FSH受体介导的肾素分泌增加及其在绝经后高血压发病中的机制研究

The increased incidence of hypertension in women after menopause is a worldwide medical problem. But the etiology and pathogenesis of postmenopausal hypertension (PMH) has not been fully understood. So it is difficult to prevent the incidence of PMH. Renin is an acid protease secreted by juxtaglomerular cells of kidney. The Renin-Angiotensin-Aldosterone system (RAAS) is essential to maintain a stable blood pressure. We found that FSH receptors (FSHR) were expressed in the juxtaglomerular cells in rat, and FSH promoted the secretion of rennin by these cells in vitro. This finding suggested that FSHR may regulate the synthesis or secretion of renin. As FSH secretion is regulated by estrogen negative feedback, a high circulating FSH level invariably accompanies hypogonadism. Thus FSH has been regarded as a symbolic marker for the onset of reproductive aging. However, it has never been testified whether FSH might directly stimulate the juxtaglomerular cells to secret more renin to cause hypertension other than hypogonadism. Our findings suggested that FSHR may regulate the synthesis or secretion of renin. Together with the risk of hypertension increasing in women after their menopause, we hypothesized that FSHR might be involved in the regulation of renin synthesis in the juxtaglomerular cells in kidney, and that the high circulating FSH level in women of reproductive aging might result in abnormal renin levels as they were tested in menopausal women. In the present project, we will test this possibility and associated mechanisms: (1) the association of serum levels of renin, blood pressure and the risk of hypertension or cardiovascular diseases with serum FSH level in women of reproductive aging; (2) the production of renin in juxtaglomerular cells of kidney and the relevant intracellular mechanism stimulated by serum FSH. Pathophysiologically, the research may give firm evidence that the hypertesion, even the cardiovascular diseases in menopause and postmenopause may be not only caused by hypogonadism that has been solely attributed to the decline of sex hormone levels, but also be resulted from elevated circulating FSH.

女性绝经后高血压发病的快速上升是世界范围内面临的重要医学难题，由于绝经后高血压的病因和发病机制不清，因此不能有效遏制绝经后高血压的快速发生。肾素是由肾脏球旁细胞合成/分泌的酸性蛋白酶，肾素-血管紧张素系统-醛固酮系统（RAAS）组成的血压调节机制是维持血压稳定的重要部分。我们的前期研究发现：大鼠肾脏球旁细胞上表达促卵泡激素（FSH）受体，FSH可以促进球旁细胞合成/分泌肾素。这提示围绝经期及绝经后妇女高水平的FSH，可能通过刺激肾脏球旁细胞分泌过多的肾素，导致RAAS血压调节失稳态，从而参与绝经后高血压的发生发展。本项目拟就该假说深入研究：临床评估生殖衰老女性FSH水平与肾素水平、高血压/心脑血管病的关联；细胞和动物模型研究FSH刺激球旁细胞合成和分泌肾素的作用及机制。揭示肾脏近球细胞上FSH受体介导的肾素分泌增加及其在绝经后高血压发病的机制，为相关疾病防治提供新的理论基础和可靠科学依据。