Aldosterone antagonism or synthase inhibition reduces end-organ damage induced by treatment with angiotensin and high salt.
Aldosterone antagonism or synthase inhibition reduces end-organ damage induced by treatment with angiotensin and high salt.
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DOI：
10.1038/ki.2009.9
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发表时间：
2009-05
影响因子：
19.6
通讯作者：
Brown NJ
中科院分区：
文献类型：
--
作者：
Lea WB;Kwak ES;Luther JM;Fowler SM;Wang Z;Ma J;Fogo AB;Brown NJ
在高盐摄入的情况下，醛固酮刺激大鼠心脏、大血管和肾脏的纤维化。我们使用未切除肾的大鼠，用血管紧张素II治疗，并给予高盐饮食，以加重肾纤维化。然后，我们测试了通过螺内酯阻断矿皮质激素受体或FAD286抑制醛固酮合成酶是否对终末器官损伤和基因表达有相似的影响。单独来说，这两种药物都能预防非肾切除术和高盐摄入引起的高血压反应，但当给予血管紧张素II时则不能。FAD286治疗4周后，血浆醛固酮降低，而螺内酯治疗8周时，血浆醛固酮升高。血管紧张素II和高盐处理导致蛋白尿、氮血症、肾血管肥大、肾小球损伤、纤溶酶原激活物抑制剂-1 （PAI-1）和骨桥蛋白mRNA表达增加，以及肾小管间质纤维化。这两种药物都能预防这些肾脏影响，减轻心脏和主动脉内侧肥厚，同时降低主动脉中骨桥蛋白和转化生长因子-β mRNA的表达。这两种药物也减少了心脏间质纤维化，但对血管周围区域没有影响。虽然螺内酯增强血管紧张素II和盐刺激主动脉和心脏PAI-1 mRNA的表达，但螺内酯和FAD286抑制肾脏PAI-1 mRNA的表达。我们的研究表明，矿化皮质激素受体拮抗和醛固酮合成酶抑制同样可以减少血管紧张素II和高盐引起的肾脏和心脏肥大和间质纤维化。
In the setting of high salt intake, aldosterone stimulates fibrosis in the heart, great vessels, and kidney of rats. We used uninephrectomized rats treated with angiotensin II and placed on a high salt diet to exaggerate renal fibrosis. We then tested whether mineralocorticoid receptor blockade by spironolactone or aldosterone synthase inhibition by FAD286 have similar effects on end-organ damage and gene expression. Individually, both drugs prevented the hypertensive response to uninephrectomy and high salt intake but not when angiotensin II was administered. Following 4 weeks of treatment with FAD286, plasma aldosterone was reduced, whereas spironolactone increased aldosterone at 8 weeks of treatment. Angiotensin II and high salt treatment caused albuminuria, azotemia, renovascular hypertrophy, glomerular injury, increased plasminogen activator inhibitor-1 (PAI-1), and osteopontin mRNA expression, as well as tubulointerstitial fibrosis in the kidney. Both drugs prevented these renal effects and attenuated cardiac and aortic medial hypertrophy while reducing osteopontin and transforming growth factor-β mRNA expression in the aorta. The two drugs also reduced cardiac interstitial fibrosis but had no effect on that of the perivascular region. Although spironolactone enhanced angiotensin II and salt-stimulated PAI-1 mRNA expression in aorta and heart, spironolactone and FAD286 prevented renal PAI-1 mRNA protein expression. Our study shows that mineralocorticoid receptor antagonism and aldosterone synthase inhibition similarly decrease hypertrophy and interstitial fibrosis of the kidney and heart caused by angiotensin II and high salt.
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