury. Genome Med 2022; 14:103. [PMID: 36085050 PMCID: PMC9462075 DOI: 10.1186/s13073-022-01108-9] [Citation(s) in RCA: 52] [Impact Index Per Article: 17.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2022] [Accepted: 08/12/2022] [Indexed: 01/07/2023] Open
Abstract
Background Acute kidney injury (AKI) occurs frequently in critically ill patients and is associated with adverse outcomes. Cellular mechanisms underlying AKI and kidney cell responses to injury remain incompletely understood. Methods We performed single-nuclei transcriptomics, bulk transcriptomics, molecular imaging studies, and conventional histology on kidney tissues from 8 individuals with severe AKI (stage 2 or 3 according to Kidney Disease: Improving Global Outcomes (KDIGO) criteria). Specimens were obtained within 1–2 h after individuals had succumbed to critical illness associated with respiratory infections, with 4 of 8 individuals diagnosed with COVID-19. Control kidney tissues were obtained post-mortem or after nephrectomy from individuals without AKI. Results High-depth single cell-resolved gene expression data of human kidneys affected by AKI revealed enrichment of novel injury-associated cell states within the major cell types of the tubular epithelium, in particular in proximal tubules, thick ascending limbs, and distal convoluted tubules. Four distinct, hierarchically interconnected injured cell states were distinguishable and characterized by transcriptome patterns associated with oxidative stress, hypoxia, interferon response, and epithelial-to-mesenchymal transition, respectively. Transcriptome differences between individuals with AKI were driven primarily by the cell type-specific abundance of these four injury subtypes rather than by private molecular responses. AKI-associated changes in gene expression between individuals with and without COVID-19 were similar. Conclusions The study provides an extensive resource of the cell type-specific transcriptomic responses associated with critical illness-associated AKI in humans, highlighting recurrent disease-associated signatures and inter-individual heterogeneity. Personalized molecular disease assessment in human AKI may foster the development of tailored therapies.
Supplementary Information The online version contains supplementary material available at 10.1186/s13073-022-01108-9.
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Affiliation(s)
- Christian Hinze
- Department of Nephrology and Hypertension, Hannover Medical School, Hannover, Germany.,Department of Nephrology and Medical Intensive Care, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität Zu Berlin, Berlin, Germany.,Max Delbrueck Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany
| | - Christine Kocks
- Berlin Institute for Medical Systems Biology, Max Delbrueck Center in the Helmholtz Association, Berlin, Germany
| | - Janna Leiz
- Department of Nephrology and Medical Intensive Care, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität Zu Berlin, Berlin, Germany.,Max Delbrueck Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany
| | - Nikos Karaiskos
- Berlin Institute for Medical Systems Biology, Max Delbrueck Center in the Helmholtz Association, Berlin, Germany
| | - Anastasiya Boltengagen
- Berlin Institute for Medical Systems Biology, Max Delbrueck Center in the Helmholtz Association, Berlin, Germany
| | - Shuang Cao
- Department of Nephrology and Hypertension, Hannover Medical School, Hannover, Germany.,Department of Nephrology and Medical Intensive Care, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität Zu Berlin, Berlin, Germany.,Max Delbrueck Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany
| | - Christopher Mark Skopnik
- Department of Nephrology and Medical Intensive Care, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität Zu Berlin, Berlin, Germany.,Deutsches Rheumaforschungszentrum, an Institute of the Leibniz Foundation, Berlin, Germany
| | - Jan Klocke
- Department of Nephrology and Medical Intensive Care, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität Zu Berlin, Berlin, Germany.,Deutsches Rheumaforschungszentrum, an Institute of the Leibniz Foundation, Berlin, Germany.,Berlin Institute of Health, Berlin, Germany
| | - Jan-Hendrik Hardenberg
- Department of Nephrology and Medical Intensive Care, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität Zu Berlin, Berlin, Germany
| | - Helena Stockmann
- Department of Nephrology and Medical Intensive Care, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität Zu Berlin, Berlin, Germany
| | - Inka Gotthardt
- Department of Nephrology and Medical Intensive Care, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität Zu Berlin, Berlin, Germany
| | | | - Laleh Haghverdi
- Berlin Institute for Medical Systems Biology, Max Delbrueck Center in the Helmholtz Association, Berlin, Germany
| | - Emanuel Wyler
- Berlin Institute for Medical Systems Biology, Max Delbrueck Center in the Helmholtz Association, Berlin, Germany
| | - Markus Landthaler
- Berlin Institute for Medical Systems Biology, Max Delbrueck Center in the Helmholtz Association, Berlin, Germany
| | - Sebastian Bachmann
- Institute for Functional Anatomy, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität Zu Berlin, Berlin, Germany
| | - Andreas C Hocke
- Berlin Institute of Health, Berlin, Germany.,Department of Infectious Diseases and Respiratory Medicine, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität Zu Berlin, Berlin, Germany
| | - Victor Corman
- Institute of Virology, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität Zu Berlin, Berlin, Germany
| | - Jonas Busch
- Department of Urology, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität Zu Berlin, Berlin, Germany
| | - Wolfgang Schneider
- Department of Pathology, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität Zu Berlin, Berlin, Germany
| | - Nina Himmerkus
- Institute of Physiology, Christian-Albrechts-Universität, Kiel, Germany
| | - Markus Bleich
- Institute of Physiology, Christian-Albrechts-Universität, Kiel, Germany
| | - Kai-Uwe Eckardt
- Department of Nephrology and Medical Intensive Care, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität Zu Berlin, Berlin, Germany
| | - Philipp Enghard
- Department of Nephrology and Medical Intensive Care, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität Zu Berlin, Berlin, Germany.,Deutsches Rheumaforschungszentrum, an Institute of the Leibniz Foundation, Berlin, Germany
| | - Nikolaus Rajewsky
- Berlin Institute for Medical Systems Biology, Max Delbrueck Center in the Helmholtz Association, Berlin, Germany
| | - Kai M Schmidt-Ott
- Department of Nephrology and Hypertension, Hannover Medical School, Hannover, Germany. .,Department of Nephrology and Medical Intensive Care, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität Zu Berlin, Berlin, Germany. .,Max Delbrueck Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany.
