Up-Regulation of Local TGF-β Contributes to a Decrease in Renal Tubular Na<sup>+</sup>-K<sup>+</sup> ATPase and Hyperkalemia in a Mouse Model of Crush Syndrome — Oak Academic Publishing
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Up-Regulation of Local TGF-β Contributes to a Decrease in Renal Tubular Na<sup>+</sup>-K<sup>+</sup> ATPase and Hyperkalemia in a Mouse Model of Crush Syndrome
Department of Biochemistry, Osaka University Graduate School of Medicine, Suita, Japan
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Department of Immunology and Microbiology, Osaka University Graduate School of Medicine, Suita, Japan
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The Institute of Experimental Animal Sciences, Suita, Japan
1 Department of Biochemistry, Osaka University Graduate School of Medicine, Suita, Japan
2 Department of Immunology and Microbiology, Osaka University Graduate School of Medicine, Suita, Japan
3 The Institute of Experimental Animal Sciences, Suita, Japan
Hyperkalemia is one of the most important risk factors in patients suffering from crush syndrome with rhabdomyolysis. Glycerol-injected animals have been used as an experimental model of rhabdomyolysis-induced acute kidney injury (AKI), but little information is available for the onset and molecular mechanism of hyperkalemia. In our murine model, plasma potassium levels increased after a single injection of 50%-glycerol solution (10 ml/kg, i.m.) during the progression of muscular and renal injuries. Renal tubular Na + -K + -ATPase functions as ion-exchange pomp for potassium clearance from blood into renal tubular epithelial cells. Renal histochemistry revealed an apparent decrease in the tubular Na + -K + -ATPase expression, especially at 24 hours post-glycerol challenge in our AKI model. In contrast to the loss in active Na+-K+-ATPase, there was a significant increase in the renal levels of transforming growth factor-β (TGF-β) that is known to suppress Na + -K + -ATPase production in vitro . When anti-TGF-β antibody was administered in mice after the glycerol challenge, the suppression of renal Na + -K + -ATPase activity was partially restored. As a result, hyperkalemia was improved in the TGF-β-neutralized AKI mice, associated with a significant decrease in plasma potassium concentration. Taken together, we predict that endogenous TGF-β is a key regulator for inhibiting Na + -K + -ATPase production and, in part, enhancing hyperkalemia during progression of rhabdomyolysis-induced AKI. This is, to our knowledge, the first report to determine a critical role of endogenous TGF-β in renal potassium metabolism during crush syndrome.
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