Ogg1 regulates TGF‑β–Smad3 signalling and fibrosis progression in chronic kidney disease

Kidney fibrosis is a hallmark of chronic kidney disease (CKD) and a major contributor to progression toward end-stage renal disease. Here, we identify 8-oxoguanine DNA glycosylase 1 (Ogg1), a DNA repair enzyme, as a regulator of kidney fibrosis. Ogg1 expression is upregulated in experimental fibrosis models in male mice, including unilateral ureteral obstruction (UUO) and aristolochic acid (AA) nephropathy, as well as in kidney tissues from CKD patients. Genetic deletion of Ogg1 reduces fibrosis, tubular atrophy and fibrotic marker expression, and improves renal function in AA nephropathy. Mechanistically, Ogg1 interacts with phosphorylated Smad3 in the nucleus and promotes transcriptional regulation of profibrotic genes. Pharmacological inhibition of Ogg1 with TH5487 alleviates fibrosis in both UUO and AA nephropathy models, supporting Ogg1 as a potential therapeutic target in CKD. Ogg1 regulates Smad3 to drive profibrotic transcription in kidney disease; genetic deletion or chemical inhibition of Ogg1 reduces fibrosis and preserves renal function in a mouse model of chronic kidney disease.