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目的研究葡萄子原花青素(GSPE)对糖尿病大鼠非酶糖基化终产物(AGEs)、肾组织结缔组织生长因子(CT-GF)及骨形态蛋白7(BMP-7)表达的影响。方法将45只链脲佐菌素(STZ)诱导的糖尿病大鼠模型随机分为糖尿病组(DM组,n=15只)、GSPE小剂量[250 mg/(kg.d)]治疗组(T1组,n=15只)和大剂量[500 mg/(kg.d)]治疗组(T2组,n=15只),另以15只正常大鼠作为对照组(C组),15只正常大鼠给予GSPE 250 mg/(kg.d)作为正常治疗组(CT组)。于24周末检测各组大鼠血糖、血清AGEs、血压2、4 h尿蛋白定量、血肌酐(Scr)、尿肌酐(Ucr)、肾重/体重水平。以光镜PAS染色及电镜观察肾脏病理改变。用RT-PCR、Western blot方法及免疫组化方法检测肾组织中CTGF、BMP-7mRNA及蛋白表达水平的改变。结果与C组相比,DM组血清AGEs、血压2、4 h尿蛋白定量、内生肌酐清除率(Ccr)、肾重/体重均显著升高(P<0.01),肾病理改变加重,肾组织CTGF mRNA及蛋白表达增加(P<0.01),而BMP-7mRNA及蛋白降低(P<0.05)。与DM组相比,T1组和T2组血清AGEs、血压、24 h尿蛋白定量、Ccr和肾重/体重显著降低(P<0.05或P<0.01),病理改变减轻,BMP-7mRNA及蛋白表达水平升高(P<0.05或P<0.01),而CTGF mRNA及蛋白显著降低(P<0.01)。T1组与T2组之间相比,Ccr、肾重/体重水平、CTGF mRNA及蛋白差异有统计学意义(P<0.05或P<0.01)。结论GSPE可以减轻糖尿病大鼠蛋白尿、改善肾脏病理,对其肾脏有明显保护作用,其机制与降低血清AGEs、抑制肾组织CTGF过高表达、上调BMP-7表达有关。
Objective To investigate the effects of grape seed proanthocyanidins (GSPE) on the expression of non-enzymatic glycated end products (AGEs), connective tissue growth factor (CT-GF) and bone morphogenetic protein 7 (BMP-7) in diabetic rats. Methods Forty-five diabetic rats induced by streptozotocin (STZ) were randomly divided into diabetic group (DM group, n = 15) and GSPE low dose [250 mg / (kg · d) (N = 15) and high-dose [500 mg / (kg.d)] treatment group (n = 15 in group T2), and 15 normal rats as control group (group C) Rats were given GSPE 250 mg / (kg.d) as a normal control group (CT group). Blood glucose, serum AGEs, urinary protein, 2,4 urinary protein, serum creatinine (Scr), urinary creatinine (Ucr) and renal weight / body weight were detected at the end of 24th week in each group. PAS staining and electron microscopy were used to observe the renal pathological changes. The expression of CTGF, BMP-7 mRNA and protein in renal tissue was detected by RT-PCR, Western blot and immunohistochemistry. Results Compared with group C, the levels of serum AGEs, urinary protein, 2,4 c urinary protein, Ccr and renal weight / body weight in DM group were significantly increased (P <0.01) Tissue CTGF mRNA and protein expression increased (P <0.01), while BMP-7 mRNA and protein decreased (P <0.05). Compared with DM group, serum AGEs, blood pressure, 24 h urinary protein, Ccr and renal weight / body weight were significantly decreased (P <0.05 or P <0.01), pathological changes were alleviated, BMP-7 mRNA and protein expression (P <0.05 or P <0.01), while CTGF mRNA and protein were significantly decreased (P <0.01). There were significant differences in Ccr, renal weight / body weight, CTGF mRNA and protein between T1 group and T2 group (P <0.05 or P <0.01). Conclusion GSPE can reduce proteinuria in diabetic rats and improve renal pathology, and has a significant protective effect on the kidneys. The mechanism is related to the reduction of serum AGEs, the over-expression of CTGF in renal tissues and the up-regulation of BMP-7 expression.