Deficiency of exocyst complex component Exoc5 exacerbates the progression of kidney fibrosis.

Abstract

Fibrosis, an undesirable side effect of the repair process, is due to aberrant cell differentiation and is a typical cause of progressive diseases including chronic kidney disease (CKD). Exocyst complex component 5 (Exoc5), a central component of the highly-conserved eight-protein exocyst complex, is involved in cell differentiation and maturation; however, the role of Exoc5 in fibrosis remains to be defined. Here we investigate the role and underlying molecular mechanisms of Exoc5 on kidney development and fibrosis using kidney proximal tubule cell-specific Exoc5-knockout (PT-Exoc5) mice generated by crossing Exoc5with PEPCK-cre mice. Exoc5-knockout mice showed normal kidney structure and function. Unilateral ureteral obstruction (UUO) led to kidney fibrosis with decreased Exoc5 expression, and Exoc5 knockout worsened the fibrosis. Exoc5 knockout alone increased Yes-associated protein (YAP) expression and exacerbated UUO-induced YAP activation and the expression of CTGF and CYR61, products of YAP, compared with wild-type (PT-Exoc5) mice. UUO induced paired box 2 (Pax2, which is mainly expressed during kidney development) expression in both mice, and the UUO-induced Pax2 expression in PT-Exoc5was greater than in PT-Exoc5mice. In HK-2 cells, a human proximal tubule cell, EXOC5 downregulation by siRNA increased YAP and Pax2 expression. EXOC5 downregulation augmented TGF-β-induced YAP activation and epithelial-to-mesenchymal transition. Taken together, our data demonstrate that Exoc5 plays a protective role in kidney fibrosis, implying that Exoc5 could potentially serve as a therapeutic target for the regulation of fibrosis.