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32
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Zivotic M, Dundjerovic D, Naumovic R, Kovacevic S, Ivanov M, Karanovic D, Nikolic G, Markovic-Lipkovski J, Radojevic Skodric S, Nesovic Ostojic J. Clinicopathological Relevance of PAX8 Expression Patterns in Acute Kidney Injury and Chronic Kidney Diseases. Diagnostics (Basel) 2022; 12:2036. [PMID: 36140438 PMCID: PMC9497907 DOI: 10.3390/diagnostics12092036] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2022] [Revised: 08/13/2022] [Accepted: 08/17/2022] [Indexed: 11/17/2022] Open
Abstract
Transcription factor PAX8, expressed during embryonic kidney development, has been previously detected in various kidney tumors. In order to investigate expression of PAX8 transcription factor in acute kidney injury (AKI) and chronic kidney diseases (CKD), immunohistochemical analysis was performed. Presence, location and extent of PAX8 expression were analyzed among 31 human kidney samples of AKI (25 autopsy cases, 5 kidney biopsies with unknown etiology and 1 AKI with confirmed myoglobin cast nephropathy), as well as in animals with induced postischemic AKI. Additionally, expression pattern was analyzed in 20 kidney biopsy samples of CKD. Our study demonstrates that various kidney diseases with chronic disease course that results in the formation of tubular atrophy and interstitial fibrosis, lead to PAX8 expression in the nuclei of proximal tubules. Furthermore, patients with PAX8 detected within the damaged proximal tubuli would be carefully monitored, since deterioration in kidney function was observed during follow-up. We also showed that myoglobin provoked acute kidney injury followed with large extent of renal damage, was associated with strong nuclear expression of PAX8 in proximal tubular cells. These results were supported and followed by data obtained in experimental model of induced postischemic acute kidney injury. Considering these findings, we can assume that PAX8 protein might be involved in regeneration process and recovery after acute kidney injury. Thus, accordingly, all investigation concerning PAX8 immunolabeling should be performed on biopsy samples of the living individuals.
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Affiliation(s)
- Maja Zivotic
- Institute of Pathology, Faculty of Medicine, University of Belgrade, 11000 Belgrade, Serbia
| | - Dusko Dundjerovic
- Institute of Pathology, Faculty of Medicine, University of Belgrade, 11000 Belgrade, Serbia
| | - Radomir Naumovic
- Clinic of Nephrology, Clinical Center of Serbia, Faculty of Medicine, University of Belgrade, 11000 Belgrade, Serbia
| | - Sanjin Kovacevic
- Institute of Pathological Physiology, Faculty of Medicine, University of Belgrade, 11000 Belgrade, Serbia
| | - Milan Ivanov
- Institute for Medical Research, Department of Cardiovascular Physiology, National Institute of Republic of Serbia, University of Belgrade, 11000 Belgrade, Serbia
| | - Danijela Karanovic
- Institute for Medical Research, Department of Cardiovascular Physiology, National Institute of Republic of Serbia, University of Belgrade, 11000 Belgrade, Serbia
| | - Gorana Nikolic
- Institute of Pathology, Faculty of Medicine, University of Belgrade, 11000 Belgrade, Serbia
| | | | | | - Jelena Nesovic Ostojic
- Institute of Pathological Physiology, Faculty of Medicine, University of Belgrade, 11000 Belgrade, Serbia
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33
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Okumura K, Grace H, Sogawa H, Yamanaga S. Acute kidney injury and the compensation of kidney function after nephrectomy in living donation. World J Transplant 2022; 12:223-230. [PMID: 36159072 PMCID: PMC9453297 DOI: 10.5500/wjt.v12.i8.223] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/16/2022] [Revised: 03/27/2022] [Accepted: 08/05/2022] [Indexed: 02/05/2023] Open
Abstract
Acute kidney injury (AKI) incidence is growing rapidly, and AKI is one of the predictors of inpatient mortality. After nephrectomy, all the patients have decreased kidney function with AKI and recover from AKI. However, the characteristic and behavior of AKI is different from usual AKI and compensatory kidney function has been well known in the postoperative setting, especially in living donors. In this review, we have focused on the compensation of kidney function after nephrectomy in living donors. We discuss factors that have been identified as being associated with kidney recovery in donors including age, sex, body mass index, remnant kidney volume, estimated glomerular filtration rate, and various comorbidities.
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Affiliation(s)
- Kenji Okumura
- Department of Surgery, Westchester Medical Center/New York Medical College, Valhalla, NY 10595, United States
| | - Holly Grace
- Department of Surgery, New York Medical College, Valhalla, NY 10595, United States
| | - Hiroshi Sogawa
- Department of Surgery, Westchester Medical Center/New York Medical College, Valhalla, NY 10595, United States
| | - Shigeyoshi Yamanaga
- Department of Surgery, Japanese Red Cross Kumamoto Hospital, Kumamoto 861-8520, Japan
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Yu C, Li T, Li J, Cui B, Liu N, Bayliss G, Zhuang S. Inhibition of polycomb repressive complex 2 by targeting EED protects against cisplatin-induced acute kidney injury. J Cell Mol Med 2022; 26:4061-4075. [PMID: 35734954 PMCID: PMC9279598 DOI: 10.1111/jcmm.17447] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2021] [Revised: 05/12/2022] [Accepted: 05/20/2022] [Indexed: 12/05/2022] Open
Abstract
Polycomb repressive complex 2 (PRC2) is a multicomponent complex with methyltransferase activity that catalyzes trimethylation of histone H3 at lysine 27 (H3K27me3). Interaction of the epigenetic reader protein EED with EZH2, a catalytic unit of PRC, allosterically stimulates PRC2 activity. In this study, we investigated the role and underlying mechanism of the PRC2 in acute kidney injury (AKI) by using EED226, a highly selective PRC2 inhibitor, to target EED. Administration of EED226 improved renal function, attenuated renal pathological changes, and reduced renal tubular cell apoptosis in a murine model of cisplatin‐induced AKI. In cultured renal epithelial cells, treatment with either EED226 or EED siRNA also ameliorated cisplatin‐induced apoptosis. Mechanistically, EED226 treatment inhibited cisplatin‐induced phosphorylation of p53 and FOXO3a, two transcriptional factors contributing to apoptosis, and preserved expression of Sirtuin 3 and PGC1α, two proteins associated with mitochondrial protection in vivo and in vitro. EED226 was also effective in enhancing renal tubular cell proliferation, suppressing expression of multiple inflammatory cytokines, and reducing infiltration of macrophages to the injured kidney. These data suggest that inhibition of the PRC2 activity by targeting EED can protect against cisplatin‐induced AKI by promoting the survival and proliferation of renal tubular cells and inhibiting inflammatory response.
