This study first reveals the critical role of Asprosin in diabetic kidney disease progression, demonstrating its mechanism of disrupting mitochondrial dynamics balance by enhancing Drp1 SUMOylation, leading to tubular epithelial cell injury and phenotypic transformation. Through gene editing and antibody intervention approaches, it provides novel diagnostic biomarkers and therapeutic targets.
Literature Overview
This article titled "Asprosin Aggravates Tubular Epithelial Cell Injury and Phenotypic Transformation via Mitochondrial Dynamics Disorder Mediated by Excessive Drp1 SUMOylation in Diabetic Nephropathy Mice", published in Advanced Science, reviews and summarizes the pathogenic effects of Asprosin on tubular epithelial cells (TEC) in diabetic kidney disease (DKD) mouse models, providing theoretical foundations for early diagnosis and therapeutic interventions.
Background Knowledge
Diabetic kidney disease, the primary microvascular complication of diabetes, can ultimately progress to end-stage renal disease (ESRD). Tubular epithelial cells (TEC) undergo epithelial-mesenchymal transition (EMT) under high-glucose conditions, triggering renal tubular interstitial fibrosis (RTF), a key pathological basis for disease progression. As essential organelles with high energy demands, mitochondria require dynamic balance (fusion and fission) to maintain TEC function. Research indicates that SUMOylation modification of the mitochondrial fission protein Drp1 stabilizes its conformation, reduces lysosomal degradation, and promotes mitochondrial fragmentation and dysfunction. This study further elucidates the pathogenic mechanism of Asprosin (ASP) in DKD, revealing its role in enhancing Drp1 SUMOylation by upregulating PIAS1 and inhibiting SENP1, thereby disrupting mitochondrial dynamics and aggravating TEC injury. Notably, interventions targeting Drp1 SUMOylation sites or ASP-neutralizing antibodies effectively alleviate these damages, suggesting therapeutic potential.
Research Methods and Experiments
The research team established a type 2 diabetic mouse model through streptozotocin (STZ) and high-fat diet (HFD), followed by Asprosin intervention experiments. Western blot, immunohistochemistry, immunofluorescence, transmission electron microscopy (TEM), and molecular docking techniques were employed to analyze ASP's effects on TEC structure, mitochondrial morphology, fusion/fission protein expression, and Drp1 SUMOylation levels. Additionally, tissue-specific ASP knockout mice (ASP−/−) and Drp1 mutants (Drp1-4KR) or inhibitors (Midivi-1) were used to validate ASP's mechanism. Molecular docking and co-immunoprecipitation (Co-IP) experiments further explored ASP interactions with PIAS1 or SENP1.
Key Conclusions and Perspectives
Research Significance and Prospects
This study establishes the first link between Asprosin and mitochondrial dynamics imbalance in DKD, offering a novel biomarker (ASP) for early diagnosis and new therapeutic strategies (e.g., AASP antibody or Drp1 SUMO modification intervention). Future research should explore ASP's clinical relevance in human DKD and develop drugs targeting the SENP1/PIAS1 axis to protect TEC function.
Conclusion
Asprosin was found significantly elevated in diabetic nephropathy mouse models, where it disrupts mitochondrial dynamics balance by enhancing Drp1 SUMOylation, resulting in tubular epithelial cell (TEC) injury and phenotypic transformation. This research not only clarifies ASP's pathogenic role in DKD progression but also validates its potential as a therapeutic target through gene editing and antibody interventions. These findings provide molecular insights for early DKD diagnosis and treatment, establishing a foundation for clinical translation.
