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

• Published in: American journal of physiology. Renal physiology Vol. 313; no. 1; pp. F103 - F115
• Main Authors: Watts, 3rd, Bruns A, George, Thampi, Sherwood, Edward R, Good, David W
• Format: Journal Article
• Language: English
• Published: United States American Physiological Society 01.07.2017
• Subjects: 1-Phosphatidylinositol 3-kinase; Adaptor Proteins, Vesicular Transport - deficiency; Adaptor Proteins, Vesicular Transport - genetics; Adaptor Proteins, Vesicular Transport - metabolism; AKT protein; Aldosterone; Animals; Bicarbonates - metabolism; Cytoprotection; Enzyme inhibitors; Extracellular signal-regulated kinase; Extracellular Signal-Regulated MAP Kinases - metabolism; Immunomodulation; In Vitro Techniques; Interferon; Interleukin 1; Interleukin 1 receptors; Kidneys; Kinases; Lipid A; Lipid A - analogs & derivatives; Lipid A - pharmacology; Lipids; Lipopolysaccharides; Lipopolysaccharides - toxicity; Loop of Henle - drug effects; Loop of Henle - enzymology; Male; Metabolic pathways; Mice, Inbred C57BL; Mice, Knockout; Monophosphoryl lipid A; MyD88 protein; Perfusion; Phosphatidylinositol 3-Kinase - antagonists & inhibitors; Phosphatidylinositol 3-Kinase - metabolism; Phosphorylation; Protein Kinase Inhibitors - pharmacology; Proto-Oncogene Proteins c-akt - metabolism; Rats, Sprague-Dawley; Renal function; Renal Reabsorption - drug effects; Rodents; Signal transduction; Signal Transduction - drug effects; TLR4 protein; Toll-Like Receptor 4 - drug effects; Toll-Like Receptor 4 - genetics; Toll-Like Receptor 4 - metabolism; Toll-like receptors; Toxicity; kidney; monophosphoryl lipid A; LPS; sepsis; Toll-like receptor 4
• ISSN: 1931-857X; 1522-1466
• DOI: 10.1152/ajprenal.00064.2017

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.