Proinflammatory cytokines cause down-regulation of renal chloride entry pathways during sepsis.
OBJECTIVE
Sepsis is the most important trigger for acute renal failure, with tubular dysfunction and collapse in urine concentration. As chloride plays a major role in the urinary concentrating mechanisms, we aimed to investigate the regulation of renal chloride entry pathways, such as kidney-specific chloride channel 1, kidney-specific chloride channel 2, Barttin, thiazide-sensitive Na+-Cl- cotransporter, renal outer medullary potassium channel, and Na+/K+-adenosine triphosphatase during sepsis.


METHODS
Prospective animal trial.


METHODS
Laboratory of the Department of Anesthesiology.


METHODS
Male C57/BL6 and B6129SF2/J mice and mice deficient for tumor necrosis factor-alpha, interleukin-1-receptor-1, interferon-gamma, or interleukin-6.


METHODS
Mice were injected with lipopolysaccharide (LPS) or proinflammatory cytokines. Hemodynamic and renal variables, cytokine concentrations, and expression of renal chloride-reabsorbing systems were investigated. Experiments with cytokine knockout mice, renal artery-clipped mice, and mice treated with glucocorticoids, low-dose LPS, and sodium nitroprusside were performed.


RESULTS
LPS-injected mice presented with decreased blood pressure and glomerular filtration rate, increased fractional chloride excretion, and depressed expression of renal chloride transporters/channels. Similar alterations were observed after application of tumor necrosis factor-alpha, interleukin-1beta, interferon-gamma, or interleukin-6. LPS-induced down-regulation of chloride transporters/channels was not affected in cytokine knockout mice. Glucocorticoid treatment inhibited LPS-induced increase of cytokine concentrations, diminished LPS-induced renal dysfunction, and attenuated the down-regulation of renal chloride transporters/channels. Injection of low-dose LPS increased renal tissue cytokines and down-regulated chloride entry pathways without arterial hypotension, indicating that renal ischemia due to systemic hypotension does not mediate down-regulation of renal chloride transporters/channels. In addition, renal ischemia induced by renal artery clipping or sodium nitroprusside administration did not influence chloride transporter/channel expression.


CONCLUSIONS
Our results demonstrate down-regulation of renal chloride transporters/channels during sepsis, which is probably mediated by proinflammatory cytokines and accounts for the development of LPS-induced tubular dysfunction. Our findings contribute to the understanding, on one hand, the failure of single-anticytokine strategies and, on the other hand, the beneficial effects of glucocorticoids in the therapy of septic patients.
Schmidt
Christoph
C
Department of Anesthesiology, Regensburg University, Regensburg, Germany.
Höcherl
Klaus
K
Schweda
Frank
F
Bucher
Michael
M
D000818:Animals; D000090007:CLC-2 Chloride Channels; D002712:Chlorides / Q000378:metabolism*; D015536:Down-Regulation; D005938:Glucocorticoids / Q000494:pharmacology; D007371:Interferon-gamma / Q000172:deficiency / Q000502:physiology*; D053583:Interleukin-1beta / Q000502:physiology*; D015850:Interleukin-6 / Q000172:deficiency / Q000502:physiology*; D007668:Kidney / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D011446:Prospective Studies; D053573:Receptors, Interleukin-1 Type I / Q000172:deficiency; D018805:Sepsis / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000172:deficiency / Q000502:physiology*
D000090007:CLC-2 Chloride Channels; D002712:Chlorides; C000715428:Clcn2 protein, mouse; D005938:Glucocorticoids; D053583:Interleukin-1beta; D015850:Interleukin-6; D053573:Receptors, Interleukin-1 Type I; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma