Endothelin System Blockade Extenuates Sepsis-Induced Acute Heart and Kidney Injuries via Modulating...

Area of Science:

• Biomedical Science
• Pharmacology
• Pathophysiology

Background:

• Sepsis-induced organ failure is a critical health issue driven by inflammation and oxidative stress.
• Endothelin-1 (ET-1) exacerbates sepsis by promoting apoptosis, inflammation, and oxidative damage, particularly affecting the heart and kidneys.

Purpose of the Study:

• To investigate the mechanistic role of ET-1 in sepsis-induced cardiorenal injuries.
• To determine if inhibiting ET-1 signaling, via receptor blockade or formation inhibition, can mitigate these injuries.

Main Methods:

• A cecal ligation and puncture (CLP) model was used to induce sepsis in animals.
• Animals were treated with ET-1 pathway inhibitors: bosentan, ambrisentan (Endothelin Receptor Antagonists), and phosphoramidon (Endothelin Converting Enzyme inhibitor).
• Evaluated outcomes included survival rates, cardiorenal function and structure, oxidative/antioxidant status, inflammatory markers (IL-6, TNF-α), and apoptosis markers (caspase-3), alongside Klotho expression.

Main Results:

• CLP induced significant cardiorenal damage, increased mortality, elevated ET-1, IL-6, and lactate levels, and dysregulated oxidant/antioxidant balance.
• ET-1 pathway inhibition with bosentan, ambrisentan, or phosphoramidon significantly improved survival rates and cardiorenal function.
• Treatments reduced inflammation, oxidative stress, and apoptosis, while enhancing antioxidant capacity (GSH, SOD) and increasing Klotho expression.

Conclusions:

• Endothelin receptor antagonists (bosentan, ambrisentan) and endothelin converting enzyme inhibitor (phosphoramidon) demonstrate significant protective effects against sepsis-induced cardiorenal damage.
• These agents attenuate sepsis by suppressing inflammation, oxidative stress, and apoptosis, and by enhancing antioxidant status and Klotho protein expression.
• Targeting the ET-1 pathway represents a promising therapeutic strategy for managing sepsis-induced organ failure.