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

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 HCO3– 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 HCO3– absorption. In MTALs pretreated with MPLA plus a phosphatidylinositol 3-kinase (PI3K) or Akt inhibitor, LPS decreased HCO3– 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 HCO3– 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 HCO3– absorption, and MPLA pretreatment did not prevent ERK-mediated inhibition of HCO3– absorption by aldosterone, consistent with MPLA's low toxicity profile. These results demonstrate th...

Source: AJP: Renal Physiology - July 7, 2017 Category: Urology & Nephrology Authors: Watts, B. A., George, T., Sherwood, E. R., Good, D. W. Tags: RESEARCH ARTICLE Source Type: research