Department of Nephrology and Endocrinology, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan.
Hypertension. 2010 Apr;55(4):813-8. doi: 10.1161/HYPERTENSIONAHA.109.149062. Epub 2010 Feb 22.
Obese persons with metabolic syndrome often have associated with salt-sensitive hypertension, microalbuminuria, and cardiac dysfunction, and the plasma aldosterone level in one-third of metabolic syndrome patients is clearly elevated. Hyperaldosteronism, which may be caused at least partially by certain adipocyte-derived factors, contributes to the development of proteinuria in obese hypertensive rats, and salt loading aggravates the proteinuria and induces cardiac diastolic dysfunction because of inadequate suppression of plasma aldosterone level. However, mineralocorticoid receptor (MR) antagonists prevent salt-induced renal and cardiac damage, suggesting that aldosterone excess and a high-salt diet exert an unfavorable synergistic action on the kidney and heart. In Dahl salt-sensitive rats, however, despite appropriate suppression of plasma aldosterone with a high-salt diet, salt loading paradoxically activated renal MR signaling, and the renal injury was markedly prevented by MR antagonists. Accordingly, we discovered an alternative pathway of MR activation in which Rac1, a small GTP-binding protein, activates MRs. Salt loading activates renal Rac1 in Dahl salt-sensitive rats, and Rac1 in turn induces MR activation, which results in renal injury, and the renal injury has been found to be prevented by Rac1 inhibitors. Moreover, several metabolic syndrome-related factors induce Rac1 activation, and one of them, hyperglycemia, activates MRs via Rac1 activation. Consistent with this, Rac1 inhibitors attenuated the proteinuria and renal injury in obese hypertensive animals. Thus, both salt and obesity activate Rac1 and cause MR activation. Abnormal activation of the aldosterone/MR pathway plays a key role in the development of salt-sensitive hypertension and renal injury in metabolic syndrome.
肥胖合并代谢综合征的患者常伴有盐敏感性高血压、微量白蛋白尿和心功能障碍，且三分之一的代谢综合征患者的血浆醛固酮水平明显升高。至少部分由某些脂肪细胞衍生因子引起的醛固酮增多症可导致肥胖高血压大鼠蛋白尿的发生，而盐负荷加重蛋白尿并引起舒张功能障碍，因为血浆醛固酮水平不能充分抑制。然而，盐皮质激素受体（MR）拮抗剂可预防盐诱导的肾和心脏损伤，这表明醛固酮过多和高盐饮食对肾脏和心脏产生不利的协同作用。然而，在 Dahl 盐敏感大鼠中，尽管高盐饮食可适当抑制血浆醛固酮，但盐负荷却反常地激活了肾 MR 信号，而 MR 拮抗剂可显著预防肾损伤。因此，我们发现了一种 MR 激活的替代途径，其中小 GTP 结合蛋白 Rac1 激活 MR。盐负荷激活 Dahl 盐敏感大鼠的肾 Rac1， Rac1 反过来诱导 MR 激活，导致肾损伤， Rac1 抑制剂可预防肾损伤。此外，几种代谢综合征相关因素可诱导 Rac1 激活，其中之一是高血糖，它通过 Rac1 激活来激活 MR。与此一致， Rac1 抑制剂可减轻肥胖高血压动物的蛋白尿和肾损伤。因此，盐和肥胖均可激活 Rac1 并导致 MR 激活。醛固酮/MR 通路的异常激活在代谢综合征的盐敏感性高血压和肾损伤的发生中起关键作用。
