IL-15 Links Muscle–Kidney Crosstalk to Preserving Podocyte Mitochondrial Fusion and Attenuating Diabetic Nephropathy

IF 9.1 1区医学 Q1 GERIATRICS & GERONTOLOGY

Journal of Cachexia Sarcopenia and Muscle Pub Date : 2026-03-17 DOI:10.1002/jcsm.70256

Yin Li, Jialing Rao, Weiyan Lai, Yuxiang Sun, Hongchun Lin, Jun Zhang, Zengchun Ye, Zhaoyong Hu, Hui Peng

{"title":"IL-15 Links Muscle–Kidney Crosstalk to Preserving Podocyte Mitochondrial Fusion and Attenuating Diabetic Nephropathy","authors":"Yin Li, Jialing Rao, Weiyan Lai, Yuxiang Sun, Hongchun Lin, Jun Zhang, Zengchun Ye, Zhaoyong Hu, Hui Peng","doi":"10.1002/jcsm.70256","DOIUrl":null,"url":null,"abstract":"<div>\n \n \n <section>\n \n <h3> Objectives</h3>\n \n <p>High glucose induces mitochondrial dysfunction in podocytes, contributing to the development of diabetic nephropathy (DN). There is increasing evidence that muscles play a protective role by secreting myokines into the kidneys. Here, we investigated how skeletal muscle influences podocyte health via muscle–kidney crosstalk.</p>\n </section>\n \n <section>\n \n <h3> Methods</h3>\n \n <p>To increase myokine release, we overexpressed PGC-1α specifically in skeletal muscle (mPGC-1α) and crossed these mice with db/m mice to generate diabetic mPGC-1α:db/db mice. In parallel, db/db mice were treated intraperitoneally with recombinant murine interleukin-15 (IL-15). Mechanistic studies were performed using isolated primary podocytes and cultured podocyte cell lines.</p>\n </section>\n \n <section>\n \n <h3> Results</h3>\n \n <p>Compared with db/db controls, mPGC-1α:db/db mice exhibited reduced urinary albumin excretion (<i>p</i> < 0.001), mesangial matrix expansion (<i>p</i> < 0.001), glomerular basement membrane thickening (<i>p</i> < 0.001) and urinary podocin excretion (<i>p</i> < 0.001), along with increased podocyte number (<i>p</i> < 0.001). Podocytes from mPGC-1α:db/db mice showed higher expression of Nephrin and COX IV (<i>p</i> < 0.05) and upregulation of multiple mitochondrial function-related genes, notably OPA1 (<i>p</i> < 0.05). Skeletal muscle from mPGC-1α:db/db mice displayed elevated IL-15 mRNA (<i>p</i> < 0.05) and protein (<i>p</i> < 0.01) levels, accompanied by increased plasma IL-15 concentrations (<i>p</i> < 0.05). IL-15 treatment enhanced podocyte mitochondrial respiration, including basal oxygen consumption rate (OCR, <i>p</i> < 0.05), ATP-coupled respiration (<i>p</i> < 0.05) and maximal respiration (<i>p</i> < 0.05). IL-15 preserved mitochondrial fusion under high-glucose conditions by increasing OPA1 expression (<i>p</i> < 0.05) and promoted OPA1 transcription via histone H3 acetylation at its promoter (<i>p</i> < 0.05).</p>\n </section>\n \n <section>\n \n <h3> Conclusions</h3>\n \n <p>Skeletal muscle-derived IL-15 mediates renal protection by maintaining mitochondrial fusion in podocytes during DN progression. Targeting this pathway may offer a therapeutic strategy to preserve kidney function and slow progression to end-stage renal disease.</p>\n </section>\n </div>","PeriodicalId":48911,"journal":{"name":"Journal of Cachexia Sarcopenia and Muscle","volume":"17 2","pages":""},"PeriodicalIF":9.1000,"publicationDate":"2026-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jcsm.70256","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of Cachexia Sarcopenia and Muscle","FirstCategoryId":"3","ListUrlMain":"https://onlinelibrary.wiley.com/doi/10.1002/jcsm.70256","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"GERIATRICS & GERONTOLOGY","Score":null,"Total":0}

引用次数: 0

Abstract

Objectives

High glucose induces mitochondrial dysfunction in podocytes, contributing to the development of diabetic nephropathy (DN). There is increasing evidence that muscles play a protective role by secreting myokines into the kidneys. Here, we investigated how skeletal muscle influences podocyte health via muscle–kidney crosstalk.

