Endothelin System Blockade Extenuates Sepsis‐Induced Acute Heart and Kidney Injuries via Modulating ET‐1/Klotho/p38‐MAPK

ABSTRACT Sepsis‐induced organ failure is a major health problem, characterised by massive inflammatory and oxidative stress responses. Endothelin‐1 (ET‐1) is one of the peptides expressed during septicemia with proapoptotic, proinflammatory, and oxidant effects. ET‐1 plays a role in heart and kidney injuries in sepsis. Accordingly, the current study was conducted to investigate, on a mechanistic basis, whether inhibition of ET‐1 signalling either by blocking its receptors or inhibiting its formation attenuates sepsis‐induced acute cardiorenal injuries. To analyse the role of ET‐1 in sepsis, we used a cecal ligation and puncture (CLP) model of sepsis. The animals were divided into five groups: CLP non‐treated group, CLP‐treated groups with bosentan, ambrisentan, and phosphoramidon (30, 5, and 0.5 mg/kg, respectively), and sham‐operated group. In addition to the same set of groups, survival analysis was assigned Survival rate, histopathological assessment, and cardiorenal functions were analysed. Oxidant and antioxidant activities, ET‐1, IL‐6, and lactate were measured. The expression of TNF‐α, p38, Klotho, and caspase‐3 was evaluated by immunohistochemistry. CLP caused acute cardiorenal damage, high mortality, upregulated levels of ET‐1, IL‐6, and lactate, as well as an imbalance in oxidant/antioxidant activities, elevated expression of TNF‐α, p38, caspase‐3 and reduced expression of klotho. Bosentan, ambrisentan, or phosphoramidon improved survival, reduced the levels of inflammatory and oxidative stress parameters, improved cardiorenal functions and structure, elevated the tissue contents of GSH and SOD, raised the expression of klotho protein, and reduced the cardiorenal expression of p38, TNF‐α and caspase‐3. Endothelin receptor antagonists (ERAs); bosentan and ambrisentan, or endothelin converting enzyme inhibitor (ECE‐i) phosphoramidon, are promising agents against sepsis‐induced organ damage. This was evident in their cardiorenal protective effects, up‐regulation of klotho, suppression of inflammation, oxidation, apoptosis, and enhancement of the antioxidant status.