卡格列净与阿米洛利或苯扎米尔联用对肾病综合征大鼠骨代谢的影响

Effects of canagliflozin combined with amiloride or benzamil on bone metabolism in rats with nephrotic syndrome

目的探讨钠-葡萄糖协同转运蛋白2抑制剂(SGLT2i)卡格列净和上皮钠通道阻滞剂阿米洛利或苯扎米尔联用对阿霉素诱导的肾病综合征(NS)模型大鼠骨代谢的影响。方法取49只雄性SD大鼠,随机抽取7只为对照组(NG组)。其余42只通过尾静脉注射阿霉素造模并随机分为模型组(MG组)、卡格列净组(KG组)、苯扎米尔组(BH组)、阿米洛利组(AL组)、卡格列净+苯扎米尔组(KB组)、卡格列净+阿米洛利组(KA组),每组7只。各用药组每日定时按大鼠体质量予以灌胃,NG组和MG组给予等量生理盐水,疗程6周。治疗前1 d检测各组大鼠的24 h尿蛋白(24 h-UTP),验证模型制备成功。治疗后第6周,分别检测各组大鼠的24 h-UTP、尿钠(UNa)、尿钾(UK)以及血清白蛋白(ALB)、甘油三酯(TG)、总胆固醇(TC)、低密度脂蛋白(LDL)、血钙(SCa)、血钠(SNa)、血钾(SK)、25-羟维生素D(25-OH-D)、碱性磷酸酶(ALP)、甲状旁腺素(PTH)、Ⅰ型前胶原氨基端原肽(PINP)和Ⅰ型胶原羧基端肽β特殊序列(β-CTX)水平。结果造模成功后,MG组的24 h-UTP、TG、TC、LDL、SCa水平均升高,ALB、25-OH-D、ALP、PINP、PTH水平均降低,差异有统计学意义(P<0.05或P<0.01)。药物干预6周后,KG组大鼠体质量下降,差异有统计学意义(P<0.05)。与MG组比较,各药物组的24 h-UTP、TC、TG、LDL、SCa水平降低,ALB水平升高,差异有统计学意义(P<0.05或P<0.01)。与MG组比较,KA组的25-OH-D、ALP、PINP、β-CTX水平升高,差异有统计学意义(P<0.05或P<0.01)。造模及药物治疗对UNa、UK、SK、SNa水平无影响(P>0.05)。结论单用卡格列净、苯扎米尔组、阿米洛利以及卡格列净分别联合苯扎米尔、阿米洛利用药均可改善阿霉素诱导的NS模型大鼠的大量蛋白尿、低蛋白血症和高脂血症。联用卡格列净和阿米洛利具有显著的促成骨作用或促破骨作用,其可能通过形成新的成骨/破骨平衡,进而发挥降低NS大鼠骨折风险的作用。

Objective To investigate the effects of sodium-glucose cotransporter 2 inhibitor(SGLT2i)canagliflozin and epithelial sodium channel inhibitor amiloride or benzamil in combination on the bone metabolism in the rats with the nephrotic syndrome(NS)induced by doxorubicin.Methods In the 49 male SD rats selected,7 were randomly selected as control group(NG),and 42 were built as adriamycin-induced nephropathy model by injecting adriamycin through the tail vein,and were randomly divided into model group(MG group),canagliflozin group(KG group),benzamil group(BH group),amiloride group(AL group),canagliflozin+benzamil group(KB group)and canagliflozin+amiloride group(KA group),with 7 cases in each group.Each medication group was given intragastric administration according to the body weight of rats regularly every day,NG group and MG group were given equal amount of normal saline,the course of treatment was 6 weeks.The 24-hour urinary protein(24 h-UTP)of each group was detected one day before treatment to verify the successful preparation of the model.At 6 weeks after treatment,the 24 h-UTP,urine sodium(UNa),urinary potassium(UK)levels in urine and the albumin(ALB),triglyceride(TG),cholesterol(TC),low density lipoprotein(LDL),serum calcium(SCa),sodium(SNa),potassium(SK),25-hydroxyvitamin D(25-OH-D),alkaline phosphatase(ALP),parathyroid hormone(PTH),procollagen typeⅠN-terminal propeptide(PINP)and beta C-terminal cross-linked telopeptides of typeⅠcollagen(β-CTX)levels in serum were measured,respectively.Results After successful modeling,the levels of 24 h-UTP,TG,TC,LDL and SCa in the MG group were significantly increased,while the levels of ALB,25-OH-D,ALP,PINP and PTH were significantly decreased(P<0.05 or P<0.01).After 6 weeks of drug intervention,the body mass of rats treated with KG alone decreased significantly(P<0.05).Compared with the MG group,the levels of 24 h-UTP,TC,TG,LDL and SCa were significantly decreased,and the level of ALB was significantly increased in all drug groups when compared to the MG(P<0.05 or P<0.01).Compared with the MG group,the levels of 25-OH-D,ALP,PINP andβ-CTX in the KA group were significantly increased when compared to the MG(P<0.05 or P<0.01).Molding and drug therapy had no impact on levels of UNa,UK,SK and SNa(P>0.05).Conclusion Calaglizin alone,benzamil alone,amiloride alone and calaglizin combined with benzamil or amiloride can improve the mass proteinuria,hypoproteinemia and hyperlipidemia in adriamycin-induced NS model rats.The combination of caraglipzin and amiloride has a significant osteogenic or osteoclastic effect,which may play a role in reducing the risk of fracture in NS rats by forming a new osteogenic/osteoclastic balance.