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Regulation of renal glucose transporters during severe inflammation

Departments of ¹Anesthesiology and ²Pharmacology, Regensburg University, Regensburg, Germany

Submitted 10 July 2006 ; accepted in final form 5 October 2006

Severe sepsis is accompanied by acute renal failure (ARF) with renal tubular dysfunction and glucosuria. In this study, we aimed to determine the regulation of renal tubular glucose transporters during severe experimental inflammation. Male C57BL/6J mice were injected with LPS or proinflammatory cytokines, and renal perfusion, glomerular filtration rate (GFR), fractional glucose excretion, and expression of tubular glucose transporters were determined. We found a decreased plasma glucose concentration with impaired renal tissue perfusion and GFR and increased fractional glucose excretion associated with decreased expression of SGLT2, SGLT3, and GLUT2 after LPS injection. Similar alterations were observed after application of TNF-, IL-1, IL-6, or IFN-. To clarify the role of proinflammatory cytokines, we performed LPS injections in knockout mice with deficiencies for TNF-, IL-1 receptor type 1, IFN-, or IL-6 as well as LPS injections in glucocorticoid-treated wild-type mice. LPS-induced alterations of glucose transporters also were present in single-cytokine knockout mice. In contrast, glucocorticoid treatment clearly attenuated LPS-induced changes in renal glucose transporter expression and improved GFR and fractional glucose excretion. LPS-induced decrease of renal perfusion was not improved by glucocorticoids, indicating a minor role of ischemia in the development of septic renal dysfunction. Our results demonstrate modifications of tubular glucose transporters during severe inflammation that are probably mediated by proinflammatory cytokines and account for the development of ARF with increased fractional glucose excretion. In addition, our findings provide an explanation why single anti-cytokine strategies fail in the therapy of septic patients and contribute to an understanding of the beneficial effects of glucocorticoids on septic renal dysfunction.

sepsis; acute renal failure; tubular function; lipopolysaccharide; cytokines; glucocorticoids

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