Cytokine-mediated regulation of urea transporters during experimental endotoxemia

Am J Physiol Renal Physiol. 2007 May;292(5):F1479-89. doi: 10.1152/ajprenal.00460.2006. Epub 2007 Jan 16.


Acute renal failure (ARF) is a frequent complication of sepsis and has a high mortality. Sepsis-induced ARF is known to be associated with significant impairment of tubular capacity. However, the pathogenesis of endotoxemic tubular dysfunction with failure of urine concentration is poorly understood. Urea plays an important role in the urinary concentrating mechanism and expression of the urea transporters UT-A1, UT-A2, UT-A3, UT-A4, and UT-B is essential for tubular urea reabsorption. The present study attempts to assess the regulation of renal urea transporters during severe inflammation in vivo. Lipopolysaccharide-(LPS)-injected mice presented with reduced glomerular filtration rate, fractional urea excretion, and inner medulla osmolality associated with a marked decrease in expression of all renal urea transporters. Similar alterations were observed after application of tumor necrosis factor (TNF)-alpha, interleukin (IL)-1beta, interferon (IFN)-gamma, or IL-6. LPS-induced downregulation of urea transporters was not affected in knockout mice with deficient TNF-alpha, IL-receptor-1, IFN-gamma, or IL-6. Glucocorticoid treatment inhibited LPS-induced increases of tissue TNF-alpha, IL-1beta, IFN-gamma, or IL-6 concentration, diminished LPS-induced renal dysfunction, and attenuated the downregulation of renal urea transporters. Renal ischemia induced by renal artery clipping did not influence the expression of urea transporters. Our data demonstrate that renal urea transporters are downregulated by severe inflammation, which likely accounts for tubular dysfunction. Furthermore, they suggest that the downregulation of renal urea transporters during LPS-induced ARF is mediated by proinflammatory cytokines and is independent from renal ischemia because of sepsis-induced hypotension.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cytokines / deficiency
  • Cytokines / metabolism*
  • Cytokines / pharmacology
  • Dexamethasone / pharmacology
  • Diuresis
  • Dose-Response Relationship, Drug
  • Endotoxemia / blood
  • Endotoxemia / metabolism*
  • Endotoxemia / physiopathology
  • Gene Expression / drug effects
  • Glomerular Filtration Rate
  • Glucocorticoids / pharmacology
  • Hypotension / etiology
  • Inflammation / chemically induced
  • Inflammation / physiopathology
  • Interleukin-1beta / pharmacology
  • Ischemia / metabolism
  • Kidney / blood supply
  • Kidney / physiopathology
  • Lipopolysaccharides / administration & dosage
  • Lipopolysaccharides / pharmacology
  • Membrane Transport Proteins / genetics
  • Membrane Transport Proteins / metabolism*
  • Mice
  • Mice, Inbred Strains
  • Mice, Knockout
  • Osmolar Concentration
  • Severity of Illness Index
  • Tachycardia / etiology
  • Urea / blood


  • Cytokines
  • Glucocorticoids
  • Interleukin-1beta
  • Lipopolysaccharides
  • Membrane Transport Proteins
  • urea transporter
  • Dexamethasone
  • Urea