摘要
背景:糖尿病(Diabetes Mellitus,DM)是引起终末期肾衰(ESRF)的主要病因。而终末期肾病(ESRD)病人中心血管病疾死亡率大大增加,与非ESRD病人相比高出10～100倍。1980年,美国新开始的终末期肾病病人由糖尿病引起的为13.1%。2002年,这一比例达到43%～64%(由于种族不同),所有开始透析的有糖尿病(原发或继发)的病人达59%。而且大多数开始透析病人发现有高血压,年龄偏大。冠状动脉钙化在透析病人非常普遍。根据病人总体年龄检查,54%～100%(平均83%)的透析病人有不同程度的冠状动脉钙化,其钙化积分显著高于一般人群。终末期肾衰病人50%以上是死于心血管并发症病,而心血管并发症中多数伴随有血管钙化,血管钙化是预测心血管病发生和死亡的独立危险因素已被人们所公认。新近认为血管钙化与骨的形成过程有关,是由细胞介导的主动调节的过程,同时伴随有血管平滑肌细胞表型变化。骨转录因子-核心结合因子(core binding factor alpha 1,CBFA1)是成骨细胞(osteoblast,OB)早期分化的特异性标志,CBFA1可与骨钙素(osteocalcin,OC)基因的启动子区成骨细胞特异性的顺式作用元件(osteoblast-specific cis-acting element2,OSE2)结合,为OB分化所必需的。OC为骨组织中一种非胶原蛋白质,含三个是γ-羧基谷氨酸残基,又称骨Gla蛋白(bone Gla protein,BGP),是成骨细胞晚期分化的标志。体外细胞培养研究显示钙、磷对人及牛的血管平滑肌细胞有直接的影响,促进钙盐沉积和矿化。动物活体研究钙、磷对血管和肾脏钙化的资料较少,为此我们在高磷饮食基础上观察高钙对糖尿病肾病大鼠组织钙化的影响。
目的:通过建立糖尿病单侧肾切除大鼠模型,喂养高磷低钙或高
Diabetes Mellitus is the leading cause of end-stage renal failure (ESRF).The increasingly risk of cardiovascular disease (CVD) mortality in adult patients with ESRD is 10 to 100 times higher than that of the non-ESRD patients. 13.1% of newpatients to dialysis had diabetes as their cause of ESRD in 1980. In 2002, 43% to 64% of individuals (range because of differences in race/ethnicity) have diabetes as their cause of ESRD, and 59% of all patients beginning dialysis have diabetes as a primary or secondary diagnosis. Hyper -tension is found in the majority of individuals at the start of dialysis. The population is also older. Coronary artery calcifica -tion is very common in dialysis patients. Depending on the age of the patient population examined, 54% to 100% (mean 83%) of dialysis patients in case series have some degree of coronary artery calcification, with scores markedly above the general population. More than half the death in patients with ESRD are due to cardiovascular disease. Vascular calcification (VC) commonly seen with CVD is independent prognostic marker of CVD morbility and mortality in patients with ESRD. Vascular calcification is currently considered an cell-mediated and actively regulated process that like bone formation with phenotypic transition of vascular smooth muscle cells(VSMC). vascular smooth muscle cells in the process of mineralization undergo a phenotypic transition toward an osteogenic phenotype. Core binding factor alpha l(CBFAl) is an osteoblast-specific transcription factor required for osteoblast differentiation and earliest specific marker. Osteocalcin is noncollagen protein in bone tissue and advanced staged marker of mature osteoblast.It conteins three γ -carboxyglutantic acid residues.It is shown that elvated calcium or
phsphote directly affect on human or bovine VSMCs and promote mineralization in vitro.A little data about this present in vivo.Using experimental diabetic nephropathy modle rats by unique nephrectomized and STZ-induceded,this study compare high calcium diet and low calcium diet affecting on among mineral metabolism, vascular calcification and CBFA1. Non-diabetes sham operation rats serves as control groups. Experimental rars was classified to four groups:① DS (diabetes sham operation );②DS-HC (diabetes sham operation+high calcium ); ③ DUN (diabetes unilater nephrectomized );④DUN-HC (diabetes unilater nephrectomized + high calcium ); ⑤ NS (non-diabetes sham operation).Experimental rars underwent one of the foliowong treatments for 6 months:① or ③ was fed with high phosphate and low calcium. ②,④and⑤ was fed with high phosphate and high calcium.Appropriate blood,urine,and kidney tissue samples were taken at six months. CBFAl expression was investigated using immunohistochemistry and Western blotting at 6 months. Osterocalcin (BGP) was investigated by immunohistochemistry at 24 weeks, calcium , phosphate,renal function and parathyroid hormone was examined respectively. Calcium deposition of vessle and kidney tissue was investigated using Von Kossa staining. There was no statistic significance among blood sugar,body weight,kidney weight and urinary volume in groups of diabetic rats.There was significantly reduce compare NS groups with diabetic rats in blood sugar,body weight,kidney weight and urinary volume. DUN blood calcium was the lowest among the other groups and was significance compare with the othrs groups.DUN had higher parathyroid hormone level than the other groups's.There ware significantly difference between groups.the 24 hour urinary protein excretion in DUN was significantly higher than the
other groups. The immunohistochemistry expression level of CBFA1 or BGP in kidney and vascular tissue was higher in DUN than the other groups.There was no expression of CBFA1 and BGP in NS. high calcium intake decreases blood urea nitrogen and serum creatinine, suppresses plasma parathyroid hormone(PTH) and phosphate level, reduces vascularity and kidney calcification.The extent of calcium salte deposition is positive corelation to the expression of CBFAl or BGP and to the level of serum cretinine,PTH and 24 hour urinary protein, the expression of CBFAl or BGP is nigetive corelation to the serum calcium level. The precise mechanism of tissue calcification is to be further study.
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