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Affiliation(s)
- Chao Yu
- Department of Nephrology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China
| | - Tingting Li
- Department of Nephrology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China
| | - Jialu Li
- Department of Nephrology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China
| | - Binbin Cui
- Department of Nephrology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China
| | - Na Liu
- Department of Nephrology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China
| | - George Bayliss
- Department of Medicine, Rhode Island Hospital, and Alpert Medical School, Brown University, Providence, Rhode Island, USA
| | - Shougang Zhuang
- Department of Nephrology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China.,Department of Medicine, Rhode Island Hospital, and Alpert Medical School, Brown University, Providence, Rhode Island, USA
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Rajagopalan KS, Glasstetter LM, Zhu XY, Thaler R, Tang H, Jordan KL, Saadiq IM, Herrmann SM, Chade AR, Irazabal MV, Lerman LO, Eirin A. Renal Ischemia Induces Epigenetic Changes in Apoptotic, Proteolytic, and Mitochondrial Genes in Swine Scattered Tubular-like Cells. Cells 2022; 11:1803. [PMID: 35681498 PMCID: PMC9180447 DOI: 10.3390/cells11111803] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2022] [Revised: 05/19/2022] [Accepted: 05/27/2022] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND Scattered tubular-like cells (STCs) are dedifferentiated renal tubular cells endowed with progenitor-like characteristics to repair injured parenchymal cells. STCs may be damaged and rendered ineffective by renal artery stenosis (RAS), but the underlying processes remain unclear. We hypothesized that RAS alters the epigenetic landscape on DNA and the ensuing gene transcriptional profile of swine STCs. METHODS CD24+/CD133+ STCs were isolated from pig kidneys after 10 weeks of RAS or sham (n = 3 each) and their whole 5-methylcytosine (5mC) and 5-hydroxymethylcytosine (5hmC) profiles were examined by 5mC and 5hmC immunoprecipitation sequencing (MeDIP-/hMeDIP-seq, respectively). A subsequent integrated (MeDIP/hMeDIP-seq/mRNA-seq) analysis was performed by comparing all online available gene sets using Gene Set Enrichment Analysis. Apoptosis, proteolysis, and mitochondrial structure and function were subsequently evaluated in vitro. RESULTS Differential expression (DE) analysis revealed 239 genes with higher and 236 with lower 5mC levels and 275 genes with higher and 315 with lower 5hmC levels in RAS-STCs compared to Normal-STCs (fold change ≥1.4 or ≤0.7, p ≤ 0.05). Integrated MeDIP-/hMeDIP-seq/mRNA-seq analysis identified several overlapping (DE-5mC/mRNA and DE-5hmC/mRNA levels) genes primarily implicated in apoptosis, proteolysis, and mitochondrial functions. Furthermore, RAS-STCs exhibited decreased apoptosis, mitochondrial matrix density, and ATP production, and increased intracellular amino acid concentration and ubiquitin expression. CONCLUSIONS Renal ischemia induces epigenetic changes in apoptosis-, proteolysis-, and mitochondria-related genes, which correlate with alterations in the transcriptomic profile and corresponding function of swine STCs. These observations may contribute to developing novel targeted interventions to preserve the reparative potency of STCs in renal disease.
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Affiliation(s)
- Kamalnath S. Rajagopalan
- Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN 55901, USA; (K.S.R.); (L.M.G.); (X.-Y.Z.); (H.T.); (K.L.J.); (I.M.S.); (S.M.H.); (M.V.I.); (L.O.L.)
| | - Logan M. Glasstetter
- Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN 55901, USA; (K.S.R.); (L.M.G.); (X.-Y.Z.); (H.T.); (K.L.J.); (I.M.S.); (S.M.H.); (M.V.I.); (L.O.L.)
| | - Xiang-Yang Zhu
- Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN 55901, USA; (K.S.R.); (L.M.G.); (X.-Y.Z.); (H.T.); (K.L.J.); (I.M.S.); (S.M.H.); (M.V.I.); (L.O.L.)
| | - Roman Thaler
- Department of Orthopedic Surgery, Mayo Clinic, Rochester, MN 55901, USA;
| | - Hui Tang
- Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN 55901, USA; (K.S.R.); (L.M.G.); (X.-Y.Z.); (H.T.); (K.L.J.); (I.M.S.); (S.M.H.); (M.V.I.); (L.O.L.)
| | - Kyra L. Jordan
- Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN 55901, USA; (K.S.R.); (L.M.G.); (X.-Y.Z.); (H.T.); (K.L.J.); (I.M.S.); (S.M.H.); (M.V.I.); (L.O.L.)
| | - Ishran M. Saadiq
- Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN 55901, USA; (K.S.R.); (L.M.G.); (X.-Y.Z.); (H.T.); (K.L.J.); (I.M.S.); (S.M.H.); (M.V.I.); (L.O.L.)
| | - Sandra M. Herrmann
- Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN 55901, USA; (K.S.R.); (L.M.G.); (X.-Y.Z.); (H.T.); (K.L.J.); (I.M.S.); (S.M.H.); (M.V.I.); (L.O.L.)
| | - Alejandro R. Chade
- Department of Physiology and Biophysics, Medicine and Radiology, University of Mississippi Medical Center, Jackson, MS 55901, USA;
| | - Maria V. Irazabal
- Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN 55901, USA; (K.S.R.); (L.M.G.); (X.-Y.Z.); (H.T.); (K.L.J.); (I.M.S.); (S.M.H.); (M.V.I.); (L.O.L.)
| | - Lilach O. Lerman
- Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN 55901, USA; (K.S.R.); (L.M.G.); (X.-Y.Z.); (H.T.); (K.L.J.); (I.M.S.); (S.M.H.); (M.V.I.); (L.O.L.)
| | - Alfonso Eirin
- Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN 55901, USA; (K.S.R.); (L.M.G.); (X.-Y.Z.); (H.T.); (K.L.J.); (I.M.S.); (S.M.H.); (M.V.I.); (L.O.L.)
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36
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Li Y, Ricardo SD, Samuel CS. Enhancing the Therapeutic Potential of Mesenchymal Stromal Cell-Based Therapies with an Anti-Fibrotic Agent for the Treatment of Chronic Kidney Disease. Int J Mol Sci 2022; 23:ijms23116035. [PMID: 35682717 PMCID: PMC9181689 DOI: 10.3390/ijms23116035] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2022] [Revised: 05/24/2022] [Accepted: 05/26/2022] [Indexed: 01/02/2023] Open
Abstract
Chronic kidney disease (CKD) affects 1 in 10 members of the general population, placing these patients at an increasingly high risk of kidney failure. Despite the significant burden of CKD on various healthcare systems, there are no effective cures that reverse or even halt its progression. In recent years, human bone-marrow-derived mesenchymal stromal cells (BM-MSCs) have been recognised as a novel therapy for CKDs, owing to their well-established immunomodulatory and tissue-reparative properties in preclinical settings, and their promising safety profile that has been demonstrated in patients with CKDs from several clinical trials. However, renal fibrosis (scarring), a hallmark of CKD, has been shown to impair the viability and functionality of BM-MSCs post-transplantation. This has suggested that BM-MSCs might require a pre-treatment or adjunct therapy that can enhance the viability and therapeutic efficacy of these stromal cells in chronic disease settings. To address this, recent studies that have combined BM-MSCs with the anti-fibrotic drug serelaxin (RLX), have demonstrated the enhanced therapeutic potential of this combination therapy in normotensive and hypertensive preclinical models of CKD. In this review, a critical appraisal of the preclinical data available on the anti-fibrotic and renoprotective actions of BM-MSCs or RLX alone and when combined, as a treatment option for normotensive vs. hypertensive CKD, is discussed.
