罗沙司他对CKD大鼠肠生物屏障功能的影响  

Effect of roxadustat on intestinal biological barrier function in CKD rats

作　　者：何荃[1] 渠宁 雷子彤 陈蕾[1] 蒋红利[1] 刘华[1] HE Quan;QU Ning;LEI Zitong;CHEN Lei;JIANG Hongli;LIU Hua(Department of Severe Kidney Disease and Blood Purification,The First Affiliated Hospital of Xi′an Jiaotong University,Xi′an 710061,China)

机构地区：[1]西安交通大学第一附属医院重症肾脏病·血液净化科,陕西西安710061

出　　处：《西部医学》2024年第2期166-174,共9页Medical Journal of West China

基　　金：陕西省重点研发—一般项目—社会发展领域项目(2023-YBSF-477);中华国际医学交流基金会肾性贫血科研基金项目(Z-2017-24-2037)。

摘　　要：目的 探讨罗沙司他对慢性肾脏病(CKD)大鼠肠生物屏障功能的影响。方法 将22只SPF级180~220 g SD雄性大鼠随机分为假手术组(Sham组,n=4)、肾切组(5/6肾切除,n=18),肾切组建模成功后随机分为CKD组(n=6)、 CKD+罗沙司他低剂量(7.5 mg/kg, tiw)灌胃组(CKD-LOW组,n=6)、 CKD+罗沙司他高剂量(10 mg/kg, tiw)灌胃组(CKD-HIGH组,n=6),Sham组及CKD组同期蒸馏水灌胃。干预6周后采集各组大鼠血标本、肾脏组织、粪便标本等,评估各组贫血、肾功能、肾脏病理、炎症状态及测序检测肠道菌群构成。结果 罗沙司他有降低CKD大鼠血清肌酐、尿素氮的趋势,可显著升高血红蛋白;肾切后大鼠肾脏组织出现肾小球硬化、肾间质纤维化、大量炎症细胞浸润等病理改变,而罗沙司他给药后病理改变减轻,TGF-β1及α-SMA表达下调(P<0.05);与sham组相比,其它3组大鼠Scr、BNU水平显著增高(P<0.05)。CKD-HIGH组大鼠的BUN、Scr水平低于CKD-LOW组(均P<0.05),但两组间Il-6、TNF-a、Hb、血清铁调素水平差异无统计学意义(P>0.05)。与sham组比较,CKD组血清Il-6、TNF-α、血清铁调素水平均显著增高,Hb显著降低(P<0.05)。CKD-HIGH组大鼠Il-6、TNF-α均较CKD组降低(P<0.05)。CKD-LOW组及CKD-HIGH组大鼠较CKD大鼠Hb显著升高,血清铁调素水平显著降低(均P<0.05)。16S rRNA测序结果:各组肠道微生物组成具有显著差异,4组样本共有376个重叠的OUT;罗沙司他对肠道菌群α多样性影响较小;β多样性分析提示四个组的肠道菌群组成差异有统计学意义(均P<0.001),给药组在PC2水平上距Sham组更近;各组菌群组成在门及属水平差异均有统计学意义(P<0.05),片球菌属、果胶杆菌属和Blautia菌属在CKD组中丰度降低,罗沙司他干预后丰度升高(均P<0.05);弧菌属、Delftia菌属和Pseudomonas菌属在CKD组中丰度升高,罗沙司他干预后丰度降低(均P<0.05)。结论 罗沙司他可以减轻CKD肾脏病理改变和TGF-β1、α-SMA表达Objective To investigate the effect of roxadustat on intestinal biological barrier function in rats with chronic renal disease(CKD).Methods A total of 22 SPF male SD rats with body weight of 180-220 g were randomly divided into two groups:Sham groups(n=4)and chronic kidney disease group(5/6 nephrectomy,CKD group(n=18).After successful modeling,CKD group was randomly divided into CKD group(n=6),low-dose roxadustat group(CKD-low group(n=6),7.5 mg/kg roxadustat),high-dose group(CKD-high group(n=6),10 mg/kg roxadustat)(Sham group and CKD group were intragastric with distilled water at the same time),blood samples,kidney tissue and fecal samples were collected after 6 weeks of intervention.Anemia,renal function,renal pathology and inflammation were evaluated in each group,and intestinal flora composition was detected by sequencing.Results Roxadustat showed a tendency to decrease serum creatinine and urea nitrogen in CKD rats,and significantly increased hemoglobin.Pathological changes such as glomerulosclerosis,interstitial fibrosis and infiltration of a large number of inflammatory cells were observed in the renal tissues of rats after renal resection,but the pathological changes and the expression of TGF-βandα-SMA were alleviated after roxadustat administration.The levels of serum inflammatory cytokines TNF-α,IL-6 and serum hepcidin were significantly increased in CKD group,and the levels of inflammatory cytokines and hepcidin were decreased by roxadustat administration.16SrRNA sequencing showed that there were significant differences in intestinal microbial composition among the four groups,with 376 overlapping OUT samples.Roxadustat had little effect onαdiversity of intestinal flora.βdiversity analysis suggested that intestinal flora composition of the four groups was significantly different,and the administration group was closer to the Sham group.The flora composition of each group was different at phylum and genus level.The abundance of pediococcus,pectin and blautia decreased in CKD group,but increased aft

关 键 词：罗沙司他 肠屏障功能 肠道菌群 炎症状态 慢性肾脏病 

分 类 号：R692.5[医药卫生—泌尿科学]