CAJ | 학술논문

目的探讨血管紧张素Ⅱ受体拮抗剂坎地沙坦治疗对自发性2型糖尿病KK/Ta小鼠肾脏晚期糖基化终末产物形成及其受体(RAGE)表达的影响.方法 KK/Ta小鼠(n=72)随机分为非治疗组(n=24)；早期治疗组(n=24):自6周龄起经口予坎地沙坦[4mg/(kg·d)]治疗；晚期治疗组(n=24):自12周龄起予坎地沙坦治疗.正常对照组采用BALB/c小鼠(n=24).应用免疫荧光和免疫组化染色检测肾脏中晚期糖基化终末产物-羧甲基赖氨酸(CML)、RAGE蛋白的表达,竞争性RT-PCR检测RAGE mRNA的表达,同时测定尿白蛋白排泄率,血压和糖耐量等临床指标.结果 28周龄KK/Ta小鼠尿白蛋白/尿肌酐比率显著增加[(427.49±89.37) mg/g vs(9.54±3.25)mg/g,P＜0.01],足细胞RAGE mRNA和蛋白表达上调,CML的形成增加.坎地沙坦治疗显著减少了KK/Ta小鼠尿白蛋白/尿肌酐比率[早期治疗组(32.18±9.41) mg/g,晚期治疗组(53.20±7.26)mg/g,P＜0.01],抑制肾脏RAGE mRNA和蛋白的表达,减少CML的形成,但早期治疗组和晚期治疗组的作用比较差异无统计学意义(P＞0.05).结论坎地沙坦治疗通过下调糖尿病状态下肾脏RAGE的表达,阻断AGEs-RAGE的相互作用,减少AGEs的生成,发挥其降低尿白蛋白排泄率和改善肾脏病理损害的保护作用.
목적 탐토혈관긴장소Ⅱ수체길항제감지사탄치료대자발성2형당뇨병KK/Ta소서신장만기당기화종말산물형성급기수체(RAGE)표체적영향.방법 KK/Ta소서(n=72)수궤분위비치료조(n=24)；조기치료조(n=24):자6주령기경구여감지사탄[4mg/(kg·d)]치료；만기치료조(n=24):자12주령기여감지사탄치료.정상대조조채용BALB/c소서(n=24).응용면역형광화면역조화염색검측신장중만기당기화종말산물-최갑기뢰안산(CML)、RAGE단백적표체,경쟁성RT-PCR검측RAGE mRNA적표체,동시측정뇨백단백배설솔,혈압화당내량등림상지표.결과 28주령KK/Ta소서뇨백단백/뇨기항비솔현저증가[(427.49±89.37) mg/g vs(9.54±3.25)mg/g,P＜0.01],족세포RAGE mRNA화단백표체상조,CML적형성증가.감지사탄치료현저감소료KK/Ta소서뇨백단백/뇨기항비솔[조기치료조(32.18±9.41) mg/g,만기치료조(53.20±7.26)mg/g,P＜0.01],억제신장RAGE mRNA화단백적표체,감소CML적형성,단조기치료조화만기치료조적작용비교차이무통계학의의(P＞0.05).결론 감지사탄치료통과하조당뇨병상태하신장RAGE적표체,조단AGEs-RAGE적상호작용,감소AGEs적생성,발휘기강저뇨백단백배설솔화개선신장병리손해적보호작용.
Objective The effects of candesartan,an angiotensin Ⅱ type 1 receptor blocker (ARB) were investigated on advanced glycation end-products accumulation and the receptor for AGE (RAGE) expression in type 2 diabetic KK/Ta mouse kidneys.Methods KK/Ta mice(n=72)were random divided into three groups(n=24) and it was treated with candesartan [4 mg/(kg·d)] or vehicle from 6 or 12 to 28 weeks of age.BALB/c mice(n=24) treated with vehicle were used as controls.Body weight,blood pressure,blood glucose,urinary microalbumin,urinary creatinine and serum creatinine were measured every four weeks.At 28 weeks,renal expressions of carboxymethyllysine and RAGE were evaluated by immunohistochemistry and/or competitive RT-PCR.Results KK/Ta mice developed high body weight,high blood glucose,and high urinary microalbumin/creatinine ratio in KK/Ta mice at 28 weeks of age,and it was significantly higher than that of BALB/c mice [(427.49±89.37)mg/g vs (9.54±3.25)mg/g,P＜0.01 ].Protein and mRNA expressions of RAGE were upregulated in KK/Ta kidneys with increased immunostaining intensities of carboxymethyllysine.Candesartan treatment has markedly reduced urinary microalbumin/creatinine ratio [Early treatment group (32.18±9.41)mg/g,Late treatment group (53.20±7.26)mg/g,P＜0.01 ].Treatment with candesartan down-regulated the protein and mRNA expressions of RAGE and reduced the accumulation of carboxymethyllysine.There were no significant differences between the two treatment groups (from 6 or 12 weeks).Conclusions The results suggest that candesartan,an ARB,reduces advanced glycation end-products accumulation and subsequent albuminuria by down-regulating RAGE expression in type 2 diabetic KK/Ta mouse kidneys.