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

Abstract

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.

• Authors: Jinzhao He, Shun Zhang, Zhiwei Qiu, Xiaowei Li, Huihui Huang, William Jin, Yue Xu, Guangying Shao, Liang Wang, Jia Meng, Shuyuan Wang, Xiaoqiang Geng, Yingli Jia, Min Li, Baoxue Yang, Hua A Jenny Lu, Hong Zhou
• Journal: Journal of the American Society of Nephrology : JASN (J Am Soc Nephrol) Vol. 32 Issue 9 Pg. 2159-2174 (09 2021) ISSN: 1533-3450 [Electronic] United States
• PMID: 34465607 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2021 by the American Society of Nephrology.

Chemical References

• Aminopyridines
• Benzamides
• GSK2256098
• Hydroxamic Acids
• PND 1186
• Pyrazines
• Sulfonamides
• defactinib
• Focal Adhesion Protein-Tyrosine Kinases

Topics

• Aminopyridines (pharmacology)
• Animals
• Benzamides (pharmacology)
• Cell Culture Techniques
• Cell Proliferation
• Disease Models, Animal
• Dogs
• Epithelial Cells (drug effects)
• Focal Adhesion Protein-Tyrosine Kinases (antagonists & inhibitors)
• Humans
• Hydroxamic Acids (pharmacology)
• Mice
• Mice, Inbred C57BL
• Polycystic Kidney, Autosomal Dominant (etiology, pathology, prevention & control)
• Pyrazines (pharmacology)
• Signal Transduction
• Sulfonamides (pharmacology)