{"title":"氯菌素过量诱导的过氧化物酶体结构改变和AKI可通过肾吲哚解毒剂(INMT)预防。","authors":"Kazuhiro Hasegawa,Yusuke Sakamaki,Masanori Tamaki,Shu Wakino","doi":"10.1681/asn.0000000751","DOIUrl":null,"url":null,"abstract":"BACKGROUND\r\nThe novel calcineurin inhibitor (CNI) voclosporin is effective in treating lupus nephritis but has been associated with acute kidney injury (AKI) through largely unknown mechanisms. Voclosporin-induced AKI revealed that voclosporin reduces the expression of indolethylamine N-methyltransferase (Inmt), an enzyme responsible for detoxifying local uremic toxins such as indole. This study investigates whether Inmt overexpression can protect against high-dose voclosporin-induced AKI. This study used genetically engineered mice to explore the role of Inmt in voclosporin-induced AKI.\r\n\r\nMETHODS\r\nTransgenic mice overexpressing Inmt and conditional knockout (conditional KO) mouse models were used assess renal proximal tubule-specific Inmt function. Gene expression changes, apoptotic cell percentages, and mitochondrial DNA copy numbers were examined through RNA sequencing, histopathology, and various molecular assays. These analyses were further complemented with immunofluorescence and electron microscopy to investigate cellular and structural changes. Human clinical specimens were also investigated.\r\n\r\nRESULTS\r\nInmt downregulation in high-dose voclosporin-induced AKI was associated with reduced peroxisome and mitochondrion numbers and function, increased production of reactive oxygen species, and increased tubular apoptosis, as observed in conditional KO mice. However, in transgenic mice treated with voclosporin, peroxisomal and mitochondrial integrity were preserved. Notably, electron microscopy revealed that the structural peroxisomal changes observed in mouse and human CNI-induced AKI specimens were reversed in high-dose voclosoprin-treated transgenic mice. Overall, proximal tubule-specific Inmt overexpression protects against high-dose voclosporin-induced AKI by promoting catalase upregulation, reducing H2O2 levels, and restoring peroxisomal function.\r\n\r\nCONCLUSIONS\r\nInmt overexpression in proximal tubules prevented high-dose voclosporin-induced structural changes and AKI.","PeriodicalId":17217,"journal":{"name":"Journal of The American Society of Nephrology","volume":"31 1","pages":""},"PeriodicalIF":10.3000,"publicationDate":"2025-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Voclosporin Overdose-Induced Peroxisomal Structural Changes and AKI Are Prevented by Renal Indole Detoxifier, INMT.\",\"authors\":\"Kazuhiro Hasegawa,Yusuke Sakamaki,Masanori Tamaki,Shu Wakino\",\"doi\":\"10.1681/asn.0000000751\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"BACKGROUND\\r\\nThe novel calcineurin inhibitor (CNI) voclosporin is effective in treating lupus nephritis but has been associated with acute kidney injury (AKI) through largely unknown mechanisms. Voclosporin-induced AKI revealed that voclosporin reduces the expression of indolethylamine N-methyltransferase (Inmt), an enzyme responsible for detoxifying local uremic toxins such as indole. This study investigates whether Inmt overexpression can protect against high-dose voclosporin-induced AKI. This study used genetically engineered mice to explore the role of Inmt in voclosporin-induced AKI.\\r\\n\\r\\nMETHODS\\r\\nTransgenic mice overexpressing Inmt and conditional knockout (conditional KO) mouse models were used assess renal proximal tubule-specific Inmt function. Gene expression changes, apoptotic cell percentages, and mitochondrial DNA copy numbers were examined through RNA sequencing, histopathology, and various molecular assays. These analyses were further complemented with immunofluorescence and electron microscopy to investigate cellular and structural changes. Human clinical specimens were also investigated.\\r\\n\\r\\nRESULTS\\r\\nInmt downregulation in high-dose voclosporin-induced AKI was associated with reduced peroxisome and mitochondrion numbers and function, increased production of reactive oxygen species, and increased tubular apoptosis, as observed in conditional KO mice. However, in transgenic mice treated with voclosporin, peroxisomal and mitochondrial integrity were preserved. Notably, electron microscopy revealed that the structural peroxisomal changes observed in mouse and human CNI-induced AKI specimens were reversed in high-dose voclosoprin-treated transgenic mice. Overall, proximal tubule-specific Inmt overexpression protects against high-dose voclosporin-induced AKI by promoting catalase upregulation, reducing H2O2 levels, and restoring peroxisomal function.