Methods

To increase myokine release, we overexpressed PGC-1α specifically in skeletal muscle (mPGC-1α) and crossed these mice with db/m mice to generate diabetic mPGC-1α:db/db mice. In parallel, db/db mice were treated intraperitoneally with recombinant murine interleukin-15 (IL-15). Mechanistic studies were performed using isolated primary podocytes and cultured podocyte cell lines.

Results

Compared with db/db controls, mPGC-1α:db/db mice exhibited reduced urinary albumin excretion (p < 0.001), mesangial matrix expansion (p < 0.001), glomerular basement membrane thickening (p < 0.001) and urinary podocin excretion (p < 0.001), along with increased podocyte number (p < 0.001). Podocytes from mPGC-1α:db/db mice showed higher expression of Nephrin and COX IV (p < 0.05) and upregulation of multiple mitochondrial function-related genes, notably OPA1 (p < 0.05). Skeletal muscle from mPGC-1α:db/db mice displayed elevated IL-15 mRNA (p < 0.05) and protein (p < 0.01) levels, accompanied by increased plasma IL-15 concentrations (p < 0.05). IL-15 treatment enhanced podocyte mitochondrial respiration, including basal oxygen consumption rate (OCR, p < 0.05), ATP-coupled respiration (p < 0.05) and maximal respiration (p < 0.05). IL-15 preserved mitochondrial fusion under high-glucose conditions by increasing OPA1 expression (p < 0.05) and promoted OPA1 transcription via histone H3 acetylation at its promoter (p < 0.05).

Conclusions

Skeletal muscle-derived IL-15 mediates renal protection by maintaining mitochondrial fusion in podocytes during DN progression. Targeting this pathway may offer a therapeutic strategy to preserve kidney function and slow progression to end-stage renal disease.

Abstract Image

查看原文本刊更多论文

IL - 15连接肌肾串扰，保护足细胞线粒体融合和减轻糖尿病肾病

目的高糖诱导足细胞线粒体功能障碍，促进糖尿病肾病（DN）的发展。越来越多的证据表明，肌肉通过向肾脏分泌肌因子发挥保护作用。在这里，我们研究了骨骼肌如何通过肌肉-肾串扰影响足细胞健康。方法通过在骨骼肌中特异性过表达PGC‐1α （mPGC‐1α）来增加肌因子的释放，并将这些小鼠与db/m小鼠杂交，生成糖尿病小鼠mPGC‐1α:db/db。同时，对db/db小鼠腹腔注射重组小鼠白细胞介素- 15 （IL - 15）。用分离的原代足细胞和培养的足细胞细胞系进行机制研究。结果与db/db对照组相比，mPGC‐1α:db/db小鼠尿白蛋白排泄减少（p < 0.001），系膜基质扩张（p < 0.001），肾小球基底膜增厚（p < 0.001），尿足蛋白排泄减少（p < 0.001），足细胞数量增加（p < 0.001）。mPGC‐1α:db/db小鼠足细胞表达Nephrin和COX IV (p < 0.05)，上调多个线粒体功能相关基因，特别是OPA1 （p < 0.05）。mPGC - 1α:db/db小鼠的骨骼肌显示IL - 15 mRNA （p < 0.05）和蛋白（p < 0.01）水平升高，同时血浆IL - 15浓度升高（p < 0.05）。IL - 15处理增强足细胞线粒体呼吸，包括基础耗氧量（OCR, p < 0.05）、ATP偶联呼吸（p < 0.05）和最大呼吸（p < 0.05）。IL - 15通过增加OPA1的表达（p < 0.05），并通过组蛋白H3在其启动子上的乙酰化，促进了OPA1的转录（p < 0.05），从而在高糖条件下保持了线粒体融合。结论骨骼肌来源的IL - 15通过维持DN进展过程中足细胞的线粒体融合介导肾脏保护。靶向这一途径可能提供一种治疗策略，以保持肾脏功能和减缓终末期肾脏疾病的进展。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

求助全文

约1分钟内获得全文求助全文

来源期刊

Journal of Cachexia Sarcopenia and Muscle MEDICINE, GENERAL & INTERNAL-

CiteScore

13.30

自引率

12.40%

发文量

234

审稿时长

16 weeks

期刊介绍： The Journal of Cachexia, Sarcopenia and Muscle is a peer-reviewed international journal dedicated to publishing materials related to cachexia and sarcopenia, as well as body composition and its physiological and pathophysiological changes across the lifespan and in response to various illnesses from all fields of life sciences. The journal aims to provide a reliable resource for professionals interested in related research or involved in the clinical care of affected patients, such as those suffering from AIDS, cancer, chronic heart failure, chronic lung disease, liver cirrhosis, chronic kidney failure, rheumatoid arthritis, or sepsis.