Focal Adhesion Kinase Signaling Mediates Acute Renal Injury Induced by Ischemia/Reperfusion

• Published in: The American journal of pathology Vol. 179; no. 6; pp. 2766 - 2778
• Main Authors: Qin, Yu, Alderliesten, Maaike C, Stokman, Geurt, Pennekamp, Petra, Bonventre, Joseph V, de Heer, Emile, Ichimura, Takaharu, de Graauw, Marjo, Price, Leo S, van de Water, Bob
• Format: Journal Article
• Language: English
• Published: Bethesda, MD Elsevier Inc 01-12-2011; American Society for Investigative Pathology
• Subjects: Acute Kidney Injury - enzymology; Animals; Biological and medical sciences; Cardiology. Vascular system; Cell Adhesion - physiology; Cytokines - biosynthesis; Enzyme Inhibitors - pharmacology; Focal Adhesion Protein-Tyrosine Kinases - antagonists & inhibitors; Focal Adhesion Protein-Tyrosine Kinases - deficiency; Focal Adhesion Protein-Tyrosine Kinases - metabolism; Hydrogen Peroxide - pharmacology; Investigative techniques, diagnostic techniques (general aspects); Kidney Tubules, Proximal - enzymology; Male; MAP Kinase Signaling System - physiology; Medical sciences; Mice; Mice, Knockout; Nephritis - enzymology; Nephrology. Urinary tract diseases; Nephropathies. Renovascular diseases. Renal failure; Oxidants - pharmacology; Oxidative Stress - physiology; Pathology; Pathology. Cytology. Biochemistry. Spectrometry. Miscellaneous investigative techniques; Regular; Renovascular diseases; Reperfusion Injury - enzymology; Signal Transduction - physiology; Tamoxifen - pharmacology; Kidney disease; Urinary system disease; Enzyme; Transferases; Acute; Ischemia reperfusion; Cardiovascular disease; Vascular disease; Kidney ischemia; Signal transduction; Anatomic pathology; Lesion; Protein-tyrosine kinase
• ISSN: 0002-9440; 1525-2191
• DOI: 10.1016/j.ajpath.2011.08.025

Renal ischemia/reperfusion (I/R) injury is associated with cell matrix and focal adhesion remodeling. Focal adhesion kinase (FAK) is a nonreceptor protein tyrosine kinase that localizes at focal adhesions and regulates their turnover. Here, we investigated the role of FAK in renal I/R injury, using a novel conditional proximal tubule–specific fak -deletion mouse model. Tamoxifen treatment of FAKloxP/loxP //γGT-Cre-ERT2 mice caused renal-specific fak recombination (FAKΔloxP/ΔloxP ) and reduction of FAK expression in proximal tubules. In FAKΔloxP/ΔloxP mice compared with FAKloxP/loxP controls, unilateral renal ischemia followed by reperfusion resulted in less tubular damage with reduced tubular cell proliferation and lower expression of kidney injury molecule-1, which was independent from the postischemic inflammatory response. Oxidative stress is involved in the pathophysiology of I/R injury. Primary cultured mouse renal cells were used to study the role of FAK deficiency for oxidative stress in vitro . The conditional fak deletion did not affect cell survival after hydrogen peroxide–induced cellular stress, whereas it impaired the recovery of focal adhesions that were disrupted by hydrogen peroxide. This was associated with reduced c-Jun N-terminal kinase–dependent phosphorylation of paxillin at serine 178 in FAK-deficient cells, which is required for focal adhesion turnover. Our findings support a role for FAK as a novel factor in the initiation of c-Jun N-terminal kinase–mediated cellular stress response during renal I/R injury and suggest FAK as a target in renal injury protection.