YAP promotes AP-1 expression in tubular epithelial cells in the kidney.

Chronic kidney disease (CKD) is a major health problem. Kidney fibrosis is a hallmark and final common pathway of CKD. The Hippo/YAP pathway regulates organ size, inflammation and tumorigenesis. Our previous study demonstrated that tubular YAP activation by tubule-specific double knockout (dKO) of Mst1/2 induced CKD in mice, but the underlying mechanisms remain to be fully elucidated. AP-1 activation was found to promote tubular atrophy and tubulointerstitial fibrosis. Therefore, we studied whether YAP regulates AP-1 expression in the kidney. We found that expression of various AP-1 components was induced in kidneys subjected to unilateral ureteric obstruction (UUO) and in Mst1/2 dKO kidneys, and these inductions were blocked by deletion of Yap in tubular cells, with Fosl1 being most affected compared with other AP-1 genes. Inhibition of Yap also most highly suppressed Fosl1 expression among AP-1 genes in HK-2 and IMCD3 renal tubular cells. YAP bound to the Fosl1 promotor and promoted Fosl1 promoter luciferase activity. Our results suggest that YAP controls AP-1 expression, and that Fosl1 is the primary target of YAP in renal tubular cells.