Ciliary protein polycystin is required for renal tubulointerstitial fibrosis

AbstractPolycystin-1 (encoded byPKD1gene) and polycystin-2 (encoded byPKD2gene) 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 ofPkd1gene 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 theEzh2diminished the anti-EMT and anti-fibrotic effect ofPkd1deletion. 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 highlightsCiliary protein polycystin1 and polycystin-2 are up-regulated in fibrotic kidneysInhibition or deletion of polycystins attenuates renal tubulointerstitial fibrosisPolycystins promote EMT in renal epithelial cellsEpigenetic regulator EZH2 mediates polycystin-driven renal fibrosis.