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Affiliation(s)
- Yifang Li
- Cardiovascular Disease Program, Department of Pharmacology, Monash Biomedicine Discovery Institute, Monash University, Melbourne, VIC 3800, Australia;
| | - Sharon D. Ricardo
- Development and Stem Cells Program, Department of Pharmacology, Monash Biomedicine Discovery Institute, Monash University, Melbourne, VIC 3800, Australia
- Correspondence: (S.D.R.); (C.S.S.)
| | - Chrishan S. Samuel
- Cardiovascular Disease Program, Department of Pharmacology, Monash Biomedicine Discovery Institute, Monash University, Melbourne, VIC 3800, Australia;
- Development and Stem Cells Program, Department of Pharmacology, Monash Biomedicine Discovery Institute, Monash University, Melbourne, VIC 3800, Australia
- Department of Biochemistry and Molecular Biology, The University of Melbourne, Melbourne, VIC 3010, Australia
- Correspondence: (S.D.R.); (C.S.S.)
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37
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Romagnani P. Mechanisms and trade-offs of kidney repair: consequences for the nephrology clinician. Nephrol Dial Transplant 2022; 37:1046-1048. [DOI: 10.1093/ndt/gfaa354] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2020] [Indexed: 11/13/2022] Open
Affiliation(s)
- Paola Romagnani
- Department of Clinical and Experimental Biomedical Sciences, Meyer Children’s Hospital, University of Florence, Florence, Italy
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38
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Li Z, Liu Z, Luo M, Li X, Chen H, Gong S, Zhang M, Zhang Y, Liu H, Li X. The pathological role of damaged organelles in renal tubular epithelial cells in the progression of acute kidney injury. Cell Death Dis 2022; 8:239. [PMID: 35501332 PMCID: PMC9061711 DOI: 10.1038/s41420-022-01034-0] [Citation(s) in RCA: 24] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2022] [Revised: 04/13/2022] [Accepted: 04/14/2022] [Indexed: 12/14/2022]
Abstract
Acute kidney injury (AKI) is a common clinical condition associated with high morbidity and mortality. The pathogenesis of AKI has not been fully elucidated, with a lack of effective treatment. Renal tubular epithelial cells (TECs) play an important role in AKI, and their damage and repair largely determine the progression and prognosis of AKI. In recent decades, it has been found that the mitochondria, endoplasmic reticulum (ER), lysosomes, and other organelles in TECs are damaged to varying degrees in AKI, and that they can influence each other through various signaling mechanisms that affect the recovery of TECs. However, the association between these multifaceted signaling platforms, particularly between mitochondria and lysosomes during AKI remains unclear. This review summarizes the specific pathophysiological mechanisms of the main TECs organelles in the context of AKI, particularly the potential interactions among them, in order to provide insights into possible novel treatment strategies.
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Affiliation(s)
- Zixian Li
- Institute of Nephrology, and Guangdong Provincial Key Laboratory of Autophagy and Major Chronic Non-communicable Diseases, Affiliated Hospital of Guangdong Medical University, Zhanjiang, 524001, China
| | - Zejian Liu
- Institute of Nephrology, and Guangdong Provincial Key Laboratory of Autophagy and Major Chronic Non-communicable Diseases, Affiliated Hospital of Guangdong Medical University, Zhanjiang, 524001, China
| | - Mianna Luo
- Institute of Nephrology, and Guangdong Provincial Key Laboratory of Autophagy and Major Chronic Non-communicable Diseases, Affiliated Hospital of Guangdong Medical University, Zhanjiang, 524001, China
| | - Xingyu Li
- Institute of Nephrology, and Guangdong Provincial Key Laboratory of Autophagy and Major Chronic Non-communicable Diseases, Affiliated Hospital of Guangdong Medical University, Zhanjiang, 524001, China
| | - Huixia Chen
- Institute of Nephrology, and Guangdong Provincial Key Laboratory of Autophagy and Major Chronic Non-communicable Diseases, Affiliated Hospital of Guangdong Medical University, Zhanjiang, 524001, China
| | - Siqiao Gong
- Institute of Nephrology, and Guangdong Provincial Key Laboratory of Autophagy and Major Chronic Non-communicable Diseases, Affiliated Hospital of Guangdong Medical University, Zhanjiang, 524001, China
| | - Minjie Zhang
- Institute of Nephrology, and Guangdong Provincial Key Laboratory of Autophagy and Major Chronic Non-communicable Diseases, Affiliated Hospital of Guangdong Medical University, Zhanjiang, 524001, China
| | - Yaozhi Zhang
- Institute of Nephrology, and Guangdong Provincial Key Laboratory of Autophagy and Major Chronic Non-communicable Diseases, Affiliated Hospital of Guangdong Medical University, Zhanjiang, 524001, China
| | - Huafeng Liu
- Institute of Nephrology, and Guangdong Provincial Key Laboratory of Autophagy and Major Chronic Non-communicable Diseases, Affiliated Hospital of Guangdong Medical University, Zhanjiang, 524001, China.
| | - Xiaoyu Li
- Institute of Nephrology, and Guangdong Provincial Key Laboratory of Autophagy and Major Chronic Non-communicable Diseases, Affiliated Hospital of Guangdong Medical University, Zhanjiang, 524001, China.
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Xu R, Jiang W, Liu Y, Hu J, Liu D, Zhou S, Zhong Y, Zhang F, Zhao M. Single cell sequencing coupled with bioinformatics reveals PHYH as a potential biomarker in kidney ischemia reperfusion injury. Biochem Biophys Res Commun 2022; 602:156-162. [PMID: 35276556 DOI: 10.1016/j.bbrc.2022.02.095] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2022] [Accepted: 02/23/2022] [Indexed: 11/02/2022]
Abstract
Ischemia reperfusion injury(IRI) is an important factor affecting the early function and long-term survival of transplanted kidney. Single cell RNA sequencing (scRNA-seq) is a powerful method for investigating cell-specific transcriptome changes in the kidney. This study aimed to identify the significant cell type and potential biomarkers in IRI. First, we downloaded the IRI related scRNA dataset GSE139506 from the GEO database. Then, classification of cell type was characterized and proximal tubule cell (PTC) was identified as a significant cell type. The functional enrichment analysis indicated that PTC were related to kidney function and is significant in the ferroptosis of IRI. Analyses of three-dimensional structure and iron binding substructure of protein was carried out basing on SWISS-MODEL database. Finally, we constructed the murine model with IRI and verify the higher expression of PHYH in IRI by PCR, Western blot (WB) and Immunohistochemistry (IHC) experiments. In conclusion, this study provided novel insights on the cell-type-specific expression gene biomarker in IRI pathogenesis.
