Klotho modulation by tempol: a potential therapeutic axis in sepsis

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Abstract
Sepsis is characterized by massive inflammatory and oxidative stress responses. The imbalance between oxidant and antioxidant activities during sepsis contributes to hyperinflammation, oxidation, endothelin system activation, and apoptosis, key elements of multiorgan failure. The current study investigated the role of tempol attenuating sepsis-induced acute cardiorenal injuries through modulation of Klotho. We used a cecal ligation and puncture (CLP) model of sepsis. Survival rate, histopathological assessment, and cardiorenal functions were analyzed. Oxidant and antioxidant activities, IL-6, and lactate were measured. The expression of tumor necrosis factor- α (TNF-α), p38-mitogen activating protein kinase (p38-MAPK), klotho, and caspase-3 were evaluated by immunohistochemistry. CLP caused acute cardiorenal damage, high mortality, upregulated levels of IL-6 and lactate, an imbalance in oxidant/antioxidant activities, elevated expression of TNF-α, p38, caspase-3, and reduced expression of klotho. Tempol improved survival, reduced inflammatory and oxidative stress parameters, improved cardiorenal functions, elevated the tissue contents of reduced glutathione (GSH) and superoxide dismutase (SOD), raised the expression of klotho protein and reduced the expression of p38, TNF- α and caspase-3. Tempol is a promising agent against sepsis-induced organ damage. This was evident in its cardiorenal protective effect, up-regulation of klotho, suppression of inflammation, oxidation, and apoptosis, and enhancement of the antioxidant status.

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