title: 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.affiliation: Department of Internal Medicine, The University of Texas Medical Branch, Galveston, Texas.
authors.forename: Bruns A
authors.initials: BA
authors.lastname: Watts
authors.affiliation: Department of Internal Medicine, The University of Texas Medical Branch, Galveston, Texas.
authors.forename: Thampi
authors.initials: T
authors.lastname: George
authors.affiliation: Department of Anesthesiology, Vanderbilt University Medical Center, Nashville, Tennessee.
authors.forename: Edward R
authors.initials: ER
authors.lastname: Sherwood
authors.affiliation: Department of Internal Medicine, The University of Texas Medical Branch, Galveston, Texas; dgood@utmb.edu.|Department of Neuroscience and Cell Biology, The University of Texas Medical Branch, Galveston, Texas; and.
authors.forename: David W
authors.initials: DW
authors.lastname: Good
mesh_terms: D033942:Adaptor Proteins, Vesicular Transport / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001639:Bicarbonates / Q000378:metabolism; D019610:Cytoprotection; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D066298:In Vitro Techniques; D008050:Lipid A / Q000031:analogs & derivatives* / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000633:toxicity*; D008138:Loop of Henle / Q000187:drug effects* / Q000201:enzymology; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010477:Perfusion; D058539:Phosphatidylinositol 3-Kinase / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D017207:Rats, Sprague-Dawley; D065608:Renal Reabsorption / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects*; D051197:Toll-Like Receptor 4 / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism
chemical_list: D033942:Adaptor Proteins, Vesicular Transport; D001639:Bicarbonates; D048049:Extracellular Signal-Regulated MAP Kinases; D008050:Lipid A; D008070:Lipopolysaccharides; D058539:Phosphatidylinositol 3-Kinase; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D051197:Toll-Like Receptor 4; C476286:Ticam1 protein, mouse; C493487:Tlr4 protein, mouse; C048436:monophosphoryl lipid A
keywords: LPS; Toll-like receptor 4; kidney; monophosphoryl lipid A; sepsis