This study first reveals the critical role of Asprosin in the progression of diabetic kidney disease, demonstrating that it disrupts mitochondrial dynamics through enhanced SUMOylation of Drp1, leading to tubular epithelial cell injury and phenotypic transformation. The research provides novel diagnostic biomarkers and therapeutic targets through gene editing and antibody interventions.
Literature Overview
The paper 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 molecular mechanisms underlying Asprosin-induced renal tubular epithelial cell (TEC) injury in a diabetic nephropathy (DKD) mouse model, offering theoretical foundations for early diagnosis and therapeutic intervention.
Background Knowledge
Diabetic nephropathy is a major microvascular complication of diabetes, potentially progressing to end-stage renal disease (ESRD). Under hyperglycemic conditions, renal tubular epithelial cells (TEC) undergo epithelial-mesenchymal transition (EMT) and contribute to renal tubular fibrosis (RTF), a key pathological basis for disease progression. Mitochondria, as high-energy-demanding organelles, rely on dynamic balance (fusion and fission) to maintain TEC function. Studies indicate that SUMOylation 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, showing that ASP exacerbates mitochondrial imbalance and TEC injury by upregulating PIAS1 and suppressing SENP1 to enhance Drp1 SUMOylation. Importantly, interventions using Drp1 SUMOylation-resistant mutants or ASP-neutralizing antibodies effectively alleviate cellular injury, highlighting their potential as therapeutic strategies.
Research Methods and Experiments
The research team established a type 2 diabetes mouse model via streptozotocin (STZ) and high-fat diet (HFD), followed by Asprosin intervention experiments. Western blot, immunohistochemistry, immunofluorescence, transmission electron microscopy (TEM), and molecular docking analyses were employed to evaluate ASP-induced effects on TEC structure, mitochondrial morphology, fusion/fission protein expression, and Drp1 SUMOylation levels. Tissue-specific ASP knockout (ASP−/−) mice, Drp1 mutants (Drp1-4KR), and the Drp1 inhibitor Midivi-1 were utilized 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 a novel link between Asprosin, mitochondrial dynamic imbalance, and TEC injury in DKD, offering ASP as a promising diagnostic biomarker and validating gene editing and antibody-based strategies as therapeutic approaches. Future research should explore ASP’s clinical relevance in human DKD and develop drugs targeting SENP1/PIAS1 to modulate the ASP/Drp1 signaling axis, preserving TEC function.
Conclusion
Asprosin is identified as a critical driver of mitochondrial dynamic imbalance in diabetic nephropathy mice, inducing renal tubular epithelial cell injury and phenotypic transformation via enhanced Drp1 SUMOylation. The study confirms ASP’s pathogenic role in DKD progression and validates its therapeutic potential through gene editing and neutralizing antibodies. These findings provide molecular insights for early DKD diagnosis and treatment, laying the groundwork for clinical translation.
