Role of Hippo pathway in autosomal dominant polycystic kidney disease

Abstract

Objective To explore the role of Hippo pathway in the pathogenesis of autosomal dominant polycystic kidney disease (ADPKD), and find potential targets for drug therapy. Methods By means of immunofluorescence staining, Western blotting, Real-time PCR, the differences of sublocalization, expression and phosphorylation level about Hippo pathway molecules in Han:SPRD (cy/+) and ADPKD patients compared with the control were observed. Knockdown Yes kinase-associated protein (YAP), transcriptional coactivator with PDZ binding motif (TAZ) and large tumor suppressor kinase1 (LATS1) in cystic lining epithelium cell line WT9-12 were took by siRNA interference, and then their effects on cell proliferation, apoptosis and cell cycle were assessed. Results In cystic lining epithelium of Han:SPRD(cy/+), decreased expression of LATS1 and increased expression of YAP were found compared with the control, and the immunofluorescence of YAP was distributed both in cytoplasm and nucleus, while distribution and expression level of TAZ were without significant variance. Abnormal mRNA expressions of Hippo pathway components in ADPKD patients were found (P<0.05). Down-regulation of LATS1 in WT9-12 cells could prohibit phosphorylation of YAP, and prompted proliferation and cell division. Knockdown YAP in WT9-12 cells could inhibited cell proliferation by arresting cell cycle in G0/G1 phase, but down-regulating TAZ showed no significant differences in proliferation and cell cycle. Conclusions Altered Hippo signaling exists in ADPKD, and YAP activation may be one leading cause of autosomal dominant polycystic kidney disease onset. In vitro, knockdown YAP in WT9-12 cells can inhibit cell proliferation by arresting cell cycle and depressing cell division, suggesting the expression level and activity of YAP are potential targets for ADPKD treatment. Key words: Polycystic kidney, autosomal dominant; Cell proliferation; Cell cycle; Hippo pathway; Yes kinase-associated protein; Large tumor suppressor kinase 1