Molecular and Clinical Study of Renal Angiotensin and Adrenomedullin Systems

肾血管紧张素和肾上腺髓质素系统的分子和临床研究

基本信息

批准号：
09671049
负责人：
MUKOYAMA Masashi
金额：
$ 1.86万
依托单位：
KYOTO UNIVERSITY
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
1997
资助国家：
日本
起止时间：
1997 至 1998
项目状态：
已结题

项目摘要

Cardiovascular hormones may be implicated in various renal and cardiovascular disorders such as chronic renal failure, glomerulonephritis, and hypertension. To explore their roles, we studied the renal renin-angiotensin system (RAS), adrenomedullin (AM) system, and natriuretic peptide system (NPS) using experimental disease models.Angiotensin II type 2 (AT_2) receptor is abundantly expressed in the fetus and markedly down-regulated after birth, but reexpressed in various disease states. In cultured rat mesangial cells (MC), the AT_2 receptor was markedly induced upon confluence and exerted antiproliferative and proapoptotic effects counteracting the AT_1 receptor, and inhibited the MAP kinase cascade. Lower expression of the AT_2 receptor in glomeruli at the younger period from spontaneously hypertensive rats (SHRSP) as well as in MC of SHRSP with highly proliferative nature, suggested its implication in pathogenesis of glomerular injury and hypertension.To clarify a role of AM as a lo … More cal regulator, we examined its secretion and action in cultured mesangial and endothelial cells (EC) using a monoclonal antibody (MAb) prepared against AM.We found secretion of AM, with a potent antigrowth property, from cultured MC as abundantly as from EC, and neutralization of endogenous AM by MAb markedly reduced basal cAMP levels and stimulated growth of EC.MC from SHRSP secreted less AM compared to WKY.These findings suggested a role of endogenous AM as an autocrine/paracrine regulator in these cells.We have previously established the transgenic mice overexpressing brain natriuretic peptide (BNP-Tg) with low blood pressure. To assess the renal RAS-NPS interaction, we examined the effect of excess of BNP, using mouse models of renal diseases with chronic RAS activation, i.e. subtotal nephrectomy and anti-GBM nephritis. We found significant renoprotective effects of BNP, suggesting that NPS acts against RAS in vivo, perhaps at cellular and molecular levels including MAP kinase and TGF-beta expression. In another model of renal RAS activation, unilateral ureteral obstruction, renal expression of AM was significantly reduced along with development of interstitial fibrosis, suggesting that AM may normally act against renal fibrosis. Less

心血管激素可能与多种肾脏和心血管疾病有关，例如慢性肾功能衰竭、肾小球肾炎和高血压。为了探讨它们的作用，我们研究了肾脏肾素-血管紧张素系统（RAS）、肾上腺髓质素（AM）系统和利尿钠肽系统。 NPS）使用实验疾病模型。血管紧张素 II 2 型 (AT_2) 受体在胎儿中大量表达，并在出生后显着下调，但在培养的大鼠系膜细胞 (MC) 中，AT_2 受体在汇合时被显着诱导，并发挥抗增殖和促凋亡作用，抵消 AT_1 受体，并抑制肾小球中 AT_2 受体的表达。自发性高血压大鼠（SHRSP）的年轻时期以及具有高度增殖性的 SHRSP 的 MC 中，表明其在肾小球损伤和高血压的发病机制。为了阐明 AM 作为低钙调节剂的作用，我们使用针对 AM 制备的单克隆抗体 (MAb) 检查了其在培养的系膜细胞和内皮细胞 (EC) 中的分泌和作用。我们发现分泌AM 具有有效的抗生长特性，来自培养的 MC 与 EC 一样丰富，并且 MAb 中和内源性 AM 显着降低了基础 cAMP 水平并刺激了 EC.MC 的生长与WKY相比，SHRSP分泌的AM较少。这些发现表明内源性AM在这些细胞中作为自分泌/旁分泌调节剂的作用。我们之前已经建立了过度表达脑钠尿肽（BNP-Tg）的低血压转基因小鼠来评估。为了研究肾脏 RAS-NPS 相互作用，我们使用慢性 RAS 激活的肾脏疾病小鼠模型（即肾次全切除术和抗 GBM）检查了过量 BNP 的影响我们发现 BNP 具有显着的肾脏保护作用，这表明 NPS 可能在细胞和分子水平上对抗 RAS，包括 MAP 激酶和 TGF-β 表达。随着间质纤维化的发展而显着减少，这表明 AM 可能通常对肾纤维化有较小的作用。