Up-Regulation of Local TGF-β Contributes to a Decrease in Renal Tubular Na⁺-K⁺ ATPase and Hyperkalemia in a Mouse Model of Crush Syndrome

作     者：Shinya Mizuno Yoko Mizuno-Horikawa Shinya Mizuno;Yoko Mizuno-Horikawa

作者机构：Department of Biochemistry Osaka University Graduate School of Medicine Suita Japan Department of Immunology and Microbiology Osaka University Graduate School of Medicine Suita Japan The Institute of Experimental Animal Sciences Suita Japan 

出 版 物：《Pharmacology & Pharmacy》 (药理与制药（英文）)

年 卷 期：2016年第7卷第12期

页      面：481-492页

学科分类：1002[医学-临床医学] 100210[医学-外科学(含：普外、骨外、泌尿外、胸心外、神外、整形、烧伤、野战外)] 10[医学] 

主　　题：Rhabdomyolysis AKI Hyperkalemia Na⁺-K⁺-ATPase TGF-β 

摘      要：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.