坎地沙坦不同治疗时机对2型糖尿病KK/Ta小鼠肾脏血管紧张素1型和2型受体表达的影响

Effects of candesartan early or late treatment on angiotensinⅡtype 1 and type 2 receptor expression in type 2 diabetic KK/Ta mice kidney

目的:探讨坎地沙坦治疗对自发性2型糖尿病KK/Ta小鼠肾脏血管紧张素1型受体(AT1)和2型受体(AT2)表达的影响。方法:KK/Ta小鼠随机分为:非治疗组;早期治疗组:自6周龄起经口予坎地沙坦(4mg.kg-1.d-1)治疗;晚期治疗组:自12周龄起予坎地沙坦治疗,正常对照组采用BALB/c小鼠。测定尿白蛋白排泄率、血压和糖耐量,计算总肾小球面积(WGA)、肾小球丛面积(GTA),细胞外系膜基质面积(EC-MA)和肾小球内细胞核数目(NIGCN)。免疫荧光和免疫组化染色检测肾脏中AT1和AT2的表达。结果:8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],WGA、GTA、ECMA和NIGCN增多,肾小球内AT1的表达增加,AT2的表达减少。坎地沙坦治疗显著减少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],减轻肾脏病理损害,抑制AT1的表达,上调AT2的表达,早期治疗组和晚期治疗组的作用无显著性差异。结论:KK/Ta小鼠肾脏中AT1受体表达增加,AT2受体表达减少。坎地沙坦治疗能够抑制AT1受体、上调AT2受体的表达,发挥其减少白蛋白尿,减轻糖尿病肾病病理损害的肾脏保护作用。

AIM： To investigate the effects of candesartan, an angiotensin II type 1 receptor blocker （ARB） on angiotensin II type 1 （AT1） and type 2 （AT2） receptor expression in type 2 diabetic KK/Ta mouse kidneys. METHODS： KK/Ta mice divided into three groups were treated with candesartan （4 mg. kg^-1.d^-1） or vehicle from 6 or 12 to 28 weeks of age. BALB/c miee（n = 6） 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, morphometric analysis ineluding the whole glomerular area （WGA）, glomerular tuft area （GTA）, extracellular matrix area （ECMA） and intraglomerular cell nuclei number （NIGCN） was pressions of AT1 and immunohistochemistry conducted, and renal ex- AT2 were evaluated by and immunofluorescence. RESULTS. KK/Ta mice developed higher body Neight, blood glucose, and urinary microalbunin/creatinine ratio in KK/Ta mice at 28 weeks ff age were significantly higher than that of SALB/e mice （427.49±89.37 mg/g vs. 9.54±3.25 mg/g,P〈0.01）. AT1 expression was up-regulated, and AT2 expression was downregu- lated in KK/Ta kidneys with increased WGA, GTA, ECMA and NIGCN. Candesartan treatment has markedly reduced urinary microalbumin/ creatinine ratid （Early treatment group： 32.18±9.41 mg/g,Late treatment group： 53.20 ±7.26 mg/g,P〈0. 01）. Treatment with candesartan inhibited AT1 expression and increased AT2 expression. Candesartan treatment reduced WGA, GTA, ECMA, NIGCN, and mean blood pressure. There were no significant differences between the two treatment groups （[rom 6 or 12 weeks）. CONCLUSION： The results suggest that candesartan, an ARB, attenuated glomeru- lar hypertrophy and mesangial matrix accumulation and subsequent albuminuria by down-regu lating AT1 expression and up-regulating AT2 expression in type 2 diabetic KK/Ta mouse kidneys.