Chrysophanol ameliorates oxidative stress and pyroptosis in mice with diabetic nephropathy through the Kelch-like ECH- associated protein 1/nuclear factor erythroid 2-related factor 2 signaling pathway

Diabetic nephropathy (DN), a microvascular complica-tion of diabetes, increases the risk of all-cause diabe-tes and cardiovascular mortalities. Moreover, oxidative stress and pyroptosis play important roles in the patho-genesis of DN. Rhubarb is widely used in traditional medicine, and chrysophanol (Chr), a free anthraquinone compound abundant in rhubarb, exhibits potent antioxi-dant properties and ameliorates renal fibrosis. Therefore, this study aimed to investigate the effects of Chr on re -nal injury, oxidative stress, and pyroptosis in mice with DN. A DN model was established by feeding the mice a high-sugar and fat diet and injecting them with 50 mg/ kg streptozotocin as a positive control. The DN mice had significantly impaired renal function, thickened glo-merular thylakoids and basement membranes, increased fibrous tissue, and inflammatory cell infiltration. Super-oxide dismutase (SOD) levels were reduced, malondial-dehyde (MDA) levels were increased, interleukin (IL)-1 beta and IL-18 increased, and cleaved caspase-1, caspase-1, and gasdermin D (GSDMD) involved in the process of pyroptosis were upregulated in DN. Kelch-like ECH-as-sociated protein 1 (Keap1) expression was upregulated, and nuclear factor erythroid 2-related factor 2 (Nrf2) ex -pression was downregulated. Compared to those in the DN group, the Chr-treated mice with DN had improved renal dysfunction, weakened glomerular thylakoid and basement membrane thickening, and reduced fibrous tissue proliferation and inflammatory cell infiltration. Additionally, Chr increased SOD levels, decreased MDA, IL-1 beta, and IL-18, down-regulated caspase-1, cleaved cas-pase-1, GSDMD, and Keap1 expression, and upregulated Nrf2 expression, which reversed the DN. Therefore, Chr reduced oxidative stress and pyroptosis in DNmice by activating the Keap1/Nrf2 pathway.