RUNX3与ATRAP的相互作用通过NLRP3炎性小体调节STZ诱导的T1DN损伤

Abstract

RUNX3 physically interacts with ATRAP in the kidney. • RUNX3 loss reduces ATRAP and activates NLRP3 inflammasome. • ATRAP overexpression attenuates diabetic kidney injury. • ATRAP may function as a downstream mediator of RUNX3. • The RUNX3-ATRAP axis represents a potential therapeutic target. Objective This study investigated whether RUNX3 regulates renal injury in diabetic nephropathy (DN) via ATRAP-dependent NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome inhibition. Methods Type 1 diabetic nephropathy (T1DN) was induced in wild-type and kidney-specific Runx3 conditional knockout mice using streptozotocin. Renal function was assessed by urinary protein, N-acetyl-β- D -glucosaminidase, and serum creatinine; histopathology by H&E and PAS staining. Protein expression of RUNX3, ATRAP, and NLRP3 pathway components was examined by immunohistochemistry and Western blot; IL-1β and IL-18 by ELISA; and Caspase-1 activity by fluorometric assay. Co-immunoprecipitation tested RUNX3-ATRAP interaction. In vitro studies used HK-2 cells. Results RUNX3 and ATRAP were downregulated in T1DN kidneys and inversely correlated with NLRP3 activation. RUNX3 deficiency worsened renal injury, further reduced ATRAP, and enhanced NLRP3 activation, whereas ATRAP overexpression attenuated these effects. ATRAP overexpression also reduced fibrosis (α-SMA), tubular injury (KIM-1), angiotensin II type 1 receptor, and inflammatory cytokines, while partially restoring nephrin. In vitro , RUNX3 overexpression upregulated ATRAP and suppressed NLRP3 under high glucose. Conclusion These findings suggest that RUNX3 deficiency may aggravate renal injury in DN, potentially through downregulation of ATRAP and subsequent NLRP3 pathway activation.