Monophosphoryl lipid a prevents impairment of medullary thick ascending limb HCO^-₃ absorption and improves plasma HCO^-₃ concentration in septic mice

Meta-bolic acidosis is the most common acid-base disorder in septic patients and is associated with increased mortality. Previously, we demonstrated that sepsis induced by cecal ligation and puncture (CLP) impairs HCO₃^- absorption in the medullary thick ascending limb (MTAL) by 1) decreasing the intrinsic HCO^-₃ absorptive capacity and 2) enhancing inhibition of HCO^-₃ absorption by LPS through upregulation of Toll-like receptor (TLR) 4 signaling. Both effects depend on ERK activation. Monophosphoryl lipid A (MPLA) is a detoxified TLR4 agonist that enhances innate antimicrobial immunity and improves survival following sepsis. Pretreatment of MTALs with MPLA in vitro prevents LPS inhibition of HCO₃^- absorption. Here we examined whether pretreatment with MPLA would protect the MTAL against sepsis. Vehicle or MPLA was administered to mice 48 h before sham or CLP surgery, and MTALs were studied in vitro 18 h postsurgery. Pretreatment with MPLA prevented the effects of sepsis to decrease the basal HCO₃^- absorption rate and enhance inhibition by LPS. These protective effects were mediated through MPLA stimulation of a Toll/IL-1 receptor domain-containing adaptor-inducing IFN-β-(TRIF)-dependent phosphatidylinositol 3-kinase-Akt pathway that prevents sepsis-and LPS-induced ERK activation. The effects of MPLA to improve MTAL HCO₃^- absorption were associated with marked improvement in plasma HCO^-₃ concentration, supporting a role for the kidneys in the pathogenesis of sepsis-induced metabolic acidosis. These studies support detoxified TLR4-based immunomodulators, such as MPLA, that enhance antimicrobial responses as a safe and effective approach to prevent or treat sepsis-induced renal tubule dysfunction and identify cell signaling pathways that can be targeted to preserve MTAL HCO₃^- absorption and attenuate metabolic acidosis during sepsis.