Research Paper Volume 13, Issue 6 pp 8421—8439
PGC-1α alleviates mitochondrial dysfunction via TFEB-mediated autophagy in cisplatin-induced acute kidney injury
- 1 Key Laboratory of Transplant Engineering and Immunology, NHFPC, Department of Nephrology, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu, China
Received: September 8, 2020 Accepted: December 19, 2020 Published: March 10, 2021https://doi.org/10.18632/aging.202653
How to Cite
Copyright: © 2021 Yuan et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Because of the key role of impaired mitochondria in the progression of acute kidney injury (AKI), it is striking that peroxisome proliferator γ coactivator 1-α (PGC-1α), a transcriptional coactivator of genes involved in mitochondrial biogenesis and autophagy, protects from kidney injury. However, the specific mechanism involved in PGC-1α-mediated autophagy remains elusive. In vivo, along with the severe kidney damage, the expression of PGC-1α was decreased in cisplatin-induced AKI mice. Conversely, PGC-1α activator (ZLN005) administration could alleviate kidney injury. Consistently, in vitro overexpression of PGC-1α or ZLN005 treatment inhibited cell apoptosis and mitochondrial dysfunction induced by cisplatin. Moreover, ZLN005 treatment increased the expression of LC3-II and co-localization between LC3 and mitochondria, suggesting that the mitophagy was activated. Furthermore, PGC-1α-mediated the activation of mitophagy was reliant on the increased expression of TFEB, and the protective effects were abrogated in TFEB-knockdown cells. These data suggest that the activation of PGC-1α could alleviate mitochondrial dysfunction and kidney injury in AKI mice via TFEB-mediated autophagy.
AKI: acute kidney injury; BUN: blood urea nitrogen; CCK8: cell counting kit 8; Cisp: cisplatin; Zln: ZLN005; C+Z: cisplatin +ZLN005; Con: control; NC: normal control; Crea: serum creatinine; HCQ: hydroxychloroquine; Cisp + HCQ: cisplatin + hydroxychloroquine; ROS: reactive oxygen species; SDS-PAGE: sodium dodecyl sulfate-polyacrylamide gel electrophoresis; TFEB: transcription factor EB; PGC-1α: peroxisome proliferator γcoactivator 1-α; TUNEL: terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling staining.