Podocyte FFAR4 deficiency aggravated glomerular diseases and aging.

IF 12.1 1区 医学 Q1 BIOTECHNOLOGY & APPLIED MICROBIOLOGY
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
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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.

足细胞FFAR4缺乏加重肾小球疾病和衰老。
足细胞损伤促进肾小球疾病的进展和衰老;然而,致病的分子/生理途径尚不明确,并且很少有治疗方法可以改善肾脏预后。我们之前研究了游离脂肪酸受体4 (FFAR4)激动剂TUG891改善足细胞损伤,减轻糖尿病肾病的肾脏炎症和纤维化。然而,足细胞FFAR4作为一个有希望的药物靶点在肾小球疾病和衰老中的作用尚未被探索。在这里,我们发现肾小球FFAR4表达在患者中异常降低,并且与肾小球疾病的肾功能下降高度相关。同样,实验性局灶节段性肾小球硬化和糖尿病肾病小鼠足细胞FFAR4减少。系统性和足细胞特异性FFAR4缺失都会加重肾小球损伤,而给予FFAR4激动剂TUG891和鱼油分别减轻阿霉素引起的肾病、糖尿病和衰老小鼠的疾病严重程度。在机制上,FFAR4的减少引发了损伤足细胞和肾小球的细胞衰老和脂质代谢紊乱。FFAR4激动作用通过激活camkk - β- ampk信号,发挥抗衰老和抗脂毒活性,保护足细胞免受损伤。这些发现为足细胞损伤的信号通路提供了新的见解,并增强了对FFAR4的机制功能的理解,揭示了治疗肾小球疾病和衰老的有希望的治疗机会。
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来源期刊
Molecular Therapy
Molecular Therapy 医学-生物工程与应用微生物
CiteScore
19.20
自引率
3.20%
发文量
357
审稿时长
3 months
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.
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