Elucidation of Tubulo-Glomerular Feedback Mechanisms

阐明肾小管-肾小球反馈机制

• 批准号: 14370783
• 负责人: ABE Youichi
• 金额: $ 8.64万
• 依托单位: KAGAWA UNIVERSITY(Faculty of Medicine)
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 2002
• 资助国家: 日本
• 起止时间: 2002 至 2003
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-14370783/
• 关键词: Tubulo-glomerular feedback mechanism; CCD camera; Afferent arteriole; Efferent arteriole; ATP; Adenosine; Microdialysis method; Dahl salt sensitive rat; 一酸化窒素

It is speculated that an abnormal tubulo-glomerular feedback (TGF) activity may induce the nephropathy via renal hemodynamic changes. However, there are no useful technique to evaluate the TGF activity. The purposes of this project are to develop the in vivo dynamic method to evaluate TGF activity, to evaluate the TGF activity in renal disease models, and to determine a possible mediator in TGF mechanisms.1.Development of in vivo dynamic method to evaluate TGF activity : We introduced the intravital CCD-video microscopy that allowed direct in vivo visualization of the renal microcirculation, and measured both afferent and efferent arteriolar diameters in rats. In Sprague-Dawley (SD) rats, the basal afferent and efferent arteriolar diameters were 8.57+/-0.43 and 7.31+1-0.81 um, respectively. Acetazolamide significantly decreased the afferent arteriolar diameter (AAD) to 6.64+/-0.57 um, but did not affect the efferent arteriolar diameter. Furosemide reversed the acetazolamide-induced aff … More erent constriction.2. TGF activity in Dahl salt sensitive (DS) rats : DS rats were given high salt diet (H : 8% NaCl) and low salt diet (L : 0.3% NaCl). Basal AADs were similar between SD and DS/L rats (8.57+/-0.43 and 8.74+/-0.20 um). In DS/L rats, acetazolamide induced the afferent constriction and furosemide reversed the acetazolamide-induced afferent constriction. In contrast to SD or DS/L rats, DS/H rats showed smaller basal AAD (6.09+/-0.49 um). Acetazolamide failed to reduce AAD, but furosemide restored AAD to that in DS/L rat. Thus, it can be considered that TGF mechanisms might be activated in DS/H rats.3. Determination of mediators in TGF mechanisms : The renal interstitial concentration of adenosine, ATP and NO metabolites. We observed the positive correlation between TGF-mediated changes in renal vascular resistance and renal interstitial concentration of ATP.Thus, we could develop the in vivo dynamic method to evaluate TGF activity and show the abnormal TGF activity in DS/H rats. In addition, we could pick up ATP as a mediator in TGF mechanism. Based on these findings we believe to be able to develop the new strategy for the treatment of nephropathy. Less

据推测，异常的肾小管-肾小球反馈（TGF）活性可能通过肾脏血流动力学改变而诱发肾病。然而，没有有用的技术来评估TGF活性。本课题的目的是建立TGF活性的体内动态评价方法，评价肾脏疾病模型中TGF的活性，并确定TGF作用机制中可能的介质。1. TGF活性体内动态评价方法的建立：我们引入了活体CCD视频显微镜，可以直接在体内观察肾微循环，并测量大鼠的传入和传出小动脉直径。在Sprague-Dawley（SD）大鼠中，基础传入和传出小动脉直径分别为8.57 ± 0.43和7.31 ± 1-0.81 μ m。乙酰唑胺可显着降低传入小动脉直径（AAD）至6.64+/-0.57 μ m，但不影响传出小动脉直径。呋塞米逆转乙酰唑胺诱导的AFF ...更多信息 血管收缩。Dahl盐敏感（DS）大鼠转化生长因子（TGF）活性：DS大鼠给予高盐饮食（H：8% NaCl）和低盐饮食（L：0.3% NaCl）。SD和DS/L大鼠之间的基础AAD相似（8.57+/-0.43和8.74+/-0.20 um）。在DS/L大鼠，乙酰唑胺引起的传入收缩和呋塞米逆转乙酰唑胺引起的传入收缩。与SD或DS/L大鼠相比，DS/H大鼠显示出较小的基础AAD（6.09+/-0.49 um）。乙酰唑胺不能降低AAD，但速尿可使AAD恢复到DS/L大鼠的水平。因此，可以认为DS/H大鼠的TGF-β机制可能被激活. TGF机制中介质的测定：腺苷、ATP和NO代谢产物的肾间质浓度。我们观察到TGF介导的肾血管阻力变化与肾间质ATP浓度呈正相关，从而建立了在体动态检测TGF活性的方法，揭示了DS/H大鼠TGF活性的异常。此外，我们还发现ATP可能是TGF-β作用机制中的一种介导物。基于这些发现，我们相信能够开发出治疗肾病的新策略。少

项目成果

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Rahman Mutlubur 等：“血管紧张素 II 对麻醉大鼠肾间质 NO2/NO3 和环 GMP 浓度的影响”J. Pharmacol. 88・4 (2002)。

Kobori H.: "Enhancement of intrarenal angiotensinogen in Dahl salt-sensitive rats on high salt diet."Hypertension. 41. 592-597 (2003)

Kobori H.：“高盐饮食对达尔盐敏感大鼠肾内血管紧张素原的增强。”高血压。

Murakami K et al.: "Perindopril effect on uncoupling protein and energy metabolism in failing hearts."Hypertension. 40. 251-255 (2002)

Murakami K 等人：“培哚普利对衰竭心脏中解偶联蛋白质和能量代谢的影响。”高血压。

Tian RX et al.: "DOI, a 5-HT2 receptor agonist, induces renal vasodilation via nitric oxide in anesthetized dogs."Eur.J.Pharmacol.. 437. 79-84 (2002)

Tian RX 等人：“DOI 是一种 5-HT2 受体激动剂，在麻醉狗中通过一氧化氮诱导肾血管舒张。”Eur.J.Pharmacