Abstract
Acidosis is associated with E. coli induced pyelonephritis but whether bacterial cell wall constituents inhibit HCO3 transport in the outer medullary collecting duct from the inner stripe (OMCDi) is not known. We examined the effect of lipopolysaccharide (LPS), on HCO3 absorption in isolated perfused rabbit OMCDi. LPS caused a ~ 40% decrease in HCO3 absorption, providing a mechanism for E. coli pyelonephritis-induced acidosis. Monophosphoryl lipid A (MPLA), a detoxified TLR4 agonist, and Wortmannin, a phosphoinositide 3-kinase inhibitor, prevented the LPS-mediated decrease, demonstrating the role of TLR4-PI3-kinase signaling and providing proof-of-concept for therapeutic interventions aimed at ameliorating OMCDi dysfunction and pyelonephritis-induced acidosis.
Highlights
Acidosis is associated with E. coli induced pyelonephritis but whether bacterial cell wall constituents inhibit HCO3 transport in the outer medullary collecting duct from the inner stripe (OMCDi) is not known
Good and Watts[7] have reported that lipopolysaccharide (LPS), the dominant bacterial cell wall constituent of Gram-negative bacteria inhibits bicarbonate reabsorption in the medullary thick ascending limb, and that this effect was likely mediated via TLR4 and phosphoinositide 3-kinase (PI3-K) and their downstream effectors[8]
The potential impact of E. coli pyelonephritis on urine acidification was examined by studying the effect of LPS and monophosphoryl lipid A (MPLA) on HCO3 absorption in isolated perfused rabbit OMCDi
Summary
Acidosis is associated with E. coli induced pyelonephritis but whether bacterial cell wall constituents inhibit HCO3 transport in the outer medullary collecting duct from the inner stripe (OMCDi) is not known. Good and Watts[7] have reported that lipopolysaccharide (LPS), the dominant bacterial cell wall constituent of Gram-negative bacteria inhibits bicarbonate reabsorption in the medullary thick ascending limb, and that this effect was likely mediated via TLR4 and phosphoinositide 3-kinase (PI3-K) and their downstream effectors[8]. The potential impact of E. coli pyelonephritis on urine acidification was examined by studying the effect of LPS and monophosphoryl lipid A (MPLA) on HCO3 absorption in isolated perfused rabbit OMCDi. MPLA is a chemically modified derivative of LPS that retains the beneficial immunomodulatory properties of LPS without any inherent toxicity[12]. Results presented demonstrate that LPS exposure inhibits bicarbonate absorption in the OMCDi, and that this effect can be blocked by basolateral (blood-side) administration of MPLA as well as by Wortmannin, a PI3-K inhibitor
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