PGC-1α Alleviates Mitochondrial Dysfunction <i>via</i> TFEB-Mediated Autophagy in Cisplatin-Induced Acute Kidney Injury

Abstract

Background: Because 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 kidney injury. However, the specific mechanism involved in PGC-1α-mediated autophagy remains elusive. Methods: In vivo Cisp-induced AKI mice were administrated with PGC-1α activator (ZLN005, Zln), and the kidneys were harvested to detect autophagy, mitochondrial function and kidney injury. In vitro the protective role of PGC-1α in Cisp-induced HK2 cells were analyzed via overexpression of PGC-1α or Zln treatment. Finally, the key of TFEB in PGC-1α-mediated autophagy was investigated by sitfeb. Findings: In vivo along with the severe kidney damage, the expression of PGC-1α was significantly decreased in AKI mice. Conversely, elevated expression of PGC-1α by Zln administration could alleviate kidney injury. Consistently, in vitro overexpression of PGC-1α or Zln treatment inhibited cell apoptosis and mitochondrial dysfunction. Moreover, Zln treatment increased the expression of LC3-II and co-localization between LC3 and mitochondria in HK2 cells, suggesting that the mitophagy was activated. Furthermore, we found that PGC-1α directly regulated the expression of TFEB, and the protective role of PGC-1α was rely on TFEB-mediated autophagy. Interpretation: These data suggest that the activation of PGC-1α could alleviate mitochondrial dysfunction and kidney injury in AKI mice via TFEB-mediated autophagy. Funding: This work was supported by grants from the National Natural Science Foundation of China (grant number: 81900666 and 81870609), 1.3.5 project for disciplines of excellence, West China Hospital, Sichuan University (ZYGD18014). Declaration of Interests: The authors declare no competing financial interests. Ethics Approval Statement: All animal experiments were approved and conducted in accordance with the guidelines of the Institutional Animal Care and Use Committee of Sichuan University.