Monophosphoryl lipid A induces protection against LPS in medullary thick ascending limb through a TLR4-TRIF-PI3K signaling pathway.

Abstract

Monophosphoryl lipid A (MPLA) is a detoxified derivative of LPS that induces tolerance to LPS and augments host resistance to bacterial infections. Previously, we demonstrated that LPS inhibits [Formula: see text] absorption in the medullary thick ascending limb (MTAL) through a basolateral Toll-like receptor 4 (TLR4)-myeloid differentiation factor 88 (MyD88)-ERK pathway. Here we examined whether pretreatment with MPLA would attenuate LPS inhibition. MTALs from rats were perfused in vitro with MPLA (1 µg/ml) in bath and lumen or bath alone for 2 h, and then LPS was added to (and MPLA removed from) the bath solution. Pretreatment with MPLA eliminated LPS-induced inhibition of [Formula: see text] absorption. In MTALs pretreated with MPLA plus a phosphatidylinositol 3-kinase (PI3K) or Akt inhibitor, LPS decreased [Formula: see text] absorption. MPLA increased Akt phosphorylation in dissected MTALs. The Akt activation was eliminated by a PI3K inhibitor and in MTALs from TLR4-/- or Toll/IL-1 receptor domain-containing adaptor-inducing IFN-β (TRIF)-/- mice. The effect of MPLA to prevent LPS inhibition of [Formula: see text] absorption also was TRIF dependent. Pretreatment with MPLA prevented LPS-induced ERK activation; this effect was dependent on PI3K. MPLA alone had no effect on [Formula: see text] absorption, and MPLA pretreatment did not prevent ERK-mediated inhibition of [Formula: see text] absorption by aldosterone, consistent with MPLA's low toxicity profile. These results demonstrate that pretreatment with MPLA prevents the effect of LPS to inhibit [Formula: see text] absorption in the MTAL. This protective effect is mediated directly through MPLA stimulation of a TLR4-TRIF-PI3K-Akt pathway that prevents LPS-induced ERK activation. These studies identify detoxified TLR4-based immunomodulators as novel potential therapeutic agents to prevent or treat renal tubule dysfunction in response to bacterial infections.

• Authors: Bruns A Watts 3rd, Thampi George, Edward R Sherwood, David W Good
• Journal: American journal of physiology. Renal physiology (Am J Physiol Renal Physiol) Vol. 313 Issue 1 Pg. F103-F115 (07 01 2017) ISSN: 1522-1466 [Electronic] United States
• PMID: 28356284 (Publication Type: Journal Article)
• Copyright: Copyright © 2017 the American Physiological Society.

Chemical References

• Adaptor Proteins, Vesicular Transport
• Bicarbonates
• Lipid A
• Lipopolysaccharides
• Phosphoinositide-3 Kinase Inhibitors
• Protein Kinase Inhibitors
• TICAM-1 protein, mouse
• Tlr4 protein, mouse
• Toll-Like Receptor 4
• Phosphatidylinositol 3-Kinase
• Proto-Oncogene Proteins c-akt
• Extracellular Signal-Regulated MAP Kinases
• monophosphoryl lipid A

Topics

• Adaptor Proteins, Vesicular Transport (deficiency, genetics, metabolism)
• Animals
• Bicarbonates (metabolism)
• Cytoprotection
• Extracellular Signal-Regulated MAP Kinases (metabolism)
• In Vitro Techniques
• Lipid A (analogs & derivatives, pharmacology)
• Lipopolysaccharides (toxicity)
• Loop of Henle (drug effects, enzymology)
• Male
• Mice, Inbred C57BL
• Mice, Knockout
• Perfusion
• Phosphatidylinositol 3-Kinase (metabolism)
• Phosphoinositide-3 Kinase Inhibitors
• Phosphorylation
• Protein Kinase Inhibitors (pharmacology)
• Proto-Oncogene Proteins c-akt (metabolism)
• Rats, Sprague-Dawley
• Renal Reabsorption (drug effects)
• Signal Transduction (drug effects)
• Toll-Like Receptor 4 (drug effects, genetics, metabolism)