Ting Yin, Letian Yang, Lei Tang, Jian Li, Dekai Liu, Fan Guo, Yingsong Mu, Qimei Wu, Yuying Feng, Zhouke Tan, Ping Fu, Xiaoniao Chen, Liang Ma
{"title":"Podocyte FFAR4 deficiency aggravated glomerular diseases and aging.","authors":"Ting Yin, Letian Yang, Lei Tang, Jian Li, Dekai Liu, Fan Guo, Yingsong Mu, Qimei Wu, Yuying Feng, Zhouke Tan, Ping Fu, Xiaoniao Chen, Liang Ma","doi":"10.1016/j.ymthe.2025.05.035","DOIUrl":null,"url":null,"abstract":"<p><p>Podocyte injury contributes to the progression of glomerular disease and aging; however, causative molecular/physiological pathways are poorly defined, and there are few therapies to improve kidney outcomes. We previously reported that free fatty acid receptor 4 (FFAR4) agonist TUG891 improved podocyte injury to alleviate renal inflammation and fibrosis in diabetic nephropathy. However, the role of podocyte FFAR4 as a promising drug target has not been explored in glomerular diseases and aging. Here, we found that glomerular FFAR4 expression was abnormally decreased in patients and highly correlated with kidney function decline of glomerular diseases. Similarly, podocyte FFAR4 decreased in experimental focal segmental glomerulosclerosis and diabetic kidney disease mice. Both systemic and podocyte-specific FFAR4 deletion aggravated glomerular damage, whereas administration of FFAR4 agonist TUG891 and fish oil alleviated the severity of disease in adriamycin-induced nephropathy, diabetic, and aging mice, respectively. Mechanistically, FFAR4 reduction triggered cellular senescence and lipid metabolism disorder in injured podocytes and glomerulus. FFAR4 agonism exerted anti-senescent and anti-lipotoxic effects via activating CaMKKβ-AMPK signaling to protect against podocyte damage. These findings provide insight into signaling pathways involved in podocyte injury and enhance the understanding of the mechanistic functions of FFAR4 to reveal promising therapeutic opportunities against glomerular diseases and aging.</p>","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":" ","pages":""},"PeriodicalIF":12.1000,"publicationDate":"2025-05-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Molecular Therapy","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1016/j.ymthe.2025.05.035","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"BIOTECHNOLOGY & APPLIED MICROBIOLOGY","Score":null,"Total":0}
引用次数: 0
Abstract
Podocyte injury contributes to the progression of glomerular disease and aging; however, causative molecular/physiological pathways are poorly defined, and there are few therapies to improve kidney outcomes. We previously reported that free fatty acid receptor 4 (FFAR4) agonist TUG891 improved podocyte injury to alleviate renal inflammation and fibrosis in diabetic nephropathy. However, the role of podocyte FFAR4 as a promising drug target has not been explored in glomerular diseases and aging. Here, we found that glomerular FFAR4 expression was abnormally decreased in patients and highly correlated with kidney function decline of glomerular diseases. Similarly, podocyte FFAR4 decreased in experimental focal segmental glomerulosclerosis and diabetic kidney disease mice. Both systemic and podocyte-specific FFAR4 deletion aggravated glomerular damage, whereas administration of FFAR4 agonist TUG891 and fish oil alleviated the severity of disease in adriamycin-induced nephropathy, diabetic, and aging mice, respectively. Mechanistically, FFAR4 reduction triggered cellular senescence and lipid metabolism disorder in injured podocytes and glomerulus. FFAR4 agonism exerted anti-senescent and anti-lipotoxic effects via activating CaMKKβ-AMPK signaling to protect against podocyte damage. These findings provide insight into signaling pathways involved in podocyte injury and enhance the understanding of the mechanistic functions of FFAR4 to reveal promising therapeutic opportunities against glomerular diseases and aging.
期刊介绍:
Molecular Therapy is the leading journal for research in gene transfer, vector development, stem cell manipulation, and therapeutic interventions. It covers a broad spectrum of topics including genetic and acquired disease correction, vaccine development, pre-clinical validation, safety/efficacy studies, and clinical trials. With a focus on advancing genetics, medicine, and biotechnology, Molecular Therapy publishes peer-reviewed research, reviews, and commentaries to showcase the latest advancements in the field. With an impressive impact factor of 12.4 in 2022, it continues to attract top-tier contributions.