This study first reveals the critical role of Asprosin in the progression of diabetic kidney disease (DKD), demonstrating that it disrupts mitochondrial dynamics by promoting 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 study, 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 the injurious effects of Asprosin on tubular epithelial cells (TECs) in diabetic nephropathy (DKD) mouse models and elucidates its molecular mechanisms, providing theoretical foundations for early diagnosis and therapeutic interventions.
Background Knowledge
Diabetic nephropathy represents a major microvascular complication of diabetes mellitus, potentially progressing to end-stage renal disease (ESRD). Under hyperglycemic conditions, tubular epithelial cells (TECs) undergo epithelial-mesenchymal transition (EMT), triggering renal tubular fibrosis (RTF) as a key pathological basis for disease progression. Mitochondria, as energy-demanding organelles, require balanced dynamics (fusion and fission) for TEC functional maintenance. Studies show that SUMOylation modification of the mitochondrial fission protein Drp1 stabilizes its conformation and reduces lysosomal degradation, thereby promoting mitochondrial fragmentation and dysfunction. This paper further uncovers Asprosin's (ASP) pathogenic mechanisms in DKD, demonstrating its role in enhancing Drp1 SUMOylation by upregulating PIAS1 and suppressing SENP1, consequently disrupting mitochondrial dynamics and exacerbating TEC injury. Notably, both Drp1 SUMOylation site mutations and ASP-neutralizing antibodies significantly alleviate these injuries, highlighting their therapeutic potential.
Research Methods and Experiments
The research team established a type 2 diabetes mouse model using streptozotocin (STZ) and high-fat diet (HFD) interventions, followed by Asprosin administration experiments. The impact of ASP on TEC structure, mitochondrial morphology, fusion/fission protein expression, and Drp1 SUMOylation levels was analyzed through Western blotting, immunohistochemistry, immunofluorescence, transmission electron microscopy (TEM), and molecular docking techniques. Additionally, tissue-specific ASP knockout (ASP−/−) mouse models and Drp1 mutants (Drp1-4KR) or inhibitors (Midivi-1) were employed to validate ASP's mechanisms. 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 connection between Asprosin and mitochondrial dynamic imbalance in DKD progression, offering novel biomarkers (ASP) for early diagnosis and new therapeutic strategies (e.g., AASP antibody or targeting Drp1 SUMO sites). Future research should explore ASP's clinical relevance in human DKD and develop regulatory drugs targeting SENP1/PIAS1 to modulate the ASP/Drp1 signaling axis for TEC functional protection.
Conclusion
Asprosin is significantly elevated in diabetic nephropathy mouse models and exacerbates TEC injury and phenotypic transformation by enhancing Drp1 SUMOylation and disrupting mitochondrial dynamic balance. This study not only identifies ASP's pathogenic role in DKD progression but also validates its therapeutic potential through gene editing and antibody interventions. These findings provide molecular insights for early DKD diagnosis and treatment while laying the foundation for future clinical translation.
