Carnosine as a protective factor in diabetic nephropathy - Association with a leucine repeat of the carnosinase gene CNDP1
Carnosine as a protective factor in diabetic nephropathy - Association with a leucine repeat of the carnosinase gene CNDP1
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DOI：
10.2337/diabetes.54.8.2320
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发表时间：
2005-08-01
期刊：
影响因子：
7.7
通讯作者：
van der Woude, FJ
中科院分区：
文献类型：
--
作者：
Janssen, B;Hohenadel, D;van der Woude, FJ
糖尿病肾病的风险部分由遗传决定。糖尿病肾病与染色体18q22.3-q23上的基因位点有关。我们的目的是确定18号染色体上的致病基因，并研究该基因的产物可能参与糖尿病肾病的发生机制。对135例糖尿病肾病患者和107例正常对照者进行了DNA多态性检测。分别在培养的人足细胞和系膜细胞中研究了肌肽对暴露于5和25 mmol/l D-葡萄糖后细胞外基质组分和转化生长因子-β（TGF-β）产生的影响。CNDP 1基因外显子2中的三核苷酸重复序列（编码肌肽酶-1前体前导肽中的亮氨酸重复序列）与肾病相关。最短等位基因形式（CNDP 1曼海姆）在无肾病的患者中更常见（P = 0.0028，比值比2.56 [95% CI 1.36-4.84]），并与较低的血清肌肽酶水平相关。肌肽抑制足细胞中纤维连接蛋白和VI型胶原的增加的产生以及由25 mmol/l葡萄糖诱导的肾小球系膜细胞中TGF-β的增加的产生。具有CNDP 1曼海姆变体的糖尿病患者对肾病的易感性较低。肌肽可防止高葡萄糖水平对肾细胞的不利影响。
The risk of diabetic nephropathy is partially genetically determined. Diabetic nephropathy is linked to a gene locus on chromosome 18q22.3-q23. We aimed to identify the causative gene on chromosome 18 and to study the mechanism by which the product of this gene could be involved in the development of diabetic nephropathy. DNA polymorphisms were determined in 135 case (diabetic nephropathy) and 107 control (diabetes without nephropathy) subjects. The effect of carnosine on the production of extracellular matrix components and transforming growth factor-beta (TGF-beta) after exposure to 5 and 25 mmol/l D-glucose was studied in cultured human podocytes and mesangial cells, respectively. A trinucleotide repeat in exon 2 of the CNDP1 gene, coding for a leucine repeat in the leader peptide of the carnosinase-1 precursor, was associated with nephropathy. The shortest allelic form (CNDP1 Mannheim) was more common in the absence of nephropathy (P = 0.0028, odds ratio 2.56 [95% CI 1.36-4.84]) and was associated with lower serum carnosinase levels. Car- nosine inhibited the increased production of fibronectin and collagen type VI in podocytes and the increased production of TGF-beta in mesangial cells induced by 25 mmol/l glucose. Diabetic patients with the CNDP1 Mannheim variant are less susceptible for nephropathy. Carnosine protects against the adverse effects of high glucose levels on renal cells.