This study first elucidates the critical role of Asprosin in diabetic kidney disease (DKD) progression, demonstrating that it induces tubular epithelial cell (TEC) injury and phenotypic transformation by disrupting mitochondrial dynamics through enhanced SUMOylation of Drp1. Utilizing gene editing and antibody intervention approaches, it provides novel diagnostic markers and therapeutic targets for DKD.
Literature Overview
The article "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 damaging effects of Asprosin on renal tubular epithelial cells (TEC) in diabetic kidney disease (DKD) mouse models and their molecular mechanisms, offering theoretical foundations for early diagnosis and therapeutic interventions.
Background Knowledge
Diabetic kidney disease (DKD) represents a major microvascular complication of diabetes, potentially progressing to end-stage renal disease (ESRD). Under hyperglycemic conditions, tubular epithelial cells (TEC) undergo epithelial-mesenchymal transition (EMT), leading to tubulointerstitial fibrosis (RTF) - a key pathological basis for disease progression. Mitochondria, as high-energy-demand organelles, rely on dynamic balance (fusion and fission) for TEC functional maintenance. Studies indicate that SUMOylation modification of mitochondrial fission protein Drp1 stabilizes its conformation and reduces lysosomal degradation, promoting mitochondrial fragmentation and dysfunction. This article further reveals Asprosin's (ASP) pathogenic mechanism in DKD, showing that ASP enhances Drp1 SUMOylation by upregulating PIAS1 and inhibiting SENP1, thereby disrupting mitochondrial dynamics and aggravating TEC injury. Notably, interventions using Drp1 SUMOylation site mutations or ASP-neutralizing antibodies significantly alleviate these damages, highlighting their therapeutic potential.
Research Methods and Experiments
The research team established a type 2 diabetes mouse model through streptozotocin (STZ) injection and high-fat diet (HFD) feeding, followed by Asprosin intervention experiments. Western blot, immunohistochemistry, immunofluorescence, transmission electron microscopy (TEM), and molecular docking techniques were employed to analyze ASP's impact on TEC structure, mitochondrial morphology, fusion/fission protein expression, and Drp1 SUMOylation levels. Tissue-specific ASP knockout mice (ASP−/−) and Drp1 mutants (Drp1-4KR) or inhibitors (Midivi-1) were further utilized to validate ASP's mechanistic roles. Molecular interactions between ASP and PIAS1/SENP1 were explored through molecular docking and co-immunoprecipitation (Co-IP) assays.
Key Conclusions and Perspectives
Research Significance and Prospects
This study establishes the first link between Asprosin and mitochondrial dynamics imbalance in DKD pathogenesis, providing new biomarkers (ASP) for early diagnosis and therapeutic strategies (e.g., AASP antibody or Drp1 SUMO site intervention). Future investigations should validate ASP's clinical relevance in human DKD and develop SENP1/PIAS1-targeting therapeutics to modulate the ASP/Drp1 signaling axis for TEC protection.
Conclusion
Asprosin is identified as a critical pathogenic factor in diabetic kidney disease mouse models, exacerbating TEC injury and phenotypic transformation through enhanced Drp1 SUMOylation and mitochondrial dynamics disruption. This research not only clarifies ASP's role in DKD progression but also demonstrates its therapeutic potential using genetic and antibody-based interventions. These findings provide new molecular insights for early DKD diagnosis and treatment while establishing a foundation for clinical translation studies.
