Inhibiting Focal Adhesion Kinase Ameliorates Cyst Development in Polycystin-1–Deficient Polycystic Kidney Disease in Animal Model

Significance Statement Focal adhesion kinase (FAK) has been widely studied and shown to have a crucial effect on tumor progression. Although autosomal dominant polycystic kidney disease (ADPKD) shares numerous commonalities with tumors, it is undetermined whether FAK is involved in cyst development. Our study demonstrates that inhibiting FAK activity using small molecule FAK inhibitor VS-4718 ameliorates ADPKD progression and improves renal function. Inhibiting FAK and its downstream Src signaling suppresses cAMP-mediated aberrant proliferation of cystic epithelial cells in ADPKD animals. This study highlights the therapeutic potential of small molecule FAK inhibitors in treating patients with ADPKD. Background Autosomal dominant polycystic kidney disease (ADPKD) is characterized by numerous cysts originating from renal tubules and is associated with significant tubular epithelial cell proliferation. Focal adhesion kinase (FAK) promotes tumor growth by regulating multiple proliferative pathways. Methods We established the forskolin (FSK)-induced three-dimensional (3D) Madin–Darby Canine Kidney cystogenesis model and 8-bromoadenosine-3`,5`-cyclic monophosphate–stimulated cyst formation in ex vivo embryonic kidney culture. Cultured human renal cyst–lining cells (OX-161) and normal tubular epithelial cells were treated with FAK inhibitors or transfected with green fluorescent protein–tagged FAK mutant plasmids for proliferation study. Furthermore, we examined the role of FAK in two transgenic ADPKD animal models, the kidney-specific Pkd1 knockout and the collecting duct–specific Pkd1 knockout mouse models. Results FAK activity was significantly elevated in OX-161 cells and in two ADPKD mouse models. Inhibiting FAK activity reduced cell proliferation in OX-161 cells and prevented cyst growth in ex vivo and 3D cyst models. In tissue-specific Pkd1 knockout mouse models, FAK inhibitors retarded cyst development and mitigated renal function decline. Mechanically, FSK stimulated FAK activation in tubular epithelial cells, which was blocked by a protein kinase A (PKA) inhibitor. Inhibition of FAK activation by inhibitors or transfected cells with mutant FAK constructs interrupted FSK-mediated Src activation and upregulation of ERK and mTOR pathways. Conclusions Our study demonstrates the critical involvement of FAK in renal cyst development, suggests that FAK is a potential therapeutic target in treating patients with ADPKD, and highlights the role of FAK in cAMP-PKA–regulated proliferation.