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Affiliation(s)
- Ruiquan Xu
- Department of Organ Transplantation, Zhujiang Hospital, Southern Medical University, Guangzhou, China; Department of Urology, First Affiliated Hospital of Gannan Medical University, Ganzhou, China
| | - Weihao Jiang
- Department of Organ Transplantation, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Yongguang Liu
- Department of Organ Transplantation, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Jianmin Hu
- Department of Organ Transplantation, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Ding Liu
- Department of Organ Transplantation, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Song Zhou
- Department of Organ Transplantation, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Yangsheng Zhong
- Department of Organ Transplantation, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Fengxia Zhang
- Department of Nephrology, First Affiliated Hospital of Gannan Medical University, Ganzhou, China; The Second School of Clinical Medicine, Southern Medical University, Guangzhou, China.
| | - Ming Zhao
- Department of Organ Transplantation, Zhujiang Hospital, Southern Medical University, Guangzhou, China.
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40
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Fischer MM, Herzel H, Blüthgen N. Mathematical modelling identifies conditions for maintaining and escaping feedback control in the intestinal epithelium. Sci Rep 2022; 12:5569. [PMID: 35368028 PMCID: PMC8976856 DOI: 10.1038/s41598-022-09202-z] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2021] [Accepted: 03/17/2022] [Indexed: 02/07/2023] Open
Abstract
The intestinal epithelium is one of the fastest renewing tissues in mammals. It shows a hierarchical organisation, where intestinal stem cells at the base of crypts give rise to rapidly dividing transit amplifying cells that in turn renew the pool of short-lived differentiated cells. Upon injury and stem-cell loss, cells can also de-differentiate. Tissue homeostasis requires a tightly regulated balance of differentiation and stem cell proliferation, and failure can lead to tissue extinction or to unbounded growth and cancerous lesions. Here, we present a two-compartment mathematical model of intestinal epithelium population dynamics that includes a known feedback inhibition of stem cell differentiation by differentiated cells. The model shows that feedback regulation stabilises the number of differentiated cells as these become invariant to changes in their apoptosis rate. Stability of the system is largely independent of feedback strength and shape, but specific thresholds exist which if bypassed cause unbounded growth. When dedifferentiation is added to the model, we find that the system can recover faster after certain external perturbations. However, dedifferentiation makes the system more prone to losing homeostasis. Taken together, our mathematical model shows how a feedback-controlled hierarchical tissue can maintain homeostasis and can be robust to many external perturbations.
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Affiliation(s)
- Matthias M Fischer
- Institute for Theoretical Biology, Charité Universitätsmedizin Berlin and Humboldt Universität zu Berlin, Berlin, 10115, Germany
- Institute of Pathology, Charité Universitätsmedizin Berlinn, Berlin, 10117, Germany
| | - Hanspeter Herzel
- Institute for Theoretical Biology, Charité Universitätsmedizin Berlin and Humboldt Universität zu Berlin, Berlin, 10115, Germany
| | - Nils Blüthgen
- Institute for Theoretical Biology, Charité Universitätsmedizin Berlin and Humboldt Universität zu Berlin, Berlin, 10115, Germany.
- Institute of Pathology, Charité Universitätsmedizin Berlinn, Berlin, 10117, Germany.
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41
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Feiteng C, Lei C, Deng L, Chaoliang X, Zijie X, Yi S, Minglei S. Relaxin inhibits renal fibrosis and the epithelial-to-mesenchymal transition via the Wnt/β-catenin signaling pathway. Ren Fail 2022; 44:513-524. [PMID: 35311469 PMCID: PMC8942541 DOI: 10.1080/0886022x.2022.2044351] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
Abstract
Renal fibrosis is a common characteristic and the final pathological mechanism of chronic kidney disease (CKD). Although CKD remains incurable, inhibition of renal fibrosis is beneficial to inhibit the CKD process. Relaxin alleviates renal fibrosis in some experimental models, but its mechanism remains unclear. In the following, we studied the regulatory effect of relaxin on epithelial-mesenchymal transition (EMT) after unilateral ureteral obstruction (UUO). Our results demonstrate that relaxin could downregulate Wnt/β-catenin signaling and decrease EMT, thus protecting against loss of transporters in tubular epithelial cells (TECs) and abrogate renal interstitial fibrosis following UUO. We confirmed that relaxin can downregulate Wnt/β-catenin signaling and decrease EMT in NRK52E, thus abrogating G2 cell cycle arrest in vitro experiments. Therefore, a novel mechanism by which relaxin is antifibrotic is that relaxin regulates the EMT program of TECs via Wnt/β-catenin signaling pathway. The inhibition of EMT contributes to protecting the functional capabilities of TECs and promoting the regeneration of TECs.
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Affiliation(s)
- Chen Feiteng
- Department of Urology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Chen Lei
- Department of Urology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Li Deng
- Department of Urology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Xu Chaoliang
- Department of Urology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Xu Zijie
- Department of Urology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Shao Yi
- Department of Urology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Sha Minglei
- Department of Geriatric, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
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Sánchez-Navarro A, Martínez-Rojas MÁ, Albarrán-Godinez A, Pérez-Villalva R, Auwerx J, de la Cruz A, Noriega LG, Rosetti F, Bobadilla NA. Sirtuin 7 Deficiency Reduces Inflammation and Tubular Damage Induced by an Episode of Acute Kidney Injury. Int J Mol Sci 2022; 23:ijms23052573. [PMID: 35269715 PMCID: PMC8910458 DOI: 10.3390/ijms23052573] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2022] [Revised: 02/06/2022] [Accepted: 02/07/2022] [Indexed: 02/06/2023] Open
Abstract
Acute kidney injury (AKI) is a public health problem worldwide. Sirtuins are a family of seven NAD+-dependent deacylases, Overexpression of Sirtuin 1, 3, and 5 protect against AKI. However, the role of Sirtuin 7 (Sirt7) in AKI is not known. Here, we analyzed how Sirt7 deficient mice (KO-Sirt7) were affected by AKI. As expected, wild-type and Sirt7 heterozygotes mice that underwent renal ischemia/reperfusion (IR) exhibited the characteristic hallmarks of AKI: renal dysfunction, tubular damage, albuminuria, increased oxidative stress, and renal inflammation. In contrast, the KO-Sirt7+IR mice were protected from AKI, exhibiting lesser albuminuria and reduction in urinary biomarkers of tubular damage, despite similar renal dysfunction. The renoprotection in the Sirt7-KO+IR group was associated with reduced kidney weight, minor expression of inflammatory cytokines and less renal infiltration of inflammatory cells. This anti-inflammatory effect was related to diminished p65 expression and in its active phosphorylation, as well as by a reduction in p65 nuclear translocation. Sirt7 deficient mice are protected from AKI, suggesting that this histone deacetylase promotes tubular damage and renal inflammation. Therefore, our findings indicate that Sirt7 inhibitors may be an attractive therapeutic target to reduce NFκB signaling.
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Affiliation(s)
- Andrea Sánchez-Navarro
- Molecular Physiology Unit, Instituto de Investigaciones Biomedicas, Universidad Nacional Autónoma de México, Mexico City 14080, Mexico; (A.S.-N.); (M.Á.M.-R.); (A.A.-G.); (R.P.-V.)
