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, characterized by progressive cyst growth, inflammation, and interstitial fibrosis. Renal fibrosis, driven by myofibroblast activation and excessive extracellular matrix (ECM) deposition, is increasingly recognized as a key contributor to disease progression, yet targeted antifibrotic therapies remain limited. Here, we evaluated the therapeutic potential of pirfenidone to suppress fibrosis and disease progression in ADPKD. Single-nucleus RNA sequencing of human ADPKD kidneys identified fibroblasts as the predominant source of fibrous and adhesive ECM, with higher ECM-associated gene expression compared with that in normal kidney fibroblasts. In vitro, primary human ADPKD renal myofibroblasts displayed a similar profibrotic gene expression profile, and pirfenidone treatment suppressed ECM gene expression, cell proliferation, migration, and contractility. In the Pkd1RC/RC mouse model of ADPKD, pirfenidone reduced renal fibrosis, myofibroblast accumulation, ECM deposition, profibrotic gene expression, and associated signaling pathways and improved kidney function. Pirfenidone also reduced kidney enlargement but reduced cyst burden only in female mice. Collectively, these findings demonstrate that pirfenidone attenuates renal fibrosis and improves kidney function in ADPKD by suppressing myofibroblast activation and ECM production, supporting fibrosis as a therapeutic target and highlighting pirfenidone as a potential adjunct to cyst-directed therapies.