Lipopolysaccharide directly alters renal tubule transport through distinct TLR4-dependent pathways in basolateral and apical membranes

David Good, Thampi George, Bruns Watts

Research output: Contribution to journalArticle

40 Citations (Scopus)

Abstract

Bacterial infection of the kidney is associated with renal tubule dysfunction and dysregulation of systemic electrolyte balance. Whether bacterial molecules directly affect renal tubule transport is unknown. We examined the effects of LPS on HCO3 - absorption in the isolated rat and mouse medullary thick ascending limb (MTAL). LPS decreased HCO3 - absorption when added to bath or lumen. The MEK/ERK inhibitor U0126 eliminated inhibition by bath LPS but had no effect on inhibition by lumen LPS. Conversely, the mammalian target of rapamycin (mTOR) inhibitor rapamycin eliminated inhibition by lumen LPS but had no effect on inhibition by bath LPS. Inhibiting basolateral Na+/H+ exchange with amiloride eliminated inhibition of HCO3 - absorption by lumen but not bath LPS. Confocal immunofluorescence showed expression of TLR4 in basolateral and apical membrane domains. Inhibition of HCO3 - absorption by bath and lumen LPS was eliminated in MTALs from TLR4-/- mice. Thus LPS inhibits HCO3 - absorption through distinct TLR4-dependent pathways in basolateral and apical membranes. These results establish that bacterial molecules can directly impair the transport function of renal tubules, identifying a new mechanism contributing to tubule dysfunction during bacterial infection. The LPS-induced reduction in luminal acidification may contribute to Gram-negative pathogenicity by promoting bacterial adherence and growth and impairing correction of infection-induced systemic acid-base disorders.

Original languageEnglish (US)
JournalAmerican Journal of Physiology - Renal Physiology
Volume297
Issue number4
DOIs
StatePublished - Oct 2009

Fingerprint

Baths
Lipopolysaccharides
Kidney
Membranes
Sirolimus
Bacterial Infections
Water-Electrolyte Balance
Amiloride
Mitogen-Activated Protein Kinase Kinases
Fluorescent Antibody Technique
Virulence
Extremities
Acids
Growth
Infection

Keywords

  • Acid-base transport
  • Bacterial kidney infection
  • Medullary thick ascending limb
  • Na/H exchange
  • Sepsis

ASJC Scopus subject areas

  • Physiology
  • Urology

Cite this

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abstract = "Bacterial infection of the kidney is associated with renal tubule dysfunction and dysregulation of systemic electrolyte balance. Whether bacterial molecules directly affect renal tubule transport is unknown. We examined the effects of LPS on HCO3 - absorption in the isolated rat and mouse medullary thick ascending limb (MTAL). LPS decreased HCO3 - absorption when added to bath or lumen. The MEK/ERK inhibitor U0126 eliminated inhibition by bath LPS but had no effect on inhibition by lumen LPS. Conversely, the mammalian target of rapamycin (mTOR) inhibitor rapamycin eliminated inhibition by lumen LPS but had no effect on inhibition by bath LPS. Inhibiting basolateral Na+/H+ exchange with amiloride eliminated inhibition of HCO3 - absorption by lumen but not bath LPS. Confocal immunofluorescence showed expression of TLR4 in basolateral and apical membrane domains. Inhibition of HCO3 - absorption by bath and lumen LPS was eliminated in MTALs from TLR4-/- mice. Thus LPS inhibits HCO3 - absorption through distinct TLR4-dependent pathways in basolateral and apical membranes. These results establish that bacterial molecules can directly impair the transport function of renal tubules, identifying a new mechanism contributing to tubule dysfunction during bacterial infection. The LPS-induced reduction in luminal acidification may contribute to Gram-negative pathogenicity by promoting bacterial adherence and growth and impairing correction of infection-induced systemic acid-base disorders.",
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AB - Bacterial infection of the kidney is associated with renal tubule dysfunction and dysregulation of systemic electrolyte balance. Whether bacterial molecules directly affect renal tubule transport is unknown. We examined the effects of LPS on HCO3 - absorption in the isolated rat and mouse medullary thick ascending limb (MTAL). LPS decreased HCO3 - absorption when added to bath or lumen. The MEK/ERK inhibitor U0126 eliminated inhibition by bath LPS but had no effect on inhibition by lumen LPS. Conversely, the mammalian target of rapamycin (mTOR) inhibitor rapamycin eliminated inhibition by lumen LPS but had no effect on inhibition by bath LPS. Inhibiting basolateral Na+/H+ exchange with amiloride eliminated inhibition of HCO3 - absorption by lumen but not bath LPS. Confocal immunofluorescence showed expression of TLR4 in basolateral and apical membrane domains. Inhibition of HCO3 - absorption by bath and lumen LPS was eliminated in MTALs from TLR4-/- mice. Thus LPS inhibits HCO3 - absorption through distinct TLR4-dependent pathways in basolateral and apical membranes. These results establish that bacterial molecules can directly impair the transport function of renal tubules, identifying a new mechanism contributing to tubule dysfunction during bacterial infection. The LPS-induced reduction in luminal acidification may contribute to Gram-negative pathogenicity by promoting bacterial adherence and growth and impairing correction of infection-induced systemic acid-base disorders.

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