新型钠磷转运蛋白抑制剂DZ1462在5/6肾切除高磷血症模型大鼠中的药效研究

Efficacy of DZ1462,a Novel Sodium-phosphate Transporter Inhibitor,on 5/6 Nephrectomy-induced Hyperphosphatemia Model Rats

目的探讨新型肠道钠磷转运蛋白小分子抑制剂DZ1462在大鼠5/6肾切除高磷血症动物模型中的降磷效果。方法首先随机选取156只Wistar大鼠,分为4组:第Ⅰ组6只为正常对照,饲喂正常饲料;第Ⅱ组60只,经过5/6肾切除后饲喂正常饲料;第Ⅲ组60只,经过5/6肾切除后饲喂高磷饲料;第Ⅳ组30只为假手术组,即只打开腹腔,不摘除肾脏,闭合伤口后饲喂高磷饲料。造模周期为10周。每两周检测各组大鼠血清磷含量,记录大鼠死亡数量,并进行HE染色观察肾脏病理变化,筛选高磷血症动物模型。选取符合入组标准的18只模型大鼠(均来源于第Ⅲ组),随机分为3组:模型对照组,记为G2组;DZ1462给药组(每次30 mg/kg,每日3次),记为G3组;商品化的降血磷药物碳酸司维拉姆片(Sevelamer)给药组(每次250 mg/kg,每日3次),记为G4组。每组6只,连续给药21 d。另外设正常对照组,记为G1组。运用无机磷检测试剂盒分析各组大鼠的血清磷水平变化。结果在手术建模后的第8周和第10周,5/6肾切除手术+高磷饲料饲喂的第Ⅲ组大鼠血清磷水平均明显高于正常对照第Ⅰ组(P<0.01);第Ⅲ组大鼠的肾脏出现了明显的肾小球硬化、肾小管萎缩、退化、间质炎症、纤维化和钙化,与人慢性肾病并发的高磷血症相似,提示肾性高磷血症动物模型建立成功。用药后,在各测量时间点上,DZ1462组大鼠的血清磷抑制率显著高于Sevelamer组(P<0.05)。结论DZ1462作为一种新型肠道钠磷转运蛋白小分子抑制剂,在大鼠高磷血症模型中能够有效抑制肠道磷离子的吸收,有望成为临床上治疗高磷血症的一种潜在有效药物。

Objective To study the efficacy of DZ1462,a novel sodium-phosphate transporter inhibitor,on rat hyperphosphatemia models established by 5/6 nephrectomy.Methods Totally 156 rats were randomly selected into four groups.Rats fed a normal diet were control group,named as groupⅠ(n=6);rats fed a normal diet after 5/6 nephrectomy were named as groupⅡ(n=60);rats fed a high phosphate diet after 5/6 nephrectomy were named as groupⅢ(n=60);rats fed a high phosphate diet after sham surgery were named as groupⅣ(n=30).The molding cycle was 10 weeks.Serum Pi was detected and the number of animal deaths was recorded every two weeks.Hematoxylin-eosin(HE)staining was performed to observe the change in kidney pathology,and to screen animal models with high phosphorus blood syndrome.Totally 18 model rats that met the inclusion criteria(all of groupⅢ)were selected and randomly assigned to three groups:the model control group recorded as the G2 group;the DZ1462 administration group(30 mg/kg,tid,21 d)recorded as the G3 group;the Sevelamer administration group(250 mg/kg,tid,21 d)recorded as the G4 group.In addition,the normal control group was set as the G1 group.Serum phosphate levels were measured using a kit.Results In the 8th and 10th weeks,compared to groupⅠ,serum phosphorus in groupⅢshowed a significant difference(P<0.01).The kidneys in groupⅢhad obvious glomerular sclerosis,renal tubular atrophy,degeneration,interstitial inflammation,fibrosis,and calcification.Similarly to chronic kidney disease accompanied by hyperphosphatemia,the animal model was established successfully.At each time point,the serum phosphorus inhibition rate of the G3 group was significantly higher than that of the G4 group(P<0.05).Conclusion DZ1462,as a novel small-molecule inhibitor of intestinal sodium and phosphorus transporter,can effectively inhibit intestinal phosphorus ion absorption in rat hyperphosphatemia model,and is expected to become a potential drug for the clinical treatment of hyperphosphatemia.