FP027
INHIBITION OF YES-ASSOCIATED PROTEIN ATTENUATES THE ACTIVATION OF PRO-FIBROTIC PROTEINS AND EPIDERMAL GROWTH FACTOR RECEPTOR BY THE ANGIOTENSIN II IN HUMAN RENAL PROXIMAL TUBULAR CELLS Free

INTRODUCTION: The present study investigated the role of upstream and downstream components of Yes-associated protein (YAP) signaling pathway in the pathogenesis of kidney fibrosis.

METHODS: Unilateral ureteral obstruction (UUO) was induced in C57BL/6J mice for 2 weeks. We determined the changes of angiotensin II type 1 receptor (AT1R), epidermal growth factor receptor (EGFR), Akt, CREB, YAP and pro-fibrotic proteins in the obstructed kidney of mice with UUO. We also investigated the protein expression of the upstream and downstream components of YAP signaling pathway after human renal proximal tubular (HK-2) cells were cultured with angiotensin II (Ang II) in the absence or presence of verteporfin, a YAP inhibitor.

RESULTS: The protein expression of AT1R, transforming growth factor (TGF)-β1, and α-smooth muscle actin (SMA) and connective tissue growth factor (CTGF) was increased in the ureteral obstructed kidney of mice with UUO. The phosphorylation of EGFR, Akt and CREB, and the expression of YAP were increased. In HK-2 cells, the treatment with Ang II increased the protein expression of TGF-β1, α-SMA, CTGF and fibronectin. These changes were counteracted by the pretreatment with verteporfin. In addition, the treatment with Ang II increased the phosphorylation of EGFR, which was also attenuated by the inhibition of YAP.

CONCLUSIONS: The expression of AT1R, EGFR, YAP and pro-fibrotic proteins is increased in the ureteral obstructed kidney. In HK-2 cells, the inhibition of YAP attenuates the activation of pro-fibrotic proteins and EGFR by the Ang II treatment. Our results suggests that YAP may regulate EGFR, an upstream component of YAP, as well as pro-fibrotic proteins.