- Departments of Nephrology and Mineral Metabolism, Instituto Nacional de Ciencias Médicas y Nutrición, Salvador Zubirán, Mexico City 14080, Mexico
| | - Miguel Ángel Martínez-Rojas
- Molecular Physiology Unit, Instituto de Investigaciones Biomedicas, Universidad Nacional Autónoma de México, Mexico City 14080, Mexico; (A.S.-N.); (M.Á.M.-R.); (A.A.-G.); (R.P.-V.)
- Departments of Nephrology and Mineral Metabolism, Instituto Nacional de Ciencias Médicas y Nutrición, Salvador Zubirán, Mexico City 14080, Mexico
| | - Adrián Albarrán-Godinez
- Molecular Physiology Unit, Instituto de Investigaciones Biomedicas, Universidad Nacional Autónoma de México, Mexico City 14080, Mexico; (A.S.-N.); (M.Á.M.-R.); (A.A.-G.); (R.P.-V.)
- Departments of Nephrology and Mineral Metabolism, Instituto Nacional de Ciencias Médicas y Nutrición, Salvador Zubirán, Mexico City 14080, Mexico
| | - Rosalba Pérez-Villalva
- Molecular Physiology Unit, Instituto de Investigaciones Biomedicas, Universidad Nacional Autónoma de México, Mexico City 14080, Mexico; (A.S.-N.); (M.Á.M.-R.); (A.A.-G.); (R.P.-V.)
- Departments of Nephrology and Mineral Metabolism, Instituto Nacional de Ciencias Médicas y Nutrición, Salvador Zubirán, Mexico City 14080, Mexico
| | - Johan Auwerx
- Laboratory of Integrative Systems Physiology (LISP), Ecole Polytechnique Federale de Lausanne, CH-1015 Lausanne, Switzerland;
| | - Abigail de la Cruz
- Immunology and Rheumatology, Instituto Nacional de Ciencias Médicas y Nutrición, Salvador Zubirán, Mexico City 14080, Mexico; (A.d.l.C.); (F.R.)
| | - Lilia G. Noriega
- Nutrition Physiology, Instituto Nacional de Ciencias Médicas y Nutrición, Salvador Zubirán, Mexico City 14080, Mexico;
| | - Florencia Rosetti
- Immunology and Rheumatology, Instituto Nacional de Ciencias Médicas y Nutrición, Salvador Zubirán, Mexico City 14080, Mexico; (A.d.l.C.); (F.R.)
| | - Norma A. Bobadilla
- Molecular Physiology Unit, Instituto de Investigaciones Biomedicas, Universidad Nacional Autónoma de México, Mexico City 14080, Mexico; (A.S.-N.); (M.Á.M.-R.); (A.A.-G.); (R.P.-V.)
- Departments of Nephrology and Mineral Metabolism, Instituto Nacional de Ciencias Médicas y Nutrición, Salvador Zubirán, Mexico City 14080, Mexico
- Correspondence: ; Tel.: +52-55-5485-2676
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Abstract
Acute kidney injury (AKI) is a common clinical complication characterized by a sudden deterioration of the kidney's excretory function, which normally occurs secondary to another serious illness. AKI is an important risk factor for chronic kidney disease (CKD) occurrence and progression to kidney failure. It is, therefore, crucial to block the development of AKI as early as possible. To date, existing animal studies have shown that senescence occurs in the early stage of AKI and is extremely critical to prognosis. Cellular senescence is an irreversible process of cell cycle arrest that is accompanied by alterations at the transcriptional, metabolic, and secretory levels along with modified cellular morphology and chromatin organization. Acute cellular senescence tends to play an active role, whereas chronic senescence plays a dominant role in the progression of AKI to CKD. The occurrence of chronic senescence is inseparable from senescence-associated secretory phenotype (SASP) and senescence-related pathways. SASP acts on normal cells to amplify the senescence signal through senescence-related pathways. Senescence can be improved by initiating reprogramming, which plays a crucial role in blocking the progression of AKI to CKD. This review integrates the existing studies on senescence in AKI from several aspects to find meaningful research directions to improve the prognosis of AKI and prevent the progression of CKD.
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Zulpaite R, Miknevicius P, Leber B, Strupas K, Stiegler P, Schemmer P. Ex-vivo Kidney Machine Perfusion: Therapeutic Potential. Front Med (Lausanne) 2021; 8:808719. [PMID: 35004787 PMCID: PMC8741203 DOI: 10.3389/fmed.2021.808719] [Citation(s) in RCA: 38] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2021] [Accepted: 12/06/2021] [Indexed: 01/11/2023] Open
Abstract
Kidney transplantation remains the gold standard treatment for patients suffering from end-stage kidney disease. To meet the constantly growing organ demands grafts donated after circulatory death (DCD) or retrieved from extended criteria donors (ECD) are increasingly utilized. Not surprisingly, usage of those organs is challenging due to their susceptibility to ischemia-reperfusion injury, high immunogenicity, and demanding immune regulation after implantation. Lately, a lot of effort has been put into improvement of kidney preservation strategies. After demonstrating a definite advantage over static cold storage in reduction of delayed graft function rates in randomized-controlled clinical trials, hypothermic machine perfusion has already found its place in clinical practice of kidney transplantation. Nevertheless, an active investigation of perfusion variables, such as temperature (normothermic or subnormothermic), oxygen supply and perfusate composition, is already bringing evidence that ex-vivo machine perfusion has a potential not only to maintain kidney viability, but also serve as a platform for organ conditioning, targeted treatment and even improve its quality. Many different therapies, including pharmacological agents, gene therapy, mesenchymal stromal cells, or nanoparticles (NPs), have been successfully delivered directly to the kidney during ex-vivo machine perfusion in experimental models, making a big step toward achievement of two main goals in transplant surgery: minimization of graft ischemia-reperfusion injury and reduction of immunogenicity (or even reaching tolerance). In this comprehensive review current state of evidence regarding ex-vivo kidney machine perfusion and its capacity in kidney graft treatment is presented. Moreover, challenges in application of these novel techniques in clinical practice are discussed.
