A two-hit mechanism for sepsis-induced impairment of renal tubule function

Bruns Watts, Thampi George, Edward R. Sherwood, David Good

Research output: Contribution to journalArticle

16 Citations (Scopus)

Abstract

Renal insufficiency is a common and severe complication of sepsis, and the development of kidney dysfunction increases morbidity and mortality in septic patients. Sepsis is associated with a variety of defects in renal tubule function, but the underlying mechanisms are incompletely understood. We used a cecal ligation and puncture (CLP) model to examine mechanisms by which sepsis influences the transport function of the medullary thick ascending limb (MTAL). MTALs from sham and CLP mice were studied in vitro 18 h after surgery. The results show that sepsis impairs the ability of the MTAL to absorb HCO- 3 through two distinct mechanisms. First, sepsis induces an adaptive decrease in the intrinsic capacity of the tubules to absorb HCO- 3. This effect is associated with an increase in ERK phosphorylation in MTAL cells and is prevented by pretreatment of CLP mice with a MEK/ERK inhibitor. The CLP-induced reduction in intrinsic HCO- 3 absorption rate appears to involve loss of function of basolateral Na+/H+ exchange. Second, sepsis enhances the ability of LPS to inhibit HCO3 absorption, mediated through upregulation of Toll-like receptor 4 (TLR4)-ERK signaling in the basolateral membrane. The two inhibitory mechanisms are additive and thus can function in a two-hit capacity to impair renal tubule function in sepsis. Both effects depend on ERK and are eliminated by interventions that prevent ERK activation. Thus the TLR4 and ERK signaling pathways represent potential therapeutic targets to treat or prevent sepsis-induced renal tubule dysfunction.

Original languageEnglish (US)
JournalAmerican Journal of Physiology - Renal Physiology
Volume304
Issue number7
DOIs
StatePublished - 2013

Fingerprint

Sepsis
Kidney
Punctures
Ligation
Toll-Like Receptor 4
Extremities
MAP Kinase Signaling System
Mitogen-Activated Protein Kinase Kinases
Renal Insufficiency
Up-Regulation
Phosphorylation
Morbidity
Membranes
Mortality

Keywords

  • Acid-base transport
  • Erk
  • Lipopolysaccharide
  • Thick ascending limb
  • TLR4

ASJC Scopus subject areas

  • Physiology
  • Urology
  • Medicine(all)

Cite this

A two-hit mechanism for sepsis-induced impairment of renal tubule function. / Watts, Bruns; George, Thampi; Sherwood, Edward R.; Good, David.

In: American Journal of Physiology - Renal Physiology, Vol. 304, No. 7, 2013.

Research output: Contribution to journalArticle

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