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

• 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
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-09671049/
• 关键词: AT_1 receptor; AT_2 receptor; Adrenomedullin; Natriuretic peptides; Mesangium; Cell proliferation; Transgenic mouse; Hypertension; アンジオテンシンII; アドレメデュリン

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

心血管激素可能涉及各种肾脏和心血管疾病，如慢性肾衰竭、肾小球肾炎和高血压。血管紧张素Ⅱ 2型受体（AngiotensinIItype 2，AT_2）在胎儿期大量表达，出生后表达明显下调，但在各种疾病状态下重新表达。在培养的大鼠系膜细胞（MC）中，AT_2受体在汇合时被显著诱导，并发挥对抗AT_1受体的抗增殖和促凋亡作用，抑制MAP激酶级联反应。自发性高血压大鼠（SHR）幼年期肾小球AT_2受体表达降低，且其MC呈高度增殖性，提示AM参与肾小球损伤和高血压的发病机制。 ...更多信息 calregulator，我们用制备的抗AM的单克隆抗体（MAb）检测了它在培养的系膜和内皮细胞（EC）中的分泌和作用。我们发现，培养的MC分泌的AM与EC一样丰富，MAb中和内源性AM后，可显著降低EC的基础cAMP水平，促进EC的生长，SHRSP MC分泌AM的量低于WKY，提示SHRSP MC分泌AM可能是一种细胞增殖抑制因子。本实验室建立了高表达脑钠肽（BNP-Tg）的低血压转基因小鼠模型。为了评估肾脏RAS-β-内酰胺酶相互作用，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肾炎，检查了过量BNP的作用。我们发现BNP具有显著的肾保护作用，表明BNP可能在细胞和分子水平（包括MAP激酶和TGF-β表达）对体内RAS起作用。在另一种肾RAS激活模型中，单侧输尿管梗阻，AM的肾表达随着间质纤维化的发展而沿着显著降低，表明AM可能正常地对抗肾纤维化。少

项目成果

Masahisa Goto: "Growth-dependent induction of angiotensin II type 2 receptor in rat mesangial cells." Hypertension. 30(3). 358-362 (1997)

Masahisa Goto：“大鼠系膜细胞中血管紧张素 II 2 型受体的生长依赖性诱导。”

Kiyoshi Mori: "Isolation and characterization of CAXIV, a novel membrane-bound carbonic anhydrase from mouse kidney." Journal of Biological Chemistry. 274発表予定. (1999)

Kiyoshi Mori：“CAXIV 的分离和表征，一种来自小鼠肾脏的新型膜结合碳酸酐酶。”《生物化学杂志》274 期即将出版。

Hideo Michibata: "Autocrine/paracrine role of adrenomedullin in cultured endothelial and mesangial cells"Kidney International. 53(4). 979-985 (1998)

Hideo Michibata：“肾上腺髓质素在培养的内皮细胞和系膜细胞中的自分泌/旁分泌作用”肾脏国际。

Y.Numata, et al.: "Immunoradiometric assay for the N-terminal fragment of proatrial natriuretic peptide in human plasma." Clinical Chemistry. 44 (5). 1008-1013 (1998)

Y.Numata 等人：“人血浆中心房钠尿肽 N 末端片段的免疫放射测定。”

Hideo Michibata: "Autocrine/paracrine role of a adrenomedullin in cultured endothelial and mesangial cells." Kidney International. 53(4)(発表予定). (1998)

Hideo Michibata：“肾上腺髓质素在培养的内皮细胞和肾小球系膜细胞中的自分泌/旁分泌作用。”53(4)（待提交）。