Pirfenidone treatment attenuates fibrosis in autosomal dominant polycystic kidney disease

ABSTRACT Autosomal dominant polycystic kidney disease (ADPKD) is a leading genetic cause of kidney failure, marked by progressive cyst expansion, inflammation and fibrosis. Renal fibrosis, characterized by myofibroblast activation and excessive extracellular matrix (ECM) deposition is a central driver of disease progression in ADPKD, yet targeted anti-fibrotic therapies remain limited. Here, we evaluated the therapeutic potential of pirfenidone to suppress fibrosis and disease progression in ADPKD. To define the ECM in human ADPKD kidneys, we analyzed snRNA-seq data and found that fibroblasts are the principal source of fibrous and adhesive ECM in ADPKD kidneys, exhibiting higher ECM gene expression than normal controls. In vitro, primary culture human ADPKD renal myofibroblasts showed a similar profibrotic gene expression profile, and pirfenidone treatment suppressed ECM gene expression, cell proliferation, migration and contractility. In the Pkd1 RC/RC mouse model of ADPKD, pirfenidone treatment significantly reduced renal fibrosis, myofibroblast accumulation, ECM deposition, pro-fibrotic gene expression and associated cell signaling pathways. Pirfenidone also decreased kidney-to-body weight ratio and improved kidney function in Pkd1 RC/RC mice, without altering cyst burden. Collectively, these findings demonstrate that pirfenidone attenuates renal fibrosis and improves kidney function in ADPKD by targeting myofibroblast activation and ECM production, supporting a complementary therapeutic approach to cyst-directed therapies.