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Renal ischemia induces tropomyosin dissociation-destabilizing microvilli microfilaments

¹Division of Nephrology, Department of Medicine, Indiana University, and ⁴Roudebush Veterans Affairs Medical Center, Department of Medicine, Indianapolis, Indiana 46202-5116; ²Oncology Research Unit, The Children's Hospital at Westmead, Westmead, New South Wales 2145; and ³Department of Paediatrics and Child Health, University of Sydney, Sydney, New South Wales 2006, Australia

Submitted 1 May 2003 ; accepted in final form 12 December 2003

Ischemic-induced cell injury results in rapid duration-dependent actin-depolymerizing factor (ADF)/cofilin-mediated disruption of the apical microvilli microfilament cores. Because intestinal microvillar microfilaments are bound and stabilized in the terminal web by the actin-binding protein tropomyosin, we questioned whether a protective effect of tropomyosin localization to the terminal web of the proximal tubule microfilament cores is disrupted during ischemic injury. With tropomyosin-specific antibodies, we examined rat cortical sections under physiological conditions and following ischemic injury by confocal microscopy. In addition, Western blot analysis of cortical extracts and urine was undertaken. Our studies demonstrated the presence of tropomyosin isoforms in the proximal tubule microvillar terminal web under physiological conditions and their dissociation in response to 25 min of ischemic injury. This correlated with the excretion of tropomyosin-containing plasma membrane vesicles in urine from ischemic rats. In addition, we noted increased tropomyosin Triton X-100 solubility following ischemia in cortical extracts. These studies suggest tropomyosin binds to and stabilizes the microvillar microfilament core in the terminal web under physiological conditions. With the onset of ischemic injury, we propose that tropomyosin dissociates from the microfilament core providing access to microfilaments in the terminal web for F-actin binding, severing and depolymerizing actions of ADF/cofilin proteins.

actin-depolymerizing factor; cofilin; brush border

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