Division of Kidney Disease and Hypertension, Rhode Island Hospital, The Warren Alpert School of Medicine at Brown University, Providence, RI, USA.
Steroids. 2013 Mar;78(3):347-55. doi: 10.1016/j.steroids.2012.12.007. Epub 2012 Dec 31.
Aldosterone induces fibrotic changes in cardiovascular tissues but its effects have usually been demonstrated in models of pre-existing renal injury and/or hypertension. This study tests the hypothesis that aldosterone can directly induce vascular fibrotic changes in the absence of prior renal injury or hypertension. Experiments were conducted in intact or adrenalectomized (ADX) mice. Mice were divided into groups and treated for 1 week with vehicle or aldosterone (8 μg/kg/day)± inhibitor (800 μg/kg/day): CONTROLS, mice treated with aldosterone, ADX-CONTROLS, ADX+corticosterone (CORT 8 μg/kg/day), ADX with aldosterone, ADX with aldosterone plus the mineralocorticoid receptor (MR) antagonist RU-318, ADX with aldosterone+CORT (CORT inhibitor dose), and ADX with aldosterone+11-dehydro-CORT. Aortic smooth muscle to collagen ratio, aorta intimal thickness (μm), heart weight/body weight ratio (mg/gm), and left ventricular collagen (%) were measured. Prior to sacrifice, blood pressures were normal in all animals. Lower dose CORT alone had no effect on any of the variables examined. Aldosterone exposure was associated with extra-cellular matrix accumulation in cardiovascular tissues in intact mice and adrenalectomy exacerbated these effects. RU-318, CORT (inhibitor dose), and 11-deydro-CORT each attenuated the early fibrotic changes induced by aldosterone. In the heart, aldosterone exposure affected all the parameters measured and caused intimal hypercellularity with monocytes adhering to endothelial cells lining coronary vessels. Cultured endothelial cells exposed to aldosterone (10nM) released E-selectin, produced collagen, and promoted monocyte adhesion. These effects were inhibited by RU-318 and 11-deydro-CORT but not by CORT. Thus, adrenalectomy enhances aldosterone induced early fibrotic changes in heart and aorta. Aldosterone initially targets vascular endothelial cells. MR antagonists and 11-dehydro-CORT, an 11β-HSD dehydrogenase end-product, directly attenuate these effects.
醛固酮可诱导心血管组织的纤维化改变，但它的作用通常在预先存在的肾损伤和/或高血压的模型中得到证实。本研究检验了醛固酮在没有预先的肾损伤或高血压的情况下是否可以直接诱导血管纤维化改变的假设。实验在完整或肾上腺切除（ADX）的小鼠中进行。将小鼠分为几组，用载体或醛固酮（8μg/kg/天）±抑制剂（800μg/kg/天）处理 1 周：对照组，用醛固酮处理的小鼠；ADX-对照组，ADX+皮质酮（CORT 8μg/kg/天）；ADX 用醛固酮，ADX 用醛固酮加盐皮质激素受体（MR）拮抗剂 RU-318，ADX 用醛固酮+CORT（皮质酮抑制剂剂量），ADX 用醛固酮+11-脱氢皮质酮。测量主动脉平滑肌与胶原的比例、主动脉内膜厚度（μm）、心脏重量/体重比（mg/gm）和左心室胶原（%）。在牺牲之前，所有动物的血压均正常。单独使用低剂量 CORT 对检查的任何变量均无影响。醛固酮暴露与完整小鼠心血管组织中细胞外基质的积累有关，而肾上腺切除术加剧了这些影响。RU-318、CORT（抑制剂剂量）和 11-脱氢皮质酮均可减轻醛固酮诱导的早期纤维化改变。在心脏中，醛固酮暴露影响了所有测量的参数，并导致内皮细胞 lining 冠状血管的单核细胞黏附在内膜上的内膜增生。暴露于醛固酮（10nM）的培养内皮细胞释放 E-选择素，产生胶原，并促进单核细胞黏附。这些作用被 RU-318 和 11-脱氢皮质酮抑制，但不受 CORT 抑制。因此，肾上腺切除术增强了心脏和主动脉中醛固酮诱导的早期纤维化改变。醛固酮最初作用于血管内皮细胞。MR 拮抗剂和 11-脱氢皮质酮，一种 11β-HSD 脱氢酶的终产物，直接减弱这些作用。
