PGC1α alleviates mitochondrial dysfunction via TFEB‐mediated autophagy in acute kidney injury mice

Objective Cisplatin is a widely used chemotherapy drug, and always led to nephrotoxicity via causing mitochondrial dysfunction. PGC‐1α, a regulator of mitochondrial biogenesis, has been recently reported to activate TFEB‐mediated autophagy, which could remove damaged mitochondria. However, The role of PGC1α/TFEB pathway remains unknown in AKI. Thus, we aim to investigate whether the activator of PGC‐1α (ZLN005) could alleviate mitochondria dysfunction though TFEB‐mediated autophagy in AKI mice. Methods Mice were administered cisplatin (16mg/kg, a single i.p. injection) to induce AKI, then treated with PBS or ZLN005 for 4 days. In vitro, HK2 cells were treated with cisplatin 5mM in the presence or absence of ZLN005. Results In vivo, comparing with the normal mice, BUN and Crea were significantly increased in AKI mice, while decreased after ZLN005 treatment (Fig. 1A). Additionally, the severity of tubular injury as determined by histologic examination was markedly ameliorated in AKI+ZLN005 group (Fig. 1B), indicating that the activation of PGC‐1α could alleviate kidney injury in AKI mice. Moreover, comparing with the AKI mice, mitochondrial fragmentation (many swollen, small and round mitochondria) induced by cisplatin was decreased after ZLN005 treatment (Fig. 1C). Consistent with the observation in vivo, along with the improvement of mitochondrial function (Fig. 2A–C), ZLN005 activated TFEB‐autophagy in cisplatin‐induced HK2 cells (Fig. 2D). Whereas, the protective effect of ZLN005 was largely abolished when the expression of TFEB was inhibited by RNAi of TFEB(Fig. 2E). Conclusion These results indicated that PGC‐1α could alleviate mitochondrial function and cisplatin‐induced kidney injury via TFEB‐autophagy pathway. Support or Funding Information This work was supported by the National Natural Science Foundation of China (No. 81900666)