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Affiliation(s)
- Ruta Zulpaite
- General, Visceral and Transplant Surgery, Department of Surgery, Medical University of Graz, Graz, Austria
- Faculty of Medicine, Vilnius University, Vilnius, Lithuania
| | - Povilas Miknevicius
- General, Visceral and Transplant Surgery, Department of Surgery, Medical University of Graz, Graz, Austria
- Faculty of Medicine, Vilnius University, Vilnius, Lithuania
| | - Bettina Leber
- General, Visceral and Transplant Surgery, Department of Surgery, Medical University of Graz, Graz, Austria
| | | | - Philipp Stiegler
- General, Visceral and Transplant Surgery, Department of Surgery, Medical University of Graz, Graz, Austria
| | - Peter Schemmer
- Faculty of Medicine, Vilnius University, Vilnius, Lithuania
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45
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Hama T, Nagesh PK, Chowdhury P, Moore BM, Yallapu MM, Regner KR, Park F. DNA damage is overcome by TRIP13 overexpression during cisplatin nephrotoxicity. JCI Insight 2021; 6:139092. [PMID: 34806647 PMCID: PMC8663775 DOI: 10.1172/jci.insight.139092] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2020] [Accepted: 10/13/2021] [Indexed: 11/17/2022] Open
Abstract
Cisplatin is a commonly used chemotherapeutic agent to treat a wide array of cancers that is frequently associated with toxic injury to the kidney due to oxidative DNA damage and perturbations in cell cycle progression leading to cell death. In this study, we investigated whether thyroid receptor interacting protein 13 (TRIP13) plays a central role in the protection of the tubular epithelia following cisplatin treatment by circumventing DNA damage. Following cisplatin treatment, double-stranded DNA repair pathways were inhibited using selective blockers to proteins involved in either homologous recombination or non-homologous end joining. This led to increased blood markers of acute kidney injury (AKI) (creatinine and neutrophil gelatinase–associated lipocalin), tubular damage, activation of DNA damage marker (γ-H2AX), elevated appearance of G2/M blockade (phosphorylated histone H3 Ser10 and cyclin B1), and apoptosis (cleaved caspase-3). Conditional proximal tubule–expressing Trip13 mice were observed to be virtually protected from the cisplatin nephrotoxicity by restoring most of the pathological phenotypes back toward normal conditions. Our findings suggest that TRIP13 could circumvent DNA damage in the proximal tubules during cisplatin injury and that TRIP13 may constitute a new therapeutic target in protecting the kidney from nephrotoxicants and reduce outcomes leading to AKI.
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Affiliation(s)
- Taketsugu Hama
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Science Center, Memphis, Tennessee, USA
| | - Prashanth Kb Nagesh
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Science Center, Memphis, Tennessee, USA.,Department of Immunology and Microbiology, School of Medicine, University of Texas Rio Grande Valley, McAllen, Texas, USA
| | - Pallabita Chowdhury
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Science Center, Memphis, Tennessee, USA
| | - Bob M Moore
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Science Center, Memphis, Tennessee, USA
| | - Murali M Yallapu
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Science Center, Memphis, Tennessee, USA.,Department of Immunology and Microbiology, School of Medicine, University of Texas Rio Grande Valley, McAllen, Texas, USA
| | - Kevin R Regner
- Division of Nephrology, Department of Medicine, Medical College of Wisconsin, Milwaukee, Wisconsin, USA
| | - Frank Park
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Science Center, Memphis, Tennessee, USA
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Li A, Cunanan J, Khalili H, Plageman T, Ask K, Khan A, Hunjan A, Drysdale T, Bridgewater D. Shroom3, a Gene Associated with CKD, Modulates Epithelial Recovery after AKI. KIDNEY360 2021; 3:51-62. [PMID: 35368578 PMCID: PMC8967620 DOI: 10.34067/kid.0003802021] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/08/2021] [Accepted: 10/28/2021] [Indexed: 01/12/2023]
Abstract
Background Ischemia-induced AKI resulting in tubular damage can often progress to CKD and is a common cause of nephrology consultation. After renal tubular epithelial damage, molecular and cellular mechanisms are activated to repair and regenerate the damaged epithelium. If these mechanisms are impaired, AKI can progress to CKD. Even in patients whose kidney function returns to normal baseline are more likely to develop CKD. Genome-wide association studies have provided robust evidence that genetic variants in Shroom3, which encodes an actin-associated protein, are associated with CKD and poor outcomes in transplanted kidneys. Here, we sought to further understand the associations of Shroom3 in CKD. Methods Kidney ischemia was induced in wild-type (WT) and Shroom3 heterozygous null mice (Shroom3Gt/+ ) and the mechanisms of cellular recovery and repair were examined. Results A 28-minute bilateral ischemia in Shroom3Gt/+ mice resulted in 100% mortality within 24 hours. After 22-minute ischemic injury, Shroom3Gt/+ mice had a 16% increased mortality, worsened kidney function, and significantly worse histopathology, apoptosis, proliferation, inflammation, and fibrosis after injury. The cortical tubular damage in Shroom3Gt/+ was associated with disrupted epithelial redifferentiation, disrupted Rho-kinase/myosin signaling, and disorganized apical F-actin. Analysis of MDCK cells showed the levels of Shroom3 are directly correlated to apical organization of actin and actomyosin regulators. Conclusion These findings establish that Shroom3 is required for epithelial repair and redifferentiation through the organization of actomyosin regulators, and could explain why genetic variants in Shroom3 are associated with CKD and allograft rejection.
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Affiliation(s)
- Aihua Li
- Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Canada
| | - Joanna Cunanan
- Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Canada
| | - Hadiseh Khalili
- Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Canada
| | | | - Kjetil Ask
- Department of Medicine, McMaster University, Hamilton, Canada
| | - Ahsan Khan
- Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Canada
| | - Ashmeet Hunjan
- Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Canada
| | - Thomas Drysdale
- Department of Physiology and Pharmacology, University of Western Ontario, London, Canada
| | - Darren Bridgewater
- Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Canada
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Moreno JCA, Bahmad HF, Febres-Aldana CA, Pirela A, Azuero A, Salami A, Poppiti R. Post-mortem assessment of vimentin expression as a biomarker for renal tubular regeneration following acute kidney injury. J Pathol Transl Med 2021; 55:369-379. [PMID: 34638220 PMCID: PMC8601956 DOI: 10.4132/jptm.2021.08.03] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2021] [Accepted: 08/03/2021] [Indexed: 11/24/2022] Open
Abstract
BACKGROUND Acute kidney injury (AKI) is a common cause of morbidity and mortality. It mainly targets the renal tubular epithelium with pathological changes, referred to as acute tubular injury. The latter is followed by a regenerative response that is difficult to visualize on routine hematoxylin and eosin (H&E) stains. In this study, we examined the regenerative capacity of renal tubules by correlating vimentin (VIM) immunohistochemical (IHC) expression and pathological findings of AKI and renal tubular regeneration (RTR) on H&E. METHODS We reviewed 23 autopsies performed in the clinical setting of AKI and RTR. VIM expression was scored in the renal cortical tubular epithelium using a statistical cutoff ≥ 3% for high expression and < 3% for low expression. RESULTS Of the 23 kidney tissues examined, seven (30.4%) had low VIM expression, and 16 (69.6%) had high VIM expression. Kidney tissues with evidence of AKI and RTR had significantly higher VIM expression. Renal peritubular microenvironment features showing regenerative changes on H&E were associated with high VIM expression. In the univariate model, kidney tissues with RTR were 18-fold more likely to have high VIM expression. CONCLUSIONS In conclusion, our findings suggest that VIM could serve as an IHC marker for RTR following AKI. However, correlation with H&E findings remains critical to excluding chronic tubular damage. Collectively, our preliminary results pave the way for future studies including a larger sample size to validate the use of VIM as a reliable biomarker for RTR.
