基于转录组学初探胰高血糖素样肽/胰高血糖素双受体激动剂Mazdutide对高尿酸血症大鼠的降尿酸作用OA北大核心CSTPCD

Objective To investigate the uric acid-lowering effect of Mazdutide,a glucagon-like peptide/glucagon dual receptor agonist,in hyperuricemic(HUA)rats and to explore its possible mechanism of action by transcriptomics.Methods Sprague Dawley rats were divided into eight groups(10 rats in each group)according to the randomized numerical table method,which was regular control group(CON),high-fat control group(HFD),model group(HUA),Mazdutide low-dose,medium-dose,and high-dose groups(Maz-LD,Maz-MD,Maz-HD),Semaglutide group(Sema),and Allopurinol group(ALL).Rats in control group were gavaged daily with 0.5％carboxymethylcellulose sodium solution(CMC-Na),and the rest of the rats were gavaged with 100 mg/kg adenine and 1 000 mg/kg potassium oxonate to induce the HUA model.The Maz-LD,Maz-MD,and Maz-HD groups were injected subcutaneously once every three days with 0.025 mg/kg,0.05 mg/kg,and 0.075 mg/kg of Mazdutide,Sema group was injected subcutaneously with 0.05 mg/kg of semaglutide once every three days,and ALL group was gavaged with 25 mg/kg of allopurinol daily.The drug was administered for 19 consecutive days,and the serum uric acid(SUA),creatinine(SCr),Urinary uric acid(UUA),and urinary protein(U-Pro)levels were detected in the rats.Hematoxylin and eosin(HE)staining was used to observe the pathological changes of kidney tissue.The role of Mazdutide in HUA rats was further explored by transcriptomics.Results Compared with the HUA group,the Maz-MD,Maz-HD groups,and the Sema group all reduced the body weight of the rats,and allopurinol did not affect the body weight.SUA and SCr were significantly reduced in the Maz-LD group(P＜0.05),and the levels of SUA,SCr,and U-Pro were significantly reduced in the Maz-MD group(P＜0.01,P＜0.05,P＜0.01).Additionally,SUA,SCr levels were significantly lower in Maz-HD group(P＜0.01).There was no significant difference in UUA levels among the groups.HE pathological staining revealed that Mazdutide improved renal histopathological changes in HUA rats.Renal transcriptomics showed that the expression of GCGR,Slc22a7,Slc23a3,and Aqp2 was significantly up-regulated after Mazdutide administration(P＜0.001,P＜0.05,P＜0.01,P＜0.05)and that the expression of Dnmt3a,Rest,Foxn3,Atp7a,Slc4a7(P＜0.000 1,P＜0.01,P＜0.01,P＜0.01,P＜0.01,P＜0.05)was significantly down-regulated.The associated KEGG-enriched pathways were bile secretion,renin-angiotensin system,histidine metabolism,platinum resistance,hematopoietic cell lineage,complement,and coagulation cascade response.Conclusions Subcutaneous injection of 0.05 mg/kg and 0.075 mg/kg of Mazdutide(3 days/dose)significantly reduce SUA levels,improved renal function,renal histopathology,and significantly reduced body weight in hyperuricemic rats by modulating GCGR,Slc22a7,Slc23a3,Aqp2,Dnmt3a,Rest,Foxn3,Atp7a,Slc4a7 gene expression levels,reducing substances that produce uric acid,regulating glycolipid metabolism,purine metabolism,and bile secretion to achieve this uric acid-lowering effect.