Lipopolysaccharide (LPS) is an endotoxin that plays a crucial role in septic acute kidney injury (AKI). Hispidulin is a natural flavonoid that possesses various biological activities. Recent studies have shown that hispidulin administration alleviates various inflammatory diseases in animal models. This study aimed to investigate the renoprotective effect of hispidulin on LPS-induced AKI. Male C57BL/6 mice were administered LPS (10 mg/kg) with or without hispidulin (50 mg/kg). Hispidulin administration attenuated renal dysfunction, histological alterations, and the upregulation of neutrophil gelatinase-associated lipocalin. This flavonoid also reduced cytokine production and Toll-like receptor 4 expression, inhibited nuclear factor-κB and mitogen-activated protein kinase cascades, and alleviated immune cell infiltration. The oxidation of lipids and DNA was also inhibited by hispidulin administration. This antioxidant effect of hispidulin was associated with the downregulation of NADPH oxidase 4, the activation of catalase and superoxide dismutase activities, and the restoration of glutathione levels. Moreover, hispidulin administration attenuated tubular cell apoptosis by inhibiting caspase-3 pathway. These data suggest that hispidulin ameliorates endotoxin-induced kidney injury by suppressing inflammation, oxidative stress, and tubular cell death.
Sepsis is a severe inflammatory condition that can cause organ dysfunction, including acute kidney injury (AKI). Hesperetin is a flavonoid aglycone that has potent antioxidant and anti-inflammatory properties. However, the effect of hesperetin on septic AKI has not yet been fully investigated. This study examined whether hesperetin has a renoprotective effect on lipopolysaccharide (LPS)-induced septic AKI. Hesperetin treatment ameliorated histological abnormalities and renal dysfunction in LPS-injected mice. Mechanistically, hesperetin attenuated LPS-induced oxidative stress, as evidenced by the suppression of lipid and DNA oxidation. This beneficial effect of hesperetin was accompanied by downregulation of the pro-oxidant NADPH oxidase 4, restoration of glutathione levels, and activation of antioxidant enzymes. This flavonoid compound also inhibited apoptotic cell death via suppression of p53-dependent caspase-3 pathway. Furthermore, hesperetin alleviated Toll-like receptor 4-mediated cytokine production and macrophage infiltration. Our findings suggest that hesperetin ameliorates LPS-induced renal structural and functional injury through suppressing oxidative stress, apoptosis, and inflammation.
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