Discoidin domain receptor 1 null mice are protected against hypertension-induced renal disease
Discoidin domain receptor 1 null mice are protected against hypertension-induced renal disease
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DOI：
10.1681/asn.2006060677
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发表时间：
2006-12-01
影响因子：
13.6
通讯作者：
Dussaule, Jean-Claude
中科院分区：
文献类型：
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作者：
Flamant, Martin;Placier, Sandrine;Dussaule, Jean-Claude
高血压的常见并发症是慢性肾衰竭的发展。这种病理学通常由炎症事件引发，其特征在于肾组织内胶原蛋白的异常积累。本研究的目的是探讨盘状结构域受体1（DDR1），一种非整合素胶原受体，显示酪氨酸激酶活性，在肾纤维化的发展中的作用。为此，在DDR1基因缺陷的小鼠和野生型对照小鼠中用血管紧张素诱导高血压。在给予血管紧张素II 4或6周后，野生型小鼠发生了与血管周围炎症、肾小球硬化和蛋白尿相关的高血压。DDR1缺陷小鼠的收缩压升高相似，但肾小球纤维化和炎症的组织学病变显著减弱，蛋白尿明显预防。淋巴细胞，巨噬细胞，胶原蛋白I和IV的免疫染色是突出的野生型小鼠的肾皮质，但在DDR1裸小鼠大幅减少。在单独的实验中，DDR1敲除小鼠的肾皮质切片显示趋化因子对LPS的钝化反应，伴随着对LPS诱导的死亡的相当大的保护。这些结果表明DDR1在介导炎症和纤维化中的重要性。DDR1抑制剂的使用可以提供一种针对具有这些组合病理的疾病的全新治疗方法。
A frequent complication of hypertension is the development of chronic renal failure. This pathology usually is initiated by inflammatory events and is characterized by the abnormal accumulation of collagens within the renal tissue. The purpose of this study was to investigate the role of discoidin domain receptor 1 (DDR1), a nonintegrin collagen receptor that displays tyrosine-kinase activity, in the development of renal fibrosis. To this end, hypertension was induced with angiotensin in mice that were genetically deficient of DDR1 and in wild-type controls. After 4 or 6 wk of angiotensin II administration, wild-type mice developed hypertension that was associated with perivascular inflammation, glomerular sclerosis, and proteinuria. Systolic pressure increase was similar in the DDR1-deficient mice, but the histologic lesions of glomerular fibrosis and inflammation were significantly blunted and proteirturia was markedly prevented. Immunostaining for lymphocytes, macrophages, and collagens I and IV was prominent in the renal cortex of wild-type mice but substantially reduced in DDR1 null mice. In separate experiments, renal cortical slices of DDR1 null mice showed a blunted response of chemokines to LPS that was accompanied by a considerable protection against the LPS-induced mortality. These results indicate the importance of DDR1 in mediating inflammation and fibrosis. Use of DDR1 inhibitors could provide a completely novel therapeutic approach against diseases that have these combined pathologies.