Cilia movement represses mitogen-activated protein kinase signaling by enhancing expression of the raf kinase inhibitor protein

Polycystic kidney disease (PKD) is characterized by the growth of fluid‐filled cysts in the kidneys and other organs. These cysts arise from uncontrolled cellular proliferation, potentially resulting from dysfunctional cilia. We hypothesized that the mechanosensory action of cilia regulates cellular proliferation by limiting signaling through the mitogen‐activated protein kinase (MAPK) pathway. Immortalized collecting duct cell lines from the Oak Ridge mouse that is a hypomorph for the Tg737 gene [cilia (−) cells] or cells in which the Tg737 gene was reinserted [cilia (+) cells] were incubated in a stationary state or subjected to 12 hr of shear stress on a rotator. Analysis of proteins from cilia (+) cells subjected to rotation revealed cilia movement increased expression of the raf kinase inhibitor protein (RKIP) and decreased expression of downstream phosphorylated proteins in the MAPK pathway when compared to all other cells. In addition, renal cortex tissue obtained from adult Tg737 conditional floxed allele mice in which cilia had been knocked out for 3 weeks [cre (+)] or in which cilia were unaffected [cre (−)] was analyzed by western blot. We found that RKIP was significantly higher in renal tissue expressing cilia. These results suggest that flow‐induced bending of cilia suppresses cellular proliferation by controlling the MAPK signaling pathway. This work was supported by NIH grants and a VA Merit Award.