\\r\\n\\r\\nCONCLUSIONS\\r\\nInmt overexpression in proximal tubules prevented high-dose voclosporin-induced structural changes and AKI.\",\"PeriodicalId\":17217,\"journal\":{\"name\":\"Journal of The American Society of Nephrology\",\"volume\":\"31 1\",\"pages\":\"\"},\"PeriodicalIF\":10.3000,\"publicationDate\":\"2025-05-21\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Journal of The American Society of Nephrology\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1681/asn.0000000751\",\"RegionNum\":1,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"UROLOGY & NEPHROLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of The American Society of Nephrology","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1681/asn.0000000751","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"UROLOGY & NEPHROLOGY","Score":null,"Total":0}
Voclosporin Overdose-Induced Peroxisomal Structural Changes and AKI Are Prevented by Renal Indole Detoxifier, INMT.
BACKGROUND
The novel calcineurin inhibitor (CNI) voclosporin is effective in treating lupus nephritis but has been associated with acute kidney injury (AKI) through largely unknown mechanisms. Voclosporin-induced AKI revealed that voclosporin reduces the expression of indolethylamine N-methyltransferase (Inmt), an enzyme responsible for detoxifying local uremic toxins such as indole. This study investigates whether Inmt overexpression can protect against high-dose voclosporin-induced AKI. This study used genetically engineered mice to explore the role of Inmt in voclosporin-induced AKI.
METHODS
Transgenic mice overexpressing Inmt and conditional knockout (conditional KO) mouse models were used assess renal proximal tubule-specific Inmt function. Gene expression changes, apoptotic cell percentages, and mitochondrial DNA copy numbers were examined through RNA sequencing, histopathology, and various molecular assays. These analyses were further complemented with immunofluorescence and electron microscopy to investigate cellular and structural changes. Human clinical specimens were also investigated.
RESULTS
Inmt downregulation in high-dose voclosporin-induced AKI was associated with reduced peroxisome and mitochondrion numbers and function, increased production of reactive oxygen species, and increased tubular apoptosis, as observed in conditional KO mice. However, in transgenic mice treated with voclosporin, peroxisomal and mitochondrial integrity were preserved. Notably, electron microscopy revealed that the structural peroxisomal changes observed in mouse and human CNI-induced AKI specimens were reversed in high-dose voclosoprin-treated transgenic mice. Overall, proximal tubule-specific Inmt overexpression protects against high-dose voclosporin-induced AKI by promoting catalase upregulation, reducing H2O2 levels, and restoring peroxisomal function.
CONCLUSIONS
Inmt overexpression in proximal tubules prevented high-dose voclosporin-induced structural changes and AKI.
期刊介绍:
The Journal of the American Society of Nephrology (JASN) stands as the preeminent kidney journal globally, offering an exceptional synthesis of cutting-edge basic research, clinical epidemiology, meta-analysis, and relevant editorial content. Representing a comprehensive resource, JASN encompasses clinical research, editorials distilling key findings, perspectives, and timely reviews.
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JASN publishes original research reports and editorial content across a spectrum of basic and clinical science relevant to the broad discipline of nephrology. Topics covered include renal cell biology, developmental biology of the kidney, genetics of kidney disease, cell and transport physiology, hemodynamics and vascular regulation, mechanisms of blood pressure regulation, renal immunology, kidney pathology, pathophysiology of kidney diseases, nephrolithiasis, clinical nephrology (including dialysis and transplantation), and hypertension. Furthermore, articles addressing healthcare policy and care delivery issues relevant to nephrology are warmly welcomed.