Title : Na,K-ATPase mediated redox signaling exacerbates inflammation and kidney dysfunction in murine sepsis model
Abstract:
Oxidative stress and associated inflammatory processes, hypotension, and kidney dysfunction are crucial in the development and progression of sepsis, resulting in an immune response that leads to multiple organ failure. Hence, the strategies to limit this systemic inflammatory response might result in the development of an effective sepsis therapy. Previous studies from our lab have demonstrated the role of Na/K-ATPase signaling in exacerbating systemic oxidative stress and inflammation and the potential role of Na/K-ATPase signaling antagonist, pNaKtide, in ameliorating several pathophysiological abnormalities. The aim of this study is to demonstrate the role of Na,K-ATPase signaling in exacerbating oxidant stress, hypotension and kidney dysfunction noted in a murine model of sepsis. Furthermore, we aim to demonstrate the effect of systemic administration of Na,K-ATPase signaling antagonist, pNaKtide, in experimental sepsis using cecal ligation and puncture (CLP) model, as a drug intervention against septic shock. Murine sepsis was induced by CLP in male C57BL6 mice with or without pNaKtide (25 mg/kg body wt) which was administered, intraperitoneally, 24 hours before CLP procedure. Sham surgery was performed without the ligation and puncture, which served as controls for the study. All mice were assessed for blood pressure and Murine Sepsis Score (MSS) at baseline (before Sham or CLP), 8hours and 24 hours after Sham or CLP. Mice were euthanized after 24 hours of Sham or CLP surgery and kidneys were collected for morphological and biochemical assessment. Blood was used to measure plasma creatinine and inflammatory cytokines. Systemic administration of pNaKtide demonstrated improved blood pressure and MSS at 24 hours following CLP surgery, as compared to CLP mice without pNaKtide. Histological assessment of kidney tissues by H&E staining showed significantly less congestion, infiltration of inflammatory cells in CLP mice administered with pNaKtide, as compared to CLP alone. pNaKtide also improved kidney function and systemic inflammatory cytokines (TNFα and MCP1), as well as improved mRNA expression of inflammatory and macrophage infiltration markers, in kidney tissues of CLP mice. Our study demonstrates that antagonism of Na,K-ATPase oxidant amplification loop by pNaKtide may attenuate CLP-induced sepsis by inhibition of inflammatory milieu noted in this pathophysiological condition. Hence, Na,K-ATPase signaling may serve as a viable clinical target for therapeutic intervention of sepsis and associated inflammatory mechanisms.
What will audience learn from your presentation?
- The findings from our study show changes in the systemic inflammation and tissue-specific phenotypic alterations induced by CLP
- Our future studies will aim to dissect underlying molecular mechanisms, as well as elucidating mediators that potentiates phenotypic alterations noted in sepsis.
- If our data is confirmed in humans, novel targets for therapeutic intervention for sepsis are apparent
