Persistent Activation of Autophagy After Cisplatin Nephrotoxicity Promotes Renal Fibrosis and Chronic Kidney Disease

Frontiers in Pharmacology

Zheng Dong¹  Ying Fu²  Juan Cai²  Yu Xiang²  Wenwen Wu²  Chengyuan Tang² 

[1] Department of Cellular Biology and Anatomy, Medical College of Georgia at Augusta University and Charlie Norwood VA Medical Center, Augusta, GA, United States;Department of Nephrology, Hunan Key Laboratory of Kidney Disease and Blood Purification, The Second Xiangya Hospital at Central South University, Changsha, China;

关键词: autophagy;    cisplatin;    kidney injury and repair;    renal fibrosis;    profibrotic growth factor;   

DOI  :  10.3389/fphar.2022.918732

来源: DOAJ

【 摘 要 】

Autophagy, a highly conserved catabolic pathway in eukaryotic cells, contributes to the maintenance of the homeostasis and function of the kidney. Upon acute kidney injury (AKI), autophagy is activated in renal tubular cells to act as an intrinsic protective mechanism. However, the role of autophagy in the development of chronic kidney pathologies including renal fibrosis after AKI remains unclear. In this study, we detected a persistent autophagy activation in mouse kidneys after nephrotoxicity of repeated low dose cisplatin (RLDC) treatment. 3-methyladenine (3-MA) and chloroquine (CQ), respective inhibitors of autophagy at the initiation and degradation stages, blocked autophagic flux and improved kidney repair in post-RLDC mice, as indicated by kidney weight, renal function, and less interstitial fibrosis. In vitro, RLDC induced a pro-fibrotic phenotype in renal tubular cells, including the production and secretion of pro-fibrotic cytokines. Notably, autophagy inhibitors blocked RLDC-induced secretion of pro-fibrotic cytokines in these cells. Together, the results indicate that persistent autophagy after AKI induces pro-fibrotic cytokines in renal tubular cells, promoting renal fibrosis and chronic kidney disease.

【 授权许可】

Unknown