Sepsis induces an increase in thick ascending limb Cox-2 that is TLR4 dependent

Tarek Ashkar (El-Achkar), Zoya Plotkin, Branislav Marcic, Pierre Dagher

Research output: Contribution to journalArticle

38 Citations (Scopus)

Abstract

Cyclooxygenase-2 (Cox-2) is an inducible enzyme responsible for the formation of inflammatory prostanoids such as prostaglandins and thromboxane. Its role in the pathophysiology of inflammatory states like sepsis is increasingly recognized. Recently, we demonstrated that sepsis upregulates the endotoxin receptor Toll-like receptor 4 (TLR4) in rat kidney. Because Cox-2 is one of the downstream products of TLR4 activation, we hypothesized that sepsis-induced changes in renal Cox-2 expression are TLR4 dependent. Indeed, we show that in Sprague-Dawley rats, cecal ligation and puncture (a sepsis model) increases Cox-2 expression in cortical and medullary thick ascending loops (cTAL and mTAL, respectively) as well as inner medullary collecting ducts. These are all sites of increased TLR4 expression during sepsis. To determine the actual dependence on TLR4, we measured Cox-2 expression in wild-type and mutant mice which harbor a TLR4 gene deletion (TLR4-/-). In wild-type mice, sepsis increased Cox-2 expression in proximal tubules, cTAL, and mTAL. In contrast, septic TLR4-/- mice showed no significant increase in cTAL or mTAL Cox-2 expression. Furthermore, renin was absent from juxtaglomerular cells of TLR4-/- mice. We conclude that the dependence of sepsis-induced renal Cox-2 expression on TLR4 is tubule specific. The TLR4-dependent Cox-2 expression is mostly restricted to cortical and medullary thick ascending loops of Henle that characteristically express and secrete Tamm-Horsfall protein.

Original languageEnglish
JournalAmerican Journal of Physiology - Renal Physiology
Volume293
Issue number4
DOIs
StatePublished - Oct 2007

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Toll-Like Receptor 4
Cyclooxygenase 2
Sepsis
Extremities
Kidney
Prostaglandins
Uromodulin
Loop of Henle
Thromboxanes
Gene Deletion
Punctures
Renin
Ligation
Sprague Dawley Rats
Up-Regulation

Keywords

  • Cyclooxygenase
  • Macula densa
  • Renin
  • Tamm-Horsfall protein
  • Toll-like receptors

ASJC Scopus subject areas

  • Physiology

Cite this

Sepsis induces an increase in thick ascending limb Cox-2 that is TLR4 dependent. / Ashkar (El-Achkar), Tarek; Plotkin, Zoya; Marcic, Branislav; Dagher, Pierre.

In: American Journal of Physiology - Renal Physiology, Vol. 293, No. 4, 10.2007.

Research output: Contribution to journalArticle

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