足细胞
尼福林
自噬
卡尔帕因
TRPC6型
肾
肾小球硬化
肾脏疾病
内分泌学
内科学
急性肾损伤
癌症研究
医学
细胞生物学
生物
化学
蛋白尿
细胞凋亡
受体
生物化学
酶
瞬时受体电位通道
作者
Yann Salemkour,Dilemin Yildiz,Léa Dionet,Daan C. ‘t Hart,Kim A.T. Verheijden,Ryuta Saito,Nassim Mahtal,Jean‐Daniel Delbet,Emmanuel Letavernier,Marion Rabant,Alexandre Karras,Johan van der Vlag,Tom Nijenhuis,Pierre‐Louis Tharaux,Olivia Lenoir
出处
期刊:Journal of The American Society of Nephrology
日期:2023-09-06
卷期号:34 (11): 1823-1842
被引量:3
标识
DOI:10.1681/asn.0000000000000212
摘要
Significance Statement Autophagy protects podocytes from injury in diabetic kidney disease (DKD). Restoring glomerular autophagy is a promising approach to limit DKD. This study demonstrates a novel regulatory mechanism of autophagy that blocks this critical protection of the glomerular filtration barrier. We demonstrated that TRPC6 induced in podocytes in mouse models of diabetes mediates calpain activation, thereby impairing podocyte autophagy, causing injury and accelerating DKD. Furthermore, this study provides proof of principle for druggable targets for DKD because restoration of podocyte autophagy by calpain inhibitors effectively limits glomerular destruction. Background Diabetic kidney disease is associated with impaired podocyte autophagy and subsequent podocyte injury. The regulation of podocyte autophagy is unique because it minimally uses the mTOR and AMPK pathways. Thus, the molecular mechanisms underlying the impaired autophagy in podocytes in diabetic kidney disease remain largely elusive. Methods This study investigated how the calcium channel TRPC6 and the cysteine protease calpains deleteriously affect podocyte autophagy in diabetic kidney disease in mice. We demonstrated that TRPC6 knockdown in podocytes increased the autophagic flux because of decreased cysteine protease calpain activity. Diabetic kidney disease was induced in vivo using streptozotocin with unilateral nephrectomy and the BTBR ob/ob mouse models. Results Diabetes increased TRPC6 expression in podocytes in vivo with decreased podocyte autophagic flux. Transgenic overexpression of the endogenous calpain inhibitor calpastatin, as well as pharmacologic inhibition of calpain activity, normalized podocyte autophagic flux, reduced nephrin loss, and prevented the development of albuminuria in diabetic mice. In kidney biopsies from patients with diabetes, we further confirmed that TRPC6 overexpression in podocytes correlates with decreased calpastatin expression, autophagy blockade, and podocyte injury. Conclusions Overall, we discovered a new mechanism that connects TRPC6 and calpain activity to impaired podocyte autophagy, increased podocyte injury, and development of proteinuria in the context of diabetic kidney disease. Therefore, targeting TRPC6 and/or calpain to restore podocyte autophagy might be a promising therapeutic strategy for diabetic kidney disease.
科研通智能强力驱动
Strongly Powered by AbleSci AI