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Affiliation(s)
- Juan Carlos Alvarez Moreno
- Arkadi M. Rywlin M.D. Department of Pathology and Laboratory Medicine, Mount Sinai Medical Center, Miami Beach, FL, USA
| | - Hisham F Bahmad
- Arkadi M. Rywlin M.D. Department of Pathology and Laboratory Medicine, Mount Sinai Medical Center, Miami Beach, FL, USA
| | - Christopher A Febres-Aldana
- Arkadi M. Rywlin M.D. Department of Pathology and Laboratory Medicine, Mount Sinai Medical Center, Miami Beach, FL, USA
| | - Andrés Pirela
- Department of Internal Medicine, Mount Sinai Medical Center, Miami Beach, FL, USA
| | - Andres Azuero
- Department of Internal Medicine, Mount Sinai Medical Center, Miami Beach, FL, USA
| | - Ali Salami
- Department of Mathematics, Faculty of Sciences, Lebanese University, Nabatieh, Lebanon
| | - Robert Poppiti
- Arkadi M. Rywlin M.D. Department of Pathology and Laboratory Medicine, Mount Sinai Medical Center, Miami Beach, FL, USA
- Herbert Wertheim College of Medicine, Florida International University, Miami, FL, USA
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48
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NLRP3 associated with chronic kidney disease progression after ischemia/reperfusion-induced acute kidney injury. Cell Death Discov 2021; 7:324. [PMID: 34716316 PMCID: PMC8556399 DOI: 10.1038/s41420-021-00719-2] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2021] [Revised: 10/07/2021] [Accepted: 10/14/2021] [Indexed: 11/08/2022] Open
Abstract
Nod-like receptor protein 3 (NLRP3), as an inflammatory regulator, has been implicated in acute kidney injury (AKI). Failed recovery after AKI can lead to chronic kidney disease (CKD). However, the role of NLRP3 in the AKI-CKD transition is still unknown. A mild or severe AKI mouse model was performed by using ischemia-reperfusion injury (IRI). We evaluated the renal NLRP3 expression in acute and chronic phases of ischemic AKI, respectively. Although serum creatinine (Cr) and blood urea nitrogen (BUN) levels in AKI chronic phase were equivalent to normal baseline, histological analysis and fibrotic markers revealed that severe AKI-induced maladaptive tubular repair with immune cell infiltration and fibrosis. Tubular damage was restored completely in mild AKI rather than in severe AKI. Of note, persistent overexpression of NLRP3 was also found in severe AKI but not in mild AKI. In the severe AKI-induced chronic phase, there was a long-term high level of NLRP3 in serum or urine. Overt NLRP3 was mainly distributed in the abnormal tubules surrounded by inflammatory infiltrates and fibrosis, which indicated the maladaptive repair. Renal Nlrp3 overexpression was correlated with infiltrating macrophages and fibrosis. Renal NLRP3 signaling-associated genes were upregulated after severe AKI by RNA-sequencing. Furthermore, NLRP3 was found increased in renal tubular epitheliums from CKD biopsies. Together, persistent NLRP3 overexpression was associated with chronic pathological changes following AKI, which might be a new biomarker for evaluating the possibility of AKI-CKD transition.
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Yan LJ, Allen DC. Cadmium-Induced Kidney Injury: Oxidative Damage as a Unifying Mechanism. Biomolecules 2021; 11:1575. [PMID: 34827573 PMCID: PMC8615899 DOI: 10.3390/biom11111575] [Citation(s) in RCA: 124] [Impact Index Per Article: 31.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2021] [Revised: 10/15/2021] [Accepted: 10/20/2021] [Indexed: 02/08/2023] Open
Abstract
Cadmium is a nonessential metal that has heavily polluted the environment due to human activities. It can be absorbed into the human body via the gastrointestinal tract, respiratory tract, and the skin, and can cause chronic damage to the kidneys. The main site where cadmium accumulates and causes damage within the nephrons is the proximal tubule. This accumulation can induce dysfunction of the mitochondrial electron transport chain, leading to electron leakage and production of reactive oxygen species (ROS). Cadmium may also impair the function of NADPH oxidase, resulting in another source of ROS. These ROS together can cause oxidative damage to DNA, proteins, and lipids, triggering epithelial cell death and a decline in kidney function. In this article, we also reviewed evidence that the antioxidant power of plant extracts, herbal medicines, and pharmacological agents could ameliorate cadmium-induced kidney injury. Finally, a model of cadmium-induced kidney injury, centering on the notion that oxidative damage is a unifying mechanism of cadmium renal toxicity, is also presented. Given that cadmium exposure is inevitable, further studies using animal models are warranted for a detailed understanding of the mechanism underlying cadmium induced ROS production, and for the identification of more therapeutic targets.
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Affiliation(s)
- Liang-Jun Yan
- Department of Pharmaceutical Sciences, College of Pharmacy, University of North Texas Health Science Center, Fort Worth, TX 76107, USA;
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50
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Little MH, Howden SE, Lawlor KT, Vanslambrouck JM. Determining lineage relationships in kidney development and disease. Nat Rev Nephrol 2021; 18:8-21. [PMID: 34594045 DOI: 10.1038/s41581-021-00485-5] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/19/2021] [Indexed: 12/17/2022]
Abstract
The lineage relationships of cells provide information about the origins of component cell types during development and repair as well as the source of aberrant cells during disease. Genetic approaches to lineage tracing applied in the mouse have revealed much about how the mammalian kidney forms, including the identification of key progenitors for the nephrons and stromal compartments. Inducible Cre systems have also facilitated lineage tracing studies in the postnatal animal that illustrate the changes in cellular fate that can occur during kidney injury. With the advent of single-cell transcriptional profiling and trajectory analyses, predictions of cellular relationships across development are now being made in model systems, such as the mouse, as well as in human fetal kidney. Importantly, these approaches provide predictions of lineage relationships rather than definitive evidence. Although genetic approaches to the study of lineage have not previously been possible in a human setting, the application of CRISPR-Cas9 gene editing of pluripotent stem cells is beginning to teach us about human lineage relationships.
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Affiliation(s)
- Melissa H Little
- Murdoch Children's Research Institute, Parkville, VIC, Australia. .,Department of Paediatrics, The University of Melbourne, Melbourne, VIC, Australia. .,Department of Anatomy and Neuroscience, The University of Melbourne, Melbourne, VIC, Australia.
| | - Sara E Howden
- Murdoch Children's Research Institute, Parkville, VIC, Australia.,Department of Paediatrics, The University of Melbourne, Melbourne, VIC, Australia
| | - Kynan T Lawlor
- Murdoch Children's Research Institute, Parkville, VIC, Australia
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