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Abstract: TH-PO493

Monophosphoryl Lipid A (MPLA) Prevents LPS-Induced Inhibition of HCO3- Absorption in Medullary Thick Ascending Limb Through Negative Regulation of Interleukin-1 Receptor-Associated Kinase-1 (IRAK-1)

Session Information

Category: Fluid and Electrolytes

  • 901 Fluid and Electrolytes: Basic

Authors

  • Watts, Bruns A., University of Texas Medical Branch, Galveston, Texas, United States
  • Tamayo, Esther, University of Texas Medical Branch, Galveston, Texas, United States
  • Sherwood, Edward R., Vanderbilt University Medical Center, Nashville, Tennessee, United States
  • Good, David W., University of Texas Medical Branch, Galveston, Texas, United States
Background

LPS inhibits HCO3- absorption in the MTAL through activation of a basolateral TLR4-MyD88-ERK pathway that is upregulated by sepsis. Recently we showed that pretreatment with the nontoxic immunomodulator MPLA prevents inhibition of HCO3- absorption by LPS through activation of a TLR4-TRIF-PI3K pathway that prevents LPS-induced ERK activation. Here, we examined molecular mechanisms that underlie the protective inhibitory interaction between the MPLA-PI3K and LPS-ERK signaling pathways.

Methods

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Results

We first examined IRAK-1, a critical mediator of LPS signaling downstream of TLR4 that is downregulated in LPS tolerant cells. Treatment of mouse MTALs with LPS for 15 min in vitro increased IRAK-1 phosphorylation 1.5-fold. The effect of LPS to activate ERK in the MTAL was prevented by a selective IRAK-1 inhibitor, establishing IRAK-1 as the upstream mediator of ERK activation in the LPS pathway. Pretreatment of MTALs with MPLA for 2 h in vitro prevented LPS-induced IRAK-1 activation. This effect of MPLA was eliminated by a PI3K inhibitor. Toll-interacting protein (Tollip) is an intracellular protein that is induced in LPS tolerant cells and negatively regulates LPS signaling by suppressing IRAK-1 activity. To assess whether Tollip may be involved in MPLA’s actions in the MTAL, mice were pretreated with MPLA or vehicle 48 h prior to sham or cecal ligation and puncture (CLP) sepsis surgery. MPLA pretreatment increased Tollip expression in microdissected MTALs and inner stripe of outer medulla from sham and CLP mice. In addition, treatment with MPLA for 2-3 h in vitro increased Tollip expression in inner stripe of control mice.

Conclusion

We conclude that MPLA activates a PI3K-dependent pathway that inhibits LPS stimulation of IRAK-1 in the MTAL, thereby preventing LPS-induced ERK activation that inhibits HCO3- absorption. These protective effects of MPLA likely are mediated through the induction of Tollip, an immunomodulatory protein that negatively regulates IRAK-1. These results provide new evidence that renal tubule epithelial cells are capable of undergoing immune reprogramming that affords resistance to LPS and identify IRAK-1 as a key molecular target through which MPLA prevents LPS impairment of HCO3- absorption in the MTAL.

Funding

  • NIDDK Support