Abstract: TH-PO1026

Monophosphoryl Lipid A Prevents Sepsis-Induced Inhibition of HCO3- Absorption in Medullary Thick Ascending Limb

Session Information

  • Acid Base: Basic
    November 02, 2017 | Location: Hall H, Morial Convention Center
    Abstract Time: 10:00 AM - 10:00 AM

Category: Fluid, Electrolytes, and Acid-Base

  • 701 Acid-Base: Basic

Authors

  • Watts, Bruns A., U TX Med Branch, Galveston, Texas, United States
  • George, Thampi, U TX Med Branch, Galveston, Texas, United States
  • Sherwood, Edward R., Vanderbilt U Med Center, Nashville, Tennessee, United States
  • Good, David W., U TX Med Branch, Galveston, Texas, United States
Background

Sepsis impairs HCO3- absorption in the MTAL through two distinct mechanisms: 1) by decreasing the intrinsic HCO3- absorptive capacity, and 2) by enhancing inhibition of HCO3- absorption by LPS through upregulation of basolateral TLR4 signaling. Both effects depend on ERK activation. Monophosphoryl lipid A (MPLA) is a detoxified derivative of LPS that enhances innate host resistance to infection and improves survival following endotoxemia or sepsis. Recently we showed that pretreatment of MTALs with MPLA in vitro prevents LPS inhibition of HCO3- absorption by activating a TLR4-TRIF-PI3K-Akt pathway that prevents LPS-induced ERK activation. Here we examined whether pretreatment with MPLA in vivo would protect the MTAL against sepsis.

Methods

Mice were treated with vehicle or MPLA 48 h before sham or cecal ligation and puncture (CLP) surgery. MTALs were studied in vitro 18 h post-surgery.

Results

As shown previously, CLP decreased basal HCO3- absorption rate by 22% and increased inhibition by LPS from 21 to 41% vs sham controls (P<0.05). Pretreatment with MPLA prevented both the effects of sepsis to decrease the basal HCO3- absorption rate and to enhance inhibition by LPS. MPLA treatment increased Akt phosphorylation and prevented the CLP-induced activation of ERK that reduces basal HCO3- absorption rate in the MTAL. These effects of MPLA on Akt and ERK were eliminated in MTALs from CLP mice treated with a PI3K inhibitor and in MTALs from TRIF-deficient mice. Treatment of MTALs from CLP mice with MPLA in vitro reduced ERK activity through activation of PI3K. In addition, treatment with a PI3K inhibitor in vitro enhanced the ability of LPS to inhibit HCO3- absorption through ERK activation in MTALs from MPLA-treated CLP mice. MPLA attenuated the decrease in plasma [HCO3-] in CLP mice.

Conclusion

MPLA treatment prevents the effects of sepsis to impair MTAL HCO3- absorption. These protective effects are mediated through MPLA stimulation of a TRIF-PI3K-Akt pathway that downregulates ERK activation in the MTAL. These results identify TLR4-based immunomodulators such as MPLA as novel agents to treat or prevent sepsis-induced renal tubule dysfunction and identify pathways that can be targeted to preserve MTAL HCO3- absorption during bacterial infection.

Funding

  • NIDDK Support