冬凌草甲素调控LXRα信号通路改善肥胖相关性肾病的作用及机制研究OA

OBJECTIVE To explore the therapeutic efficacy and mechanism of oridonin(ORI)against obesity-related glomerulopathy(ORG)based on the liver X receptor α(LXRα)signaling pathway.METHODS Kidney tissues of LXRα wild-type homozygous(LXRα+/+)mice and LXRα homozygous knockout(LXRα-/-)mice were subjected to high-throughput renal transcriptome sequencing and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis to predict key pathways and targets regulated by LXRα,followed by verification via Western blot assay.An ORG mouse model was established by feeding a high-fat diet.The LXRα agonist GW3965(30 mg/kg)was set as the positive control.After intragastric administration of 50 mg/kg and 100 mg/kg ORI once daily for 4 consecutive weeks,the body weight,renal weight,renal histopathological alterations,serum renal function indicators,blood lipid levels and inflammatory factor levels in renal tissue of mice were detected and observed to evaluate the efficacy of ORI in alleviating ORG.Meanwhile,the mRNA and protein expression levels of LXRα and its downstream targets in mouse renal tissues were detected to validate the mechanism by which ORI relieves ORG.RESULTS Compared with LXRα+/+mice,the upregulated differentially expressed genes in renal tissues of LXRα-/-mice were significantly enriched in the arachidonic acid(AA)metabolic pathway,and the expression level of Cyp4a12 was markedly elevated(adjusted P＜0.05).Western blot results verified that cytochrome P450 family 4 subfamily A member 12(CYP4A12)protein expression was significantly increased in the kidneys of LXRα-/-mice(P＜0.05).Pharmacodynamic results showed that both 50 mg/kg and 100 mg/kg ORI notably improved renal pathological lesions in ORG mice;these two doses reduced body weight,renal weight,serum creatinine,blood urea nitrogen,blood lipid levels as well as renal interleukin-6(IL-6)and IL-1β levels(P＜0.05).In addition,ORI significantly upregulated the mRNA and protein expression of renal nuclear LXRα and ABCA1,and downregulated the mRNA and protein expression of CYP4A12(P＜0.05).CONCLUSIONS ORI may exert an ameliorative effect on ORG by activating the LXRα signaling pathway,downregulating CYP4A12 expression,and inhibiting AA-induced inflammatory metabolism.