Cockayne syndrome mice reflect human kidney disease and are defective in de novo NAD biosynthesis

Introduction
Cockayne syndrome (CS) is a rare, premature aging disorder caused by mutations in the CSA and CSB genes, which affect DNA repair and transcription. CS patients frequently exhibit kidney abnormalities, but the molecular mechanisms underlying renal dysfunction remain poorly understood. Recent studies have implicated NAD+ biosynthesis, a critical pathway for cellular metabolism and the stress response, in CS pathogenesis.

Methods
This study utilized CS mouse models to investigate their renal pathology and the role of NAD+ biosynthesis. RNA sequencing was performed to analyze the differential gene expression, with a focus on NAD+ metabolism. Human kidney proximal tubular epithelial cells (HK-2) were used to validate our findings through siRNA knockdown of CSA/B. Our techniques included immunohistochemistry, NAD+ quantification, Western blotting, and chromatin immunoprecipitation (ChIP).

Results
The CS mice exhibited renal atrophy, fibrosis, and tubular epithelial cell abnormalities. RNA sequencing revealed impaired NAD+ biosynthesis pathways, with significant downregulation of quinolinate phosphoribosyl transferase (QPRT), a key enzyme in de novo NAD+ biosynthesis. Mechanistically, CSA/B deficiency stabilized ATF3, a transcriptional repressor, leading to QPRT downregulation and NAD+ depletion. These findings were confirmed in the HK-2 cells, where CSA/B knockdown recapitulated the effects on the QPRT expression and NAD+ levels.

Conclusions
Our study demonstrates that CS-related kidney dysfunction is driven by impaired NAD+ biosynthesis, mediated through ATF3-dependent QPRT repression. These findings provide novel insights into the molecular basis of renal pathology in CS and suggest potential therapeutic strategies targeting NAD+ metabolism for alleviating renal complications.