ND-630, an acetyl-CoA carboxylase inhibitor, prevents renal fibrosis in adenine-induced CKD mice.

Abstract

To evaluate the protective potential of ND-630, an acetyl-CoA carboxylase (ACC) inhibitor, in preventing renal fibrosis using an adenine-induced chronic kidney disease (CKD) mouse model. Male C57BL/6 mice were divided into four groups: control, CKD, CKD + ND-630 low-dose (4 mg/kg/d), and CKD + ND-630 high-dose (16 mg/kg/d). CKD was induced by feeding 0.2% adenine diet for 4 weeks with concurrent ND-630 treatment. Renal function was assessed by serum creatinine (Scr) and blood urea nitrogen (BUN). Histopathological analysis included PAS and Sirius red staining. Fibrosis markers (α-smooth muscle actin and vimentin), ACC1 expression, lipid deposition, oxidative stress markers (catalase, superoxide dismutase 2, and NADPH oxidase 4), inflammatory cytokines (tumor necrosis factor-α and interleukin-6), and transforming growth factor-β1 (TGF-β1)/Smad signaling were evaluated using immunohistochemistry, ELISA, and immunofluorescence. ND-630 significantly decreased Scr and BUN levels in CKD mice, with greater efficacy at higher doses. Administration of ND-630 limited renal tubular injury and collagen deposition. ND-630 suppressed the expression of fibrosis markers such as α-smooth muscle actin and vimentin, inhibited ACC1 expression, malonyl-CoA production, and lipid accumulation. Additionally, ND-630 protected against oxidative stress, decreased inflammatory cytokines levels, and antagonized TGF-β1/Smad signaling activation in CKD kidneys. ND-630 demonstrates nephroprotective effects in adenine-induced CKD mice by inhibiting ACC1-mediated lipid accumulation, suppressing oxidative stress and inflammation, and antagonizing TGF-β1/Smad signaling.