Targeting tubular NAT10 ameliorates the renal Tubulointerstitial Fibrosis in Obstructive and Folic Acid-Induced Nephropathy

Abstract

Renal tubulointerstitial fibrosis (TIF) represents a common pathological hallmark during the progression of chronic kidney disease (CKD). NAT10, an RNA acetyltransferase, catalyzes N4-acetylcytidine modification of mRNA and has been associated with multiple pathological events, including bladder cancer progression, tumor metastasis, and cardiac remodeling. Nevertheless, NAT10's precise function and underlying molecular mechanisms in TIF remain inadequately elucidated. In this investigation, transforming growth factor-β1 (TGF-β1) was found to promote NAT10 expression in BUMPT cells via p53 upregulation. Functionally, NAT10 was demonstrated to regulate FN, Collagen I, and Collagen III expression triggered by TGF-β1 stimulation. Mechanistically, NAT10 enhanced Spred2 expression by promoting acetylation-dependent mRNA stability, which subsequently activated the JNK and ERK/TGF-β signaling pathways. Furthermore, a renal tubular epithelial cell-specific NAT10 knockout mouse model was established, and NAT10 deficiency's influence on TIF progression was examined using unilateral ureteral obstruction (UUO)- and folic acid (FA)-induced renal fibrosis models. The findings indicated that tubular epithelial-specific NAT10 deletion markedly alleviated UUO- and FA-induced renal TIF via inhibiting Spred2/JNK and ERK/TGF-β signaling. Finally, 5-Fluorouridine, a potent ribozyme self-cleavage inhibitor, was observed to attenuate UUO- and FA-induced renal TIF by targeting NAT10. Collectively, a previously unrecognized p53/NAT10/Spred2/JNK and ERK/TGF-β regulatory axis driving renal TIF is identified, and 5-Fluorouridine represents a viable therapeutic intervention for renal TIF.