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 lipopolysaccharide (LPS) or proinflammatory cytokines and renal perfusion, 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-receptor-1, IFN- or IL-6 as well as LPS-injections in glucocorticoid-treated wildtype mice. LPS-induced alterations of glucose transporters were also 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 which 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 failed in the therapy of septic patients and contribute to understand the beneficial effects of glucocorticoids on septic renal dysfunction.