Regulation of renal glucose transporters during severe inflammation

Abstract

Schmidt C, Höcherl K, Bucher M. Regulation of renal glucose transporters during severe inflammation. Am J Physiol Renal Physiol 292: F804 -F811, 2007. First published October 10, 2006; doi:10.1152/ajprenal.00258.2006.-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 glucocorticoidtreated 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.

Renal Cortical Pyruvate Depletion during AKI

“…First, an AKI-induced decrease in GFR decreases glucose filtration; second, proximal tubule glucose reabsorption is coupled to Na transport. 19 Given that Na transport is decreased by AKI, decreased, not increased, glucose uptake should result. Indeed, the frequent occurrence of renal tubular glycosuria in response to AKI [19][20][21] speaks to this point.…”

“…19 Given that Na transport is decreased by AKI, decreased, not increased, glucose uptake should result. Indeed, the frequent occurrence of renal tubular glycosuria in response to AKI [19][20][21] speaks to this point. To our knowledge, the current observation of AKI-initiated glucose and glycogen loading is the first of its kind and strongly suggests that enhanced gluconeogenesis contributes to postischemic pyruvate consumption and hence, suppressed renal cortical pyruvate levels.…”

Tumor necrosis factor-α: regulation of renal function and blood pressure

“…Injection of TNF-␣ (1 mg/kg, bolus) decreases expression of sodium glucose transporters SGLT2 and SGLT3 and Na-K-ATPase within 12 h; however, it also increases Glut1 and SGLT1 in the kidney. The increase in Glut1 and SGLT1 may occur as a compensatory response to the reduced intracellular glucose levels resulting from 1) decreased glucose entry due to reductions in SGLT2 and 3, and 2) the lower Na gradient due to reduced Na-K-ATPase (125).…”

Delayed and acute effects of interferon-γ on activity of an inwardly rectifying K+ channel in cultured human proximal tubule cells

“…For example, TNF-␣ and IL-1 inhibited Rb ϩ uptake in rat thick ascending limb of Henle's loop (5). Furthermore, IFN-␥ , IL-1, and TNF-␣ were reported to affect the renal transport of Na ϩ and glucose during severe inflammation (26,27). However, there are few reports concerning the effects of cytokines on K ϩ channel activity in renal tubular cells.…”