Le Menuet D, Isnard R, Bichara M, Viengchareun S, Muffat-Joly M, Walker F, Zennaro M C, Lombès M
INSERM U478, Faculté de Médecine Xavier Bichat, 75018 Paris, Service de cardiologie, Institut Féderatif de Recherche 14, Centre hospitalier Universitaire Pitié-Salpetrière, 75013 Paris, France.
J Biol Chem. 2001 Oct 19;276(42):38911-20. doi: 10.1074/jbc.M103984200. Epub 2001 Aug 8.
The mineralocorticoid receptor (MR), a ligand-dependent transcription factor, mediates aldosterone actions in a large variety of tissues. To explore the functional implication of MR in pathophysiology, transgenic mouse models were generated using the proximal human MR (hMR) promoter to drive expression of hMR in aldosterone target tissues. Tissue-specific analysis of transgene expression in two independent transgenic animal (TG) lines by ribonuclease protection assays revealed that hMR is expressed in all mineralocorticoid-sensitive tissues, most notably in the kidney and the heart. TG exhibit both renal and cardiac abnormalities. Enlarged kidneys were histologically associated with renal tubular dilation and cellular vacuolization whose prevalence increased with aging. Renal clearance studies also disclosed a significant decrease in urinary potassium excretion rate in TG. hMR-expressing animals had normal blood pressure but developed mild dilated cardiomyopathy (increased left ventricle diameters and decreased shortening fraction), which was accompanied by a significant increase in heart rate. Differential gene expression analysis revealed a 2- to 5-fold increase in cardiac expression of atrial natriuretic peptide, serum- and glucocorticoid-induced kinase, and early growth response gene 1 as detected by microarrays; renal serum- and glucocorticoid-induced kinase was also induced significantly. Altogether, TG exhibited specific alteration of renal and cardiac functions, thus providing useful pathophysiological models to gain new insights into the tissue-specific mineralocorticoid signaling pathways.
盐皮质激素受体（MR）是一种依赖配体的转录因子，介导醛固酮在多种组织中的作用。为了探究MR在病理生理学中的功能意义，利用人MR（hMR）近端启动子构建转基因小鼠模型，以驱动hMR在醛固酮靶组织中的表达。通过核糖核酸酶保护试验对两个独立转基因动物（TG）品系中的转基因表达进行组织特异性分析，结果显示hMR在所有盐皮质激素敏感组织中均有表达，最显著的是在肾脏和心脏中。TG表现出肾脏和心脏异常。组织学检查发现，肾脏增大与肾小管扩张和细胞空泡化有关，且其发生率随年龄增长而增加。肾脏清除率研究还表明，TG的尿钾排泄率显著降低。表达hMR的动物血压正常，但出现轻度扩张型心肌病（左心室直径增加，缩短分数降低），同时心率显著增加。差异基因表达分析显示，通过微阵列检测，心房利钠肽、血清和糖皮质激素诱导激酶以及早期生长反应基因1在心脏中的表达增加了2至5倍；肾脏中的血清和糖皮质激素诱导激酶也显著上调。总之，TG表现出肾脏和心脏功能的特异性改变，从而为深入了解组织特异性盐皮质激素信号通路提供了有用的病理生理模型。
