ERRα-NOS2-mediated citrulline metabolism attenuates tubular epithelial cell senescence in diabetic kidney disease

Diabetic kidney disease (DKD) is a leading cause of end-stage renal disease, characterized by tubular epithelial cell (TECs) senescence, inflammation, and fibrosis. This study investigates the role of estrogen-related receptor alpha (ERRα) in regulating TECs senescence in DKD through nitric oxide synthase 2 (NOS2)-mediated citrulline metabolism. We demonstrate that ERRα expression is significantly downregulated in renal tubular cells of both diabetic mice and DKD patients, correlating with increased senescence markers and the senescence-associated secretory phenotype (SASP). Mechanistically, transcriptome and chromatin immunoprecipitation sequencing confirmed that ERRα regulates NOS2 transcription. TECs-specific knockout of ERRα led to reduced NOS2 expression and decreased citrulline levels, exacerbating TECs injury and senescence. In contrast, TECs-specific knock-in of ERRα alleviated TECs injury and senescence and restored citrulline metabolism. These findings indicate that ERRα plays a critical role in regulating NOS2-mediated citrulline metabolism, which is essential for maintaining kidney function and mitigating tubular senescence in DKD. Furthermore, overexpression of NOS2 and supplementation with citrulline ameliorated renal dysfunction and cellular senescence in diabetic mice, underscoring the importance of this metabolic axis. Modulating ERRα and NOS2 activity may present a potential therapeutic strategy to reduce kidney injury and slow the progression of DKD.