Endothelin-1 increases glomerular permeability and inflammation independent of blood pressure in the rat.
Endothelin-1 increases glomerular permeability and inflammation independent of blood pressure in the rat.
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DOI：
10.1161/hypertensionaha.110.156570
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发表时间：
2010-11
期刊：
影响因子：
--
通讯作者：
Pollock DM
中科院分区：
文献类型：
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作者：
Saleh MA;Boesen EI;Pollock JS;Savin VJ;Pollock DM
内皮素-1（ET-1）是一种强有力的血管活性肽，参与高血压和肾脏疾病的发病机制。目前的研究的目的是测试的假设，ET-1增加白蛋白渗透性肾小球分离正常大鼠和慢性ET-1输液将增加肾小球通透性和炎症独立的血压。肾小球对白蛋白的渗透性（Palb）通过将分离的肾小球暴露于onglucose梯度诱导的肾小球体积变化来确定。用不产生直接肾小球收缩的浓度（1 nM）的ET-1孵育取自正常大鼠的肾小球显著增加Palb，4小时后达到最大值。在Sprague-Dawley大鼠中长期输注ET-1 2周可显著增加Palb和nephrin排泄率;在给予ETA受体拮抗剂（ABT-627，5 mg/kg/天）的大鼠中，该效应减弱。尿蛋白和白蛋白排泄和平均动脉压（遥测）没有改变ET-1输注。从ET-1输注大鼠中分离的肾小球与选择性ETA拮抗剂的急性孵育显著降低了Palb;与选择性ETB拮抗剂的急性治疗未观察到这种效应。慢性ET-1输注增加肾小球和血浆sICAM-1（可溶性细胞间粘附分子-1）和MCP-1（单核细胞趋化蛋白-1），并增加肾皮质中巨噬细胞和淋巴细胞的数量（分别为艾德-1和CD 3阳性染色）。在给予ETA选择性拮抗剂的大鼠中，这些作用均减弱。这些数据支持ET-1通过ETA受体激活直接增加肾小球对白蛋白的通透性和肾脏炎症的假设，而不依赖于动脉压的变化。
Endothelin-1 (ET-1) is a potent vasoactive peptide implicated in the pathogenesis of hypertension and renal disease. The aim of the current study was to test the hypotheses that ET-1 increases albumin permeability of glomeruli isolated from normal rats and that chronic ET-1 infusion will increase glomerular permeability and inflammation independent of blood pressure. Glomerular permeability to albumin (Palb) was determined from the change in glomerular volume induced by exposing isolated glomeruli to oncotic gradients. Incubation of glomeruli taken from normal rats with ET-1 at a concentration that did not produce direct glomerular contraction (1 nM) significantly increased Palb, reaching a maximum after 4 hrs. Chronic ET-1 infusion for 2 weeks in Sprague-Dawley rats significantly increased Palb and nephrin excretion rate; effects that were attenuated in rats given an ETA receptor antagonist (ABT-627, 5 mg/kg/day). Urinary protein and albumin excretion and mean arterial pressure (telemetry) were not changed by ET-1 infusion. Acute incubation of glomeruli isolated from ET-1-infused rats with the selective ETA antagonist significantly reduced Palb; an effect not observed with acute treatment with a selective ETB antagonist. Chronic ET-1 infusion increased glomerular and plasma sICAM-1 (soluble inter-cellular adhesion molecule-1) and MCP-1 (monocyte chemoattractant protein-1) and elevated the number of macrophages and lymphocytes in renal cortices (ED-1 and CD3 positive staining, respectively). These effects were all attenuated in rats given an ETA selective antagonist. These data support the hypothesis that ET-1 directly increases glomerular permeability to albumin and renal inflammation via ETA receptor activation independent of changes in arterial pressure.