Antioxidant, Antiapoptotic, and Anti-Inflammatory Effects of Hesperetin in a Mouse Model of Lipopolysaccharide-Induced Acute Kidney Injury

Abstract

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.

Sirtuins as Players in the Signal Transduction of Citrus Flavonoids

“…Indeed, the flavonoid nobiletin (NOB) was able to reduce liver inflammation and fibrosis through the suppression of the NOD-like receptor thermal protein domain-associated protein 3 (NLRP3) inflammasome in a SIRT1-dependent manner [108]. Liver inflammation was also mitigated by HSP, another relevant flavonoid found in Citrus fruits, exerting, similar to HES, antioxidant, anti-inflammatory, and anticancer properties, and also counteracting lung disorders [109][110][111]. In particular, HSP acted as a SIRT1 activator, which in turn led to the suppression of RelA/p65 acetylation, hampering NF-κB activation [112].…”