The vascular ectonucleotidase ENTPD1 is a novel renoprotective factor in diabetic nephropathy
The vascular ectonucleotidase ENTPD1 is a novel renoprotective factor in diabetic nephropathy
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DOI：
10.2337/db06-1593
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发表时间：
2007-09-01
期刊：
影响因子：
7.7
通讯作者：
Robson, Simon C.
中科院分区：
文献类型：
--
作者：
Friedman, David J.;Rennke, Helmut G.;Robson, Simon C.
外核苷酸三磷酸二磷酸水解酶1（ENTPD 1）（也称为CD 39）是主要的血管外核苷酸酶。通过将ATP和ADP水解为AMP，ENTPD 1调节P2（嘌呤能）受体大家族的配体可用性。细胞外核苷酸代谢的调节是几种急性和亚急性血管损伤模型中的重要因素。我们假设异常的核苷酸信号传导会促进糖尿病肾病的慢性肾小球损伤。与匹配的糖尿病野生型小鼠相比，用链脲佐菌素诱导ENTPD 1基因缺失小鼠糖尿病导致蛋白尿增加，肾小球硬化更严重。糖尿病ENTPD 1基因敲除小鼠的肾小球纤维蛋白沉积和肾小球纤溶酶原激活物抑制剂-1（派-1）染色也比野生型对照组多。此外，ENTPD 1基因敲除小鼠肾小球炎症增加，与较高水平的单核细胞趋化蛋白-1（MCP-1）表达相关。ATP和UTP可上调系膜细胞派-1和MCP-1 mRNA的表达，而ADP和腺苷则无此作用。稳定的核苷酸类似物ATP γ S在体外刺激派-1和MCP-1的持续表达，而稳定的腺苷类似物NECA [5 '-（N-乙基甲酰胺基）腺苷]下调这两个基因的表达。细胞外核苷酸刺激的MCP-1上调至少部分依赖于蛋白激酶C。我们的结论是ENTPD 1是糖尿病肾病的血管保护因子，调节肾小球炎症和血栓调节。
Ectonucleoside triphosphate diphosphohydrolase 1 (ENTPD1) (also known as CD39) is the dominant vascular ectonucleotidase. By hydrolyzing ATP and ADP to AMP, ENTPD1 regulates ligand availability to a large family of P2 (purinergic) receptors. Modulation of extracellular nucleotide metabolism is an important factor in several acute and subacute models of vascular injury. We hypothesized that aberrant nucleotide signaling would promote chronic glomerular injury in diabetic nephropathy. Inducing diabetes in ENTPD1-null mice with streptozotocin resulted in increased proteinuria, and more severe glomerular sclerosis compared with matched diabetic wild-type mice. Diabetic ENTPD1-null mice also had more glomerular fibrin deposition and glomerular plasminogen activator inhibitor-1 (PAI-1) staining than wild-type controls. In addition, ENTPD1-null mice showed increased glomerular inflammation, in association with higher levels of monocyte chemoattractant protein-1 (MCP-1) expression. Mesangial cell PAI-1 and MCP-l mRNA expression were upregulated by ATP and UTP but not ADP or adenosine in vitro. The stable nucleotide analog ATP gamma S stimulated sustained expression of PAI-1 and MCP-1 in vitro, whereas the stable adenosine analog NECA [5'-(N-ethylcarboxamido)adenosine] downregulated expression of both genes. Extracellular nucleotide-stimulated upregulation of MCP-1 is, at least in part, protein kinase C dependent. We conclude that ENTPD1 is a vascular protective factor in diabetic nephropathy that modulates glomerular inflammation and thromboregulation.