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Originally published online as doi:10.2353/ajpath.2007.060805 on July 9, 2007

Published online before print July 9, 2007
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(American Journal of Pathology. 2007;171:452-462.)
© 2007 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2007.060805

Extracellular Signal-Regulated Kinase Activation during Renal Ischemia/Reperfusion Mediates Focal Adhesion Dissolution and Renal Injury

Maaike Alderliesten, Marjo de Graauw, Judith Oldenampsen, Yu Qin, Chantal Pont, Liesbeth van Buren and Bob van de Water

From the Division of Toxicology, Leiden/Amsterdam Center for Drug Research, Leiden University, Leiden, The Netherlands

Acute renal failure due to ischemia/reperfusion involves disruption of integrin-mediated cellular adhesion and activation of the extracellular signal-regulated kinase (ERK) pathway. The dynamics of focal adhesion organization and phosphorylation during ischemia/reperfusion in relation to ERK activation are unknown. In control kidneys, protein tyrosine-rich focal adhesions, containing focal adhesion kinase, paxillin, and talin, were present at the basolateral membrane of tubular cells and colocalized with short F-actin stress fibers. Unilateral renal ischemia/reperfusion caused a reversible protein dephosphorylation and loss of focal adhesions. The focal adhesion protein phosphorylation rebounded in a biphasic manner, in association with increased focal adhesion kinase, Src, and paxillin tyrosine phosphorylation. Preceding phosphorylation of these focal adhesion proteins, reperfusion caused increased phosphorylation of ERK. The specific mitogen-activated protein kinase kinase 1/2 inhibitor U0126 prevented ERK activation and attenuated focal adhesion kinase, paxillin, and Src phosphorylation, focal adhesion restructuring, and ischemia/reperfusion-induced renal injury. We propose a model whereby ERK activation enhanced protein tyrosine phosphorylation during ischemia/reperfusion, thereby driving the dynamic dissolution and restructuring of focal adhesions and F-actin cytoskeleton during reperfusion and renal injury.




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Copyright © 2007 by the American Society for Investigative Pathology.