MOLECULAR MECHANISMS OF ACTION AND PHYSIOLOGICAL ROLES OF LIPID AUTACOIDS IN THE NEPHRON

肾单位中脂质类脂的作用分子机制和生理作用

• 批准号: 07457239
• 负责人: WATANABE Tsuyoshi
• 金额: $ 4.67万
• 依托单位: UNIVERSITY OF TOKYO
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 1995
• 资助国家: 日本
• 起止时间: 1995 至 1996
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-07457239/
• 关键词: platelet-activating factor receptor; thromboxane A_2 receptor; microdissection; nephron; RT-PCR; mRNA expression; glomerular mesangial cells; homologous down-regulation; 血小板活性化因子(PAF); プロスタグランジン; MRT-PCR; micro-perfusion; mRNA定量; 情報伝達; 遺伝子多型

In order to clarify the action mechanisms and physiological and pathophysiological significances of lipid autacoids such as platelet activating factor (PAF) and thromboxane (TX) A_2, we performed molecular and cellular biological studies in microdissected nephron segments from rodent kidneys, cultured renel-derived cells such as glomerular mesangial cells, genetically target mouse and DNA samples from patients with renal diseases, the results of which are as follows ; (1) Using our new quantitative RT-PCR method (MRT-PCR) in microdissected segments, we demonstrated ubiquitous distribution of PAF and TXA_2 receptor mRNA in the nephron, (2) homologous down-regulation of PAF receptor mRNA expression was shown to be mediated by cAMP formed though PAF-induced PGE_2 production in cultured mesangial cells, (3) pathophysilogical contribution of PAF on the pathogenesis of diabetic and cisplatin nephropathy was demonstrated in PAF receptor gene-targeted mouse, but, however, (4) significant co-relation between polymorphism of PAF acetylhydralase gene and pathogenesis and/or progression of diabetic nephropathy has not been shown so far.These results will lead to new insight to the significances of lipid autacoids in the kidney.

为了阐明血小板活化因子（PAF）和血栓素（TX）A_2等脂质自分泌物的作用机制及其生理和病理生理意义，本研究对啮齿类动物肾单位、肾小球系膜细胞、基因靶向小鼠和肾脏疾病患者DNA标本进行了分子和细胞生物学研究，其结果如下：（1）应用我们的新的定量RT-PCR方法（MRT-PCR），在显微解剖的肾组织切片中，我们证实了PAF和TXA_2受体mRNA在肾单位中的普遍分布，（2）PAF诱导PGE_2产生cAMP，下调PAF受体mRNA表达，这可能与PAF诱导PGE_2产生cAMP有关。2在培养的系膜细胞中产生，（3）PAF在糖尿病和顺铂肾病的发病机制中的病理生理作用在PAF受体基因靶向小鼠中得到证实，但是，（4）PAF乙酰水解酶基因多态性与发病有显著相关性;这些结果将对脂质自体在肾脏中的意义产生新的认识。

项目成果

F.Takemoto,S.Uchida,H.Katagiri,Y.Oka: "Desensitization of endothelin-1 binding by vasopressin via a cAMP mediated pathway in rat CCD" Am.J.Physiol. 268. F385-390 (1995)

F.Takemoto、S.Uchida、H.Katagiri、Y.Oka：“大鼠 CCD 中通过 cAMP 介导的途径使血管加压素与内皮素-1 结合脱敏”Am.J.Physiol。

ザビ-ネ ノイゲバウアー,他: "Defective homocysteine metabolism as a risk factor for diabeticretinopathy." Lancet. (in press).

Sabine Neugebauer 等人：“同型半胱氨酸代谢缺陷是糖尿病视网膜病变的危险因素”（正在出版）。

谷口 茂夫,他: "Mechanism of aldosterone action." Principles of Medical Biology,Edited by E.E.Bittar,JAI Press INC(in press),

Shigeo Taniguchi 等人：“醛固酮作用机制”，E.E.Bittar 编辑，JAI Press INC（正在印刷中），

K.Asano, S.Taniguchi, A.Nakao, T.Watanabe and K.Kurokawa: "Distribution of platelet-activating factor receptor mRNA along the rat nephron segments" Biochem.Biophys.Res.Commun.225. 352-357 (1996)

K.Asano、S.Taniguchi、A.Nakao、T.Watanabe 和 K.Kurokawa：“血小板激活因子受体 mRNA 沿大鼠肾单位段的分布”Biochem.Biophys.Res.Commun.225。

H.Yi, M.Fukagawa, H.Yamato, M.Kumagai, T.Watanabe and K.Kurokawa: "Prevention of enhanced parathyroid hormone secretion, synthesis and hyperplasia by mild dietary phosphorus restriction in rats with early chronic renal failure : possible direct role of ph

H.Yi、M.Fukakawa、H.Yamato、M.Kumagai、T.Watanabe 和 K.Kurokawa：“早期慢性肾功能衰竭大鼠通过轻度膳食磷限制预防甲状旁腺激素分泌、合成和增生增强：可能直接