坎地沙坦对糖尿病肾病小鼠血清和糖皮质激素诱导的蛋白激酶1表达的影响及意义

目的研究血管紧张素Ⅱ(AngⅡ)Ⅰ型受体(AT1)拮抗剂坎地沙坦(candesartan)对糖尿病肾病(D iabetic nephrop-athy,DN)小鼠血清和糖皮质激素诱导的蛋白激酶1(SGK1)表达的影响及意义。方法采用链脲佐菌素(STZ)单次腹腔注射诱导小鼠糖尿病肾病(DN)模型。将正常C57BL/6小鼠随机分成3组,每组12只:正常对照组(N组)、糖尿病肾病组(D组)、Candesartan治疗组(DC组)。治疗8 wk后取肾组织,观察肾脏病理改变;半定量RT-PCR法检测各组肾皮质SGK1及结缔组织生长因子(CTGF)mRNA的表达;W estern b lot检测各组肾皮质中SGK1及CTGF蛋白的表达。结果与N组相比,D组小鼠肾重/体重、24 h尿蛋白量,肾小球滤过率均明显增加;肾皮质中SGK1、CTGF mRNA及蛋白质的表达均明显升高。经Candesartan干预后(DC组),相应生化指标较D组有明显改善,SGK1、CTGF的表达水平较D组亦有明显下调。纤维化指标CTGF的表达与SGK1呈正相关。结论Candesartan可以延缓糖尿病肾病的肾脏纤维化过程,它对细胞内SGK1信号转导途径的抑制作用可能是其抗纤维化作用的主要环节,该作用与AngⅡ-AT1途径被阻断有关。

The effect and significance of candesartan on the SGK1 expression in murine diabetic nephropathy kidney

Aim To study the effect of angiotensinⅡtype 1 receptor antagonist candesartan on the expression of SGK1 in diabetic nephropathy kidney and evaluate the significance and feasibility for candesartan as an operative drug against diabetic nephropathy.Methods STZ-induced diabetic mice were used in this study.Normal C57 BL/6 mice were randomly divided into three groups(normal control,diabetic nephropathy and candesartan treated) each of which has 12 mice.Pathologic changes of the kidneys were observed,and expression of SGK1 and CTGF was examined by semi-quantified RT-PCR and Western blot at mRNA level and protein level respectively after 8 weeks of treatment.Results In comparison with normal control group,weight of kidneys,quantity of 24 h urine protein,GFR(glomerular filtration rate) had significantly higher,and mRNA expression of SGK1 and CTGF was also raised in the diabetic nephropathy group.All the biochemical values were ameliorated with treatment of candesartan.Expression of SGK1 and CTGF was also reduced in candesartan treated group.There was a positive co-relationship between expression of SGK1 and CTGF.Conclusion Candesartan can exert the effect of anti-fibrosis in the kidney of diabetic nephropathy and can postpone its spontaneous fibrosis process.This effect,at least partially,was mediated by weakening the intracellular SGK1 signaling cascades.The role may be associated with the inhibition of AngⅡ-AT1 pathway.