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1 Renal Epithelial Biology Experimental Laboratories, Division of Nephrology, Department of Medicine, Indiana University School of Medicine, Roudebush Veterans Affairs Medical Center, Indianapolis, Indiana 46202; and 2 Department of Biochemistry and Molecular Biology, Colorado State University, Fort Collins, Colorado 80523
Apical membrane of renal proximal tubule cells is extremely
sensitive to ischemia, with structural alterations occurring
within 5 min. These changes are felt secondary to actin cytoskeletal disruption, yet the mechanism responsible is unknown. Actin
depolymerizing factor (ADF), a 19-kDa actin-binding protein, has
recently been shown to play an important role in regulation of actin
filament dynamics. Because ADF is known to mediate pH-dependent F-actin binding, depolymerization, and severing, and because ADF activation occurs by dephosphorylation, we questioned whether ADF played a role in
microvilli microfilament disruption during ischemia. To test
our hypothesis, we induced renal ischemia in the rat with the
clamp model. Initial immunofluorescence and Western blot studies on
cortical tissue documented the presence of ADF in proximal tubule
cells. Under physiological conditions, ADF was distributed homogeneously throughout the cytoplasm, primarily in the Triton X-100-soluble fraction, and both phosphorylated (pADF) and
nonphosphorylated forms were identified. During ischemia,
marked alterations occurred. Intraluminal vesicle/bleb structures
contained extremely high concentrations of ADF along with G-actin, but
not F-actin. Western blot showed a rapidly occurring duration-dependent
dephosphorylation of ADF. At 0-30 min of ischemia, total
ADF levels were unchanged, whereas pADF decreased significantly to 72%
and 19% of control levels, at 5 and 15 min, respectively. Urine
collected under physiological conditions did not contain ADF or actin,
whereas urine collected after 30 min of ischemia contained both
ADF and actin. Reperfusion was associated with normalization of
cellular pADF levels, pADF intracellular distribution, and repair of
apical microvilli. These data suggest that activation of
ADF during ischemia via dephosphorylation is, in part,
responsible for apical actin disruption resulting in microvillar
destruction and formation of intraluminal vesicles.
acute renal failure; cofilin; LIM kinase; ATP depletion; actin cytoskeleton; renal proximal tubule cell
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