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1 Department of Pediatrics, Medical College of Wisconsin, New Haven, CT, USA
2 Magnetic Resonance Research Center, Medical College of Wisconsin, New Haven, CT, USA
3 Department of Pathology, Medical College of Wisconsin, New Haven, CT, USA
4 Department of Pediatrics, Medical College of Wisconsin, Milwaukee, WI, USA
* To whom correspondence should be addressed. E-mail: norman.siegel{at}yale.edu.
The molecular mechanisms associated with re-establishment of renal epithelial polarity after injury remain incompletely delineated. Stress proteins may act as molecular chaperones, potentially modulating injury or enhancing recovery. We tested if over expression of HSP70 would stabilize NaK ATPase attachment to the cytoskeleton, under conditions of ATP depletion, and whether a direct association existed between NaK ATPase and HSP70 in cultured renal epithelial cells. LLC-PK1 cells were transfected with a tagged HSP70 (70FLAG) or vector alone (VA). Detachment of NaK ATPase was detected in Triton soluble lysate after ATP depletion. 70FLAG cells demonstrated a significant (p<0.01) decrease in detachment of NaK ATPase after either 2 or 4 hours of ATP depletion. Interactions between HSP70 and NaK ATPase were determined by co-immunoprecipitation of 70FLAG and NaK ATPase, by direct and competitive binding assays and by immunocytochemical localization. Binding of HSP70 and NaK ATPase increased dramatically following injury. Interactions were: a) reversible; b) reciprocal to changes in the HSP70 binding protein clathrin; c) present only when ATP turnover was inhibited in cell lysate, an established characteristic of HSP binding. These studies indicate that a) over expression of HSP70 is associated with decreased detachment of NaK ATPase from the cytoskeleton following injury; b) HSP70 binds to NaK ATPase; c) binding of HSP70 to NaK ATPase is dynamic and specific, increasing in response to injury and decreasing during recovery. Interaction between the molecular chaperone HSP70 and damaged or displaced NaK ATPase may represent a fundamental cellular mechanism underlying maintenance and recovery of renal tubule polarity following energy deprivation.
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