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Significance and molecular mechanisms of natriuretic peptide family in the protection from renal dysfunction

利尿钠肽家族预防肾功能障碍的意义及分子机制

基本信息

批准号：
11671066
负责人：
SUGAWARA Akira
金额：
$ 1.92万
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：
1999
资助国家：
日本
起止时间：
1999 至 2000
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-11671066/
关键词：
natriuretic peptide blood pressure renal dysfunction CTGF transgenic mouse anti-GBM antibody GN kidney protection renin-angiotensin system 尿細管結紮水腎症モデル

项目摘要

(1) Pathohysioloical significance of natriuretic peptide family in the animal models of renal diseasesWe have established animal models of renal diseases (anti-glomerular basement membrane antibody glomerulonephritis ; anti-GBM antibody GN, STZ diabetic nephropathy model and unilateral ureteral obstruction hydronephrosis model) in rats and mice, and elucidated the localization of natriuretic peptide family by Nothern blot analysis and immunohistochemical method using anti-ANP, BNP, CNP monoclonal antibodies. The results indicated that these peptides may be the parameter of renal dysfunction.(2) Study on the cross-talk of natriuretic peptide system and renin-angiotensin systemNatriuretic peptide system is thought to antagonize renin-angiotensin system. To clarify the intra-cellular mechanism of natriuretic psptides, we have investigated the induction of TGF-β, CTGF and extra-cellular matrix using cultured mesangial cells. We have also succeeded the cloning of rat CTGF and raised the specific antibody.(3) Kidney protection in BNP transgenic mouse and its molecular mechanismWe have established the 5/6 nephrecomized model using BNP transgenic mice which show the activation of renal renin-angiotensin system. Using this animal model, significant increase in size of glomeruli is observed in the control rats, whereas in the BNP transgenic mice, such glomerular change is not observed, showing that excessive BNP may work as kidney protection. Using this BNP transgenic mice, we have further established the unilateral ureteral obstruction hydronephrosis model and anti-GBM antibody GN model. With these models, we have shown the kidey-protection of BNP, at least in part, by the immunological mechanism.

(1)利钠肽家族在肾脏疾病动物模型中的病理生理意义我们建立了肾脏疾病动物模型(抗肾小球基底膜抗体肾小球肾炎；大鼠和小鼠抗gbm抗体GN、STZ糖尿病肾病模型和单侧输尿管梗阻肾积水模型)，并利用抗anp、BNP、CNP单克隆抗体，通过northern blot分析和免疫组化方法阐明利钠肽家族的定位。结果表明，这些肽可能是肾功能不全的参数。(2)利钠肽系统与肾素-血管紧张素系统相互作用的研究利钠肽系统被认为具有拮抗肾素-血管紧张素系统的作用。为了阐明利钠肽的细胞内机制，我们利用培养的系膜细胞研究了TGF-β、CTGF和细胞外基质的诱导作用。我们还成功克隆了大鼠CTGF，并提出了特异性抗体。(3) BNP转基因小鼠的肾脏保护作用及其分子机制我们建立了5/6肾化模型，显示了肾肾素-血管紧张素系统的激活。在该动物模型中，对照大鼠肾小球明显增大，而在BNP转基因小鼠中，肾小球未见明显变化，说明过量的BNP可能具有肾保护作用。利用该BNP转基因小鼠，我们进一步建立了单侧输尿管梗阻肾积水模型和抗gbm抗体GN模型。通过这些模型，我们至少在一定程度上通过免疫机制证明了BNP的保护作用。