罗沙司他对腹膜透析大鼠腹膜HIF-1α/VEGF信号通路表达及纤维化的影响  

Effect of roxadustat(ROX)on expression and fibrosis of hypoxia-inducible factors-1α(HIF-1α)and vascular endothelial growth factor(VEGF)signaling pathway in peritoneal dialysis rats

作　　者：张静[1] 刘张晨 李小军 刘海义 李思情 阿依江·马合沙提 任荣[1] ZHANG Jing;LIU Zhangchen;LI Xiaojun;LIU Haiyi;LI Siqing;Ayijiang Maheshati;REN Rong(Department of Nephrology,the Fifth Affiliated Hospital of Xinjiang Medical University;The Fifth Clinical Medical College,Xinjiang Medical University,Urumqi 830000,China)

机构地区：[1]新疆医科大学第五附属医院肾病科,乌鲁木齐830000 [2]新疆医科大学第五临床医学院,乌鲁木齐830000

出　　处：《新疆医科大学学报》2024年第11期1446-1451,共6页Journal of Xinjiang Medical University

基　　金：新疆维吾尔自治区自然科学基金项目(2021D01C435);新疆医科大学大学生创新训练计划项目第17期立项课题(S202210760152)。

摘　　要：目的评估罗沙司他(Roxadustat,ROX)对腹膜透析(Peritoneal dialysis,PD)大鼠腹膜组织的缺氧诱导因子-1α(Hypoxia-inducible factors-1α,HIF-1α)以及血管内皮生长因子(Vascular endothelial growth factor,VEGF)表达的影响,同时探讨其对腹膜纤维化程度的潜在作用及其机制。方法购入30只雄性SPF级大鼠,采用5/6肾脏切除法成功构建尿毒症腹膜透析大鼠模型27只,随机分为空白对照组、PD组、PD+ROX组(联合给予5 mg/kg ROX,每周3次),每组9只,持续给药1个月,在灌胃后6、12、24 h以及4周时,采用ELISA法检测腹膜透析液、血液中HIF-1α和VEGF的浓度。利用HE和Masson染色观察大鼠腹膜组织病理变化,WB和免疫组化检测腹膜组织中HIF-1α、VEGF蛋白表达变化。结果HE和Masson染色观察各组大鼠腹膜组织,与空白对照组比较,PD组大鼠的腹膜组织出现了明显的纤维化和血管增生现象;与PD组相比,PD+ROX组大鼠的腹膜组织纤维化和血管增生现象明显改善。PD组腹膜组织中HIF-1α和VEGF蛋白表达水平显著高于空白对照组(P均<0.05),增加ROX干预后,PD+ROX组大鼠腹膜组织中HIF-1α和VEGF蛋白表达水平显著降低(P均<0.05)。PD+ROX组血清中HIF-1α和VEGF浓度均高于空白对照组和PD组(P均<0.05)。PD+ROX组腹膜透析液中HIF-1α和VEGF浓度均低于空白对照组和PD组(P均<0.05)。结论ROX治疗能有效降低腹膜组织及腹膜透析液中的HIF-1α和VEGF表达水平,缓解由葡萄糖腹膜透析引起的腹膜组织纤维化和血管增生。同时,血清中HIF-1α和VEGF水平的提升有助于改善腹膜组织的缺氧状况,抑制HIF-1α/VEGF信号通路,对抗腹膜纤维化。Objective To evaluate the impact of roxadustat(ROX)on the expression of hypoxia-inducible factors-1α(HIF-1α)and vascular endothelial growth factor(VEGF)in the peritoneal tissue of rats under-going peritoneal dialysis(PD)and to explore its potential effects and mechanisms on the degree of perito-neal fibrosis.Methods 30 male Sprague-Dawley rats were purchased,and 27 uremia peritoneal dialysis rat models were successfully established using the 5/6 kidney resection method.The rats were randomly di-vided into a blank control group,a PD group and a PD+ROX group(co-administered 5 mg/kg ROX,3 times a week),with 9 rats in each group.The medication was administered for 1 month,and the concen-trations of HIF-1αand VEGF in the peritoneal dialysis fluid and blood were detected by ELISA at 6,12,and 24 h after gavage,as well as at 4 weeks.The pathological changes in the rat peritoneal tissue were ob-served by hematoxylin and eosin(HE)and Masson staining,and the expression changes of HIF-1αand VEGF proteins in the peritoneal tissue were detected by WB and immunohistochemistry.Results HE and Masson staining were used to observe the peritoneal tissue of rats in each group.Compared with blank control group,the peritoneal tissue of the rats in PD group showed obvious fibrosis and angiogenesis;compared with PD group,the peritoneal tissue fibrosis and angiogenesis in PD+ROX group were signifi-cantly improved.The expression levels of HIF-1αand VEGF proteins in the peritoneal tissue of PD group were significantly higher than those in the blank control group(both P<0.05),and after the intervention with ROX,the expression levels of HIF-1αand VEGF proteins in the peritoneal tissue of the PD+ROX group were significantly decreased(both P<0.05).The serum concentrations of HIF-1αand VEGF in the PD+ROX group were higher than those in blank control and PD groups(both P<0.05).The concen-trations of HIF-1αand VEGF in peritoneal dialysis fluid of the PD+ROX group were lower than those in blank control and PD groups(both P<0.05).Conclusion

关 键 词：罗沙司他 腹膜透析 腹膜组织纤维化 HIF-1α/VEGF信号通路 

分 类 号：R692[医药卫生—泌尿科学]