Tubular NAT10 Promotes the Secretion of TGF-β and Lactate to Drive Fibroblast Activation in Diabetic Kidney Disease

Abstract

In advanced diabetic kidney disease (DKD), tubulointerstitial fibrosis (TIF) is a key histopathological lesion accompanying progressive renal functional decline. However, the tubular mechanisms that drive tubulointerstitial fibrogenesis remain incompletely understood. N-acetyltransferase 10 (NAT10) mediates mRNA N4-acetylcytidine (ac4C) modification, but its role and therapeutic potential in DKD are unknown. We investigated NAT10 regulation and function using cultured tubular cells, diabetic mouse models, patient kidney specimens, and tubule-specific Nat10 knockout mice, together with pharmacological treatment using guanosine diphosphate disodium salt. High glucose or diabetes increased tubular NAT10 abundance in cultured cells, mouse kidneys, and human DKD tissues through activation of NF-κB signaling. Mechanistically, NAT10 in tubular cells stabilized Brd4 and Pfkm mRNAs through ac4C modification, activating the STAT3/TGF-β and lactate/H3K18 lactylation pathways. These pathways synergistically promoted fibroblast activation through NOTCH/SMAD3 signaling and formed a positive feedback loop with NF-κB. Tubule-specific Nat10 deletion reduced Brd4 and Pfkm expression, suppressed the associated signaling cascades, and mitigated kidney fibrosis in the DKD model. Consistently, guanosine diphosphate disodium salt alleviated renal injury and fibrosis in db/db mice. Thus, NAT10 drives tubular fibrosis through ac4C-dependent profibrotic signaling, supporting NAT10 inhibition as a potential therapeutic strategy for DKD.