Blasi Eileen R, Rocha Ricardo, Rudolph Amy E, Blomme Eric A G, Polly Melissa L, McMahon Ellen G
Pharmacia Corporation, Cardiovascular and Metabolic Diseases, Global Medical Affairs, and Global Toxicology, St. Louis, Missouri 63167, USA.
Kidney Int. 2003 May;63(5):1791-800. doi: 10.1046/j.1523-1755.2003.00929.x.
We evaluated the role of aldosterone as a mediator of renal inflammation and fibrosis in a rat model of aldosterone/salt hypertension using the selective aldosterone blocker, eplerenone.
Unnephrectomized, Sprague-Dawley rats were given 1% NaCl (salt) to drink and randomized to receive treatment for 28 days: vehicle infusion (control); 0.75 microg/hour aldosterone subcutaneous infusion; or aldosterone infusion + 100 mg/kg/day oral dose of eplerenone. Blood pressure and urinary albumin were measured and kidneys were evaluated histologically. Renal injury, inflammation, and fibrosis were assessed by immunohistochemistry, in situ hybridization, and reverse transcription-polymerase chain reaction (RT-PCR).
Aldosterone/salt induced severe hypertension compared to controls (220 +/- 4 mm Hg vs. 131 +/- 4 mm Hg, P < 0.05), which was partially attenuated by eplerenone (179 +/- 4 mm Hg, P < 0.05). In aldosterone/salt treated rats, renal histopathologic evaluation revealed severe vascular and glomerular sclerosis, fibrinoid necrosis and thrombosis, interstitial leukocyte infiltration, and tubular damage and regeneration. Aldosterone/salt increased circulating osteopontin (925.0 +/- 80.2 ng/mL vs. 53.6 +/- 6.3 ng/mL) and albuminuria (75.8 +/- 10.9 mg/24 hours vs. 13.2 +/- 3.0 mg/24 hours) compared to controls and increased expression of proinflammatory molecules. Treatment with eplerenone reduced systemic osteopontin (58.3 +/- 4.2 ng/mL), albuminuria (41.5 +/- 7.2 mg/24 hours), and proinflammatory gene expression: osteopontin (OPN), monocyte chemoattractant protein-1 (MCP-1), interleukin-6 (IL-6), and interleukin-1beta (IL-1beta).
These findings indicate that aldosterone/salt-induced renal injury and fibrosis has inflammatory components involving macrophage infiltration and cytokine up-regulation. Attenuation of renal damage and inflammation by eplerenone supports the protective effects of aldosterone blockade in hypertensive renal disease.
我们使用选择性醛固酮阻滞剂依普利酮，在醛固酮/盐性高血压大鼠模型中评估了醛固酮作为肾炎症和纤维化介质的作用。
对未切除肾脏的Sprague-Dawley大鼠给予1%氯化钠（盐）饮用，并随机分组接受28天的治疗：输注溶媒（对照组）；皮下输注0.75微克/小时醛固酮；或醛固酮输注+口服100毫克/千克/天依普利酮。测量血压和尿白蛋白，并对肾脏进行组织学评估。通过免疫组织化学、原位杂交和逆转录-聚合酶链反应（RT-PCR）评估肾损伤、炎症和纤维化。
与对照组相比，醛固酮/盐诱导了严重高血压（220±4毫米汞柱对131±4毫米汞柱，P<0.05），依普利酮使其部分减轻（179±4毫米汞柱，P<0.05）。在醛固酮/盐处理的大鼠中，肾脏组织病理学评估显示严重的血管和肾小球硬化、纤维蛋白样坏死和血栓形成、间质白细胞浸润以及肾小管损伤和再生。与对照组相比，醛固酮/盐增加了循环骨桥蛋白（925.0±80.2纳克/毫升对53.6±6.3纳克/毫升）和蛋白尿（75.8±10.9毫克/24小时对13.2±3.0毫克/24小时），并增加了促炎分子的表达。依普利酮治疗降低了全身骨桥蛋白（58.3±4.2纳克/毫升）、蛋白尿（41.5±7.2毫克/24小时）以及促炎基因表达：骨桥蛋白（OPN）、单核细胞趋化蛋白-1（MCP-1）、白细胞介素-6（IL-6）和白细胞介素-1β（IL-1β）。
这些发现表明，醛固酮/盐诱导的肾损伤和纤维化具有涉及巨噬细胞浸润和细胞因子上调的炎症成分。依普利酮减轻肾损伤和炎症支持了醛固酮阻断在高血压肾病中的保护作用。
