RUNX3 interaction with ATRAP regulates STZ-induced T1DN injury through NLRP3 inflammasome

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.

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.

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.

These findings suggest that RUNX3 deficiency may aggravate renal injury in DN, potentially through downregulation of ATRAP and subsequent NLRP3 pathway activation.