Asprosin Aggravates Tubular Epithelial Cell Injury and Phenotypic Transformation via Mitochondrial Dynamics Disorder Mediated by Excessive Drp1 SUMOylation in Diabetic Nephropathy Mice.

Abstract

Epidemiological studies show that some diabetic patients develop end-stage renal dysfunction without significant proteinuria or glomerulopathy, underscoring the role of renal tubular epithelial cell (TEC) impairment in diabetic kidney disease (DKD). However, the primary pathogenic determinants underlying TEC impairment and disease advancement in DKD progression remain unclear. This study reveals that asprosin (ASP) is up-regulated and positively correlated with kidney dysfunction in DKD mice. Moreover, elevated ASP is mainly located in the renal TEC, and negatively impacts TEC. In addition, supraphysiological ASP concentration impairs mitochondrial dynamics and function in both DKD mice and HK2 cells. Mechanistically, ASP promotes Drp1 over-SUMOylation, thus reducing Drp1 degradation and disrupting mitochondrial dynamics homeostasis. However, the mutation of Drp1-SUMOylation modification sites alleviates the mitochondrial dynamics disorder, TEC injury, and phenotypic transformation induced by ASP. Also, it is further elucidated that such a regulatory effect of ASP on the Drp1-SUMOylation modification is fulfilled by modulating PIAS1 or SENP1 (a de-SUMOylation protease). Importantly, either adipose tissue-specific ASP deficiency (ASP) or ASP antibody (AASP) intervention significantly alleviates the kidney injury and mitochondrial dynamics disorder induced by STZ/HFD. These findings identify ASP as a novel predictor of DKD and offer new therapeutic strategies for DKD prevention and treatment.