Mitophagy induced by UMI-77 preserves mitochondrial fitness in renal tubular epithelial cells and alleviates renal fibrosis

Renal fibrosis is the final common outcome of chronic kidney disease (CKD), which remains a huge challenge due to a lack of targeted treatment. Growing evidence suggests that during the process of CKD, the integrity and function of mitochondria in renal tubular epithelial cells (TECs) are generally impaired and strongly connected with the progression of renal fibrosis. Mitophagy, a selective form of autophagy, could remove aberrant mitochondria to maintain mitochondrial homeostasis. Deficiency of mitophagy has been reported to aggravate renal fibrosis. However, whether induction of mitophagy could alleviate renal fibrosis has not been stated. In this study, we explored the effect of mitophagy activation by UMI-77, a compound recently verified to induce mitophagy, on murine CKD model of unilateral ureteral obstruction (UUO) in vivo and TECs in vitro. In UUO mice, we found the changes of mitochondrial damage, ROS production, transforming growth factor (TGF)-beta 1/Smad pathway activation, as well as epithelial-mesenchymal transition phenotype and renal fibrosis, and these changes were ameliorated by mitophagy enhancement using UMI-77. Moreover, TEC apoptosis, nuclear factor (NF)-kappa B signaling activation, and interstitial inflammation after UUO were significantly mitigated by augmented mitophagy. Then, we found UMI-77 could effectively and safely induce mitophagy in TECs in vitro, and reduced TGF-beta 1/Smad signaling and downstream profibrotic responses in TGF-beta 1-treated TECs. These changes were restored by a mitophagy inhibitor. In conclusion, we demonstrated that mitophagy activation protected against renal fibrosis through improving mitochondrial fitness, downregulating TGF-beta 1/Smad signaling and alleviating TEC injuries and inflammatory infiltration in kidneys.

Automated summary

Activation of mitophagy improves mitochondrial health, reduces TGF-beta 1/Smad signaling, alleviates TEC injuries, and decreases inflammatory infiltration in the kidneys.