Chade Alejandro R, Best Patricia J, Rodriguez-Porcel Martin, Herrmann Joerg, Zhu Xiangyang, Sawamura Tatsuya, Napoli Claudio, Lerman Amir, Lerman Lilach O
Department of Internal Medicine, Division of Hypertension, Mayo Clinic, Rochester, Minnesota, USA.
Kidney Int. 2003 Sep;64(3):962-9. doi: 10.1046/j.1523-1755.2003.00170.x.
The potent vasoconstrictor endothelin-1 is involved in regulation of renal function, and is up-regulated in hypercholesterolemia (HC), a risk factor for renal disease that increases oxidative stress and impairs renal hemodynamic responses. However, the involvement of endothelin (ET) in this disease process is yet unknown.
Regional renal hemodynamics and function in vivo were quantified in pigs at baseline and during infusion of acetylcholine using electron beam computed tomography after a 12-week normal diet (N = 6), HC diet (N = 6), and HC diet orally supplemented (4 mg/kg/day) with the selective ET receptor-A (ET-A) blocker ABT-627 (HC+ET-A, N = 6). Plasma levels of 8-epi-PGF2-alpha-isoprostanes, markers of oxidative stress, were measured using enzyme immunoassay, and renal tissue was studied ex vivo using Western blotting, electrophoretic mobility shift assay, and immunohistochemistry.
Total and low-density lipoprotein (LDL) cholesterol were similarly increased, but isoprostanes were decreased in HC+ET-A compared to HC alone. Basal renal perfusion was similar among the groups, while glomerular filtration rate (GFR) increased in HC+ET-A compared to HC. Stimulated perfusion and GFR were blunted in HC, but normalized in HC+ET-A. Moreover, ET blockade increased expression of endothelial nitric oxide synthase, and decreased endothelial expression of the oxidized-LDL receptor LOX-1, as well as tubular immunoreactivity of inducible nitric oxide synthase, nitrotyrosine, nuclear factor-kappaB, transforming growth factor-beta, and tubulointerstitial and perivascular trichrome staining.
ET-A blockade improves renal hemodynamic and function in HC, and decreases oxidative stress, and renal vascular and tubulointerstitial inflammation and fibrosis. These findings support a role for the endogenous ET system in renal injury in HC and atherosclerosis.
强效血管收缩剂内皮素 -1参与肾功能调节，在高胆固醇血症（HC）中上调，HC是肾脏疾病的危险因素，可增加氧化应激并损害肾血流动力学反应。然而，内皮素（ET）在该疾病过程中的作用尚不清楚。
对12周正常饮食（N = 6）、HC饮食（N = 6）以及口服补充选择性ET受体 -A（ET -A）阻滞剂ABT -627（HC + ET -A，N = 6）的猪，在基线时和输注乙酰胆碱期间，使用电子束计算机断层扫描对局部肾血流动力学和体内功能进行定量。使用酶免疫测定法测量氧化应激标志物8-表 -前列腺素F2α -异前列腺素的血浆水平，并使用蛋白质印迹法、电泳迁移率变动分析和免疫组织化学对肾组织进行离体研究。
与单独的HC相比，HC + ET -A中的总胆固醇和低密度脂蛋白（LDL）胆固醇同样升高，但异前列腺素减少。各组间基础肾灌注相似，而与HC相比，HC + ET -A中的肾小球滤过率（GFR）增加。HC中刺激后的灌注和GFR减弱，但在HC + ET -A中恢复正常。此外，ET阻断增加了内皮型一氧化氮合酶的表达，并降低了氧化型LDL受体LOX -1的内皮表达，以及诱导型一氧化氮合酶、硝基酪氨酸、核因子 -κB、转化生长因子 -β的肾小管免疫反应性，以及肾小管间质和血管周围三色染色。
ET -A阻断可改善HC中的肾血流动力学和功能，并降低氧化应激以及肾血管和肾小管间质炎症及纤维化。这些发现支持内源性ET系统在HC和动脉粥样硬化肾损伤中的作用。
