Ciliary protein polycystin is required for renal tubulointerstitial fibrosis

Polycystin-1 (encoded by PKD1 gene) and polycystin-2 (encoded by PKD2 gene) are located in the primary cilia, forming a transmembrane complex and function as a stress sensor; their mutation causes autosomal dominant polycystic kidney disease. Recent studies showed that increased expression of polycystins and other ciliary proteins contributes to organ fibrosis. However, the role of polycystins in renal tubulointerstitial fibrosis remains unclear. In this study, we demonstrated that polycystin-1 or polycystin-2 was highly expressed in the kidney of two different fibrotic mouse models and positively correlated with expression of collagen-I. Pharmaceutical inhibition of polycystin-2 with triptolide or genetic knockout of polycystin-2 reduced expression of epithelial-mesenchymal transition (EMT) markers and deposition of extracellular matrix proteins in fibrotic kidneys. Similarly, conditional knockout of Pkd1 gene also attenuated renal fibrosis in mouse models. Moreover, we found that enhancer of Zeste homolog 2 (EZH2), a methyltransferase that promotes renal fibrosis, was positively correlated with expression of polycystins in fibrotic kidneys, and conditional deletion of the Ezh2 diminished the anti-EMT and anti-fibrotic effect of Pkd1 deletion. These data indicate that polycystins drive EMT and renal tubulointerstitial fibrosis through upregulation of EZH2. Targeting ciliary protein may provide a new strategy to treat patients with renal tubulointerstitial fibrosis. Research highlights Ciliary protein polycystin1 and polycystin-2 are up-regulated in fibrotic kidneys Inhibition or deletion of polycystins attenuates renal tubulointerstitial fibrosis Polycystins promote EMT in renal epithelial cells Epigenetic regulator EZH2 mediates polycystin-driven renal fibrosis.