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

Abstract

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)‐β1/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)‐κB 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‐β1/Smad signaling and downstream profibrotic responses in TGF‐β1‐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‐β1/Smad signaling and alleviating TEC injuries and inflammatory infiltration in kidneys.

The molecular mechanisms and intervention strategies of mitophagy in cardiorenal syndrome

“…As reported, UMI-77 enhanced mitophagy, reversed mitochondrial damage, reduced ROS production, and inhibited renal fibrosis in UUO mice ( Jin L. et al, 2022 ). In addition, mito-TEMPO, a mitochondrial targeting antioxidant, activated PINK1-Parkin pathway to induce mitophagy in vivo and in vitro , which significantly ameliorated the podocyte injury in a rat model of CKD ( Liu B. et al, 2022 ).…”

Heidihuangwan alleviates renal fibrosis in rats with 5/6 nephrectomy by inhibiting autophagy

“…In contrast, curcumin reversed this process and attenuated RIF (Lu et al, 2021). The UUO mouse model exhibited mitochondrial damage, ROS production, TGF-β1/Smad pathway activation, epithelial-mesenchymal transition, and renal fibrosis, and these changes were ameliorated by the use of UMI-77 (mitochondrial autophagy activator) (Jin et al, 2022), suggesting that activation of autophagy protects the damaged kidney. In adult Sprague Dawley rats, the expression of autophagy marker proteins Beclin1, LC3II, PRR, ATG7, and ATG5 was significantly lower in glomeruli than in normal rats 8 weeks after undergoing 5/6 nephrectomy (Yildirim et al, 2021).…”

Relative comparison of chronic kidney disease-mineral and bone disorder rat models

“…In the UUO group (Jiang et al, 2021;Jin et al, 2022), six rats were anesthetized with isoflurane as previously described. Then, the left kidney and ureter were exposed via a flank incision, and the left ureter was ligated with 3-0 silk sutures at two points before closing the incision.…”

“…In recent years, 5/6 nephrectomy (5/6 Nx) (Shalhoub et al, 2012;Watanabe et al, 2018;Liu et al, 2021a), adenine with highphosphorus diet consumption (Tani et al, 2020;Tsuboi et al, 2020), unilateral ureteral obstruction (UUO) (Nordholm et al, 2018;Jiang et al, 2021;Jin et al, 2022), and Adriamycin nephropathy (AN) (Zhang et al, 2019;Li et al, 2020) have been utilized to model CKD-MBD. However, there is a lack of systematic studies comparing these models.…”