Hyperkalemia is one of the most important risk factors in patients suffering from\ncrush syndrome with rhabdomyolysis. Glycerol-injected animals have been used as\nan experimental model of rhabdomyolysis-induced acute kidney injury (AKI), but\nlittle information is available for the onset and molecular mechanism of hyperkalemia.\nIn our murine model, plasma potassium levels increased after a single injection\nof 50%-glycerol solution (10 ml/kg, i.m.) during the progression of muscular and\nrenal injuries. Renal tubular Na+-K+-ATPase functions as ion-exchange pomp for\npotassium clearance from blood into renal tubular epithelial cells. Renal histochemistry\nrevealed an apparent decrease in the tubular Na+-K+-ATPase expression, especially\nat 24 hours post-glycerol challenge in our AKI model. In contrast to the loss in\nactive Na+-K+-ATPase, there was a significant increase in the renal levels of transforming\ngrowth factor-�² (TGF-�²) that is known to suppress Na+-K+-ATPase production\nin vitro . When anti-TGF-�² antibody was administered in mice after the glycerol\nchallenge, the suppression of renal Na+-K+-ATPase activity was partially restored. As\na result, hyperkalemia was improved in the TGF-�²-neutralized AKI mice, associated\nwith a significant decrease in plasma potassium concentration. Taken together, we\npredict that endogenous TGF-�² is a key regulator for inhibiting Na+-K+-ATPase\nproduction and, in part, enhancing hyperkalemia during progression of rhabdomyolysis-\ninduced AKI. This is, to our knowledge, the first report to determine a critical\nrole of endogenous TGF-�² in renal potassium metabolism during crush syndrome.
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