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

ABSTRACT: 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 level

SUBMITTER: Hu M 

PROVIDER: S-EPMC12906104 | biostudies-literature | 2026 Mar

REPOSITORIES: biostudies-literature