Regulation of renal sodium transporters during severe inflammation.
Sepsis-associated acute renal failure is characterized by decreased GFR and tubular dysfunction. The pathogenesis of endotoxemic tubular dysfunction with failure in urine concentration and increased fractional sodium excretion is poorly understood. This study investigated the regulation of renal sodium transporters during severe inflammation in vivo and in vitro. Injection of high-dosage LPS reduced BP and GFR, increased fractional sodium excretion, and strongly decreased the expression of Na(+)/H(+)-exchanger, renal outer medullary potassium channel, Na(+)-K(+)-2Cl(-) co-transporter, epithelial sodium channel, and Na(+)/K(+)-ATPase in mice. Also, injection of TNF-alpha, IL-1beta, or IFN-gamma decreased renal function and expression of renal sodium transporters. LPS-induced downregulation of sodium transporters was not affected in cytokine-knockout mice. However, supplementary glucocorticoid treatment, which inhibited LPS-induced increase of tissue cytokine concentrations, attenuated LPS-induced renal dysfunction and downregulation of tubular sodium transporters. Injection of low-dosage LPS increased renal tissue cytokines and downregulated renal sodium transporters without arterial hypotension. In vitro, in cortical collecting duct cells, cytokines also decreased expression of renal outer medullary potassium channel, epithelial sodium channel, and Na(+)/K(+)-ATPase. Renal hypoperfusion by renal artery clipping did not influence renal sodium transporter expression, in contrast to renal ischemia-reperfusion injury, which depressed transporter expression. These findings demonstrate downregulation of renal sodium transporters that likely accounts for tubular dysfunction during inflammation. These data suggest that alteration of renal sodium transporters during LPS-induced acute renal failure is mediated by cytokines rather than renal ischemia. However, in a complex in vivo model of severe inflammation, the possible presence and influence of renal hypoperfusion and reperfusion on the expression of renal sodium transporters cannot be completely excluded.
Schmidt
Christoph
C
Department of Anesthesiology, Regensburg University, 93042 Regensburg, Germany.
Höcherl
Klaus
K
Schweda
Frank
F
Kurtz
Armin
A
Bucher
Michael
M
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D016207:Cytokines / Q000502:physiology; D003907:Dexamethasone / Q000494:pharmacology; D053503:Epithelial Sodium Channels / Q000235:genetics; D005919:Glomerular Filtration Rate; D007249:Inflammation / Q000378:metabolism*; D007371:Interferon-gamma / Q000494:pharmacology; D053583:Interleukin-1beta / Q000494:pharmacology; D007668:Kidney / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000633:toxicity; D026901:Membrane Transport Proteins / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D024661:Potassium Channels, Inwardly Rectifying / Q000235:genetics; D012964:Sodium / Q000378:metabolism*; D000074083:Sodium-Hydrogen Exchanger 3; D017923:Sodium-Hydrogen Exchangers / Q000235:genetics
D016207:Cytokines; D053503:Epithelial Sodium Channels; D053583:Interleukin-1beta; C510693:Kcnj1 protein, mouse; D008070:Lipopolysaccharides; D026901:Membrane Transport Proteins; D024661:Potassium Channels, Inwardly Rectifying; D000074083:Sodium-Hydrogen Exchanger 3; D017923:Sodium-Hydrogen Exchangers; D003907:Dexamethasone; D007371:Interferon-gamma; D012964:Sodium