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

ERRα expression is significantly downregulated in renal tubular cells of both diabetic mice and DKD patients.

• Downregulation of ERRα correlated with increased senescence markers in tubular epithelial cells (TECs).
• Reduced ERRα expression was associated with the senescence-associated secretory phenotype (SASP).
• The finding was observed in both animal models and human DKD patient samples.

ERRα transcriptionally regulates NOS2 expression in tubular epithelial cells.

• Transcriptome analysis confirmed ERRα regulation of NOS2 transcription.
• Chromatin immunoprecipitation sequencing (ChIP-seq) provided mechanistic confirmation of ERRα binding at the NOS2 locus.
• This regulatory relationship was identified as a key mechanistic link in the ERRα-NOS2-citrulline axis.

TECs-specific knockout of ERRα reduced NOS2 expression and decreased citrulline levels, exacerbating TECs injury and senescence.

• TECs-specific ERRα knockout led to reduced NOS2 expression.
• Decreased citrulline levels were observed following ERRα knockout.
• Loss of ERRα worsened tubular epithelial cell injury and cellular senescence in the context of DKD.

TECs-specific knock-in of ERRα alleviated TECs injury and senescence and restored citrulline metabolism.

• ERRα knock-in in TECs had protective effects against cellular senescence.
• Restoration of ERRα expression was sufficient to rescue citrulline metabolism.
• These gain-of-function results corroborated the loss-of-function findings from the knockout model.

Overexpression of NOS2 and supplementation with citrulline ameliorated renal dysfunction and cellular senescence in diabetic mice.

• Both NOS2 overexpression and citrulline supplementation were tested as interventions in diabetic mouse models.
• These interventions reduced markers of renal dysfunction.
• The findings underscore the importance of the NOS2-citrulline metabolic axis downstream of ERRα.
• Results suggest citrulline supplementation as a potential therapeutic approach for DKD.

ERRα-NOS2-mediated citrulline metabolism is essential for maintaining kidney function and mitigating tubular senescence in DKD.

• The ERRα→NOS2→citrulline axis was identified as a critical regulatory pathway in DKD.
• Disruption of this axis correlated with progression of tubular senescence, inflammation, and fibrosis.
• Modulating ERRα and NOS2 activity was proposed as a potential therapeutic strategy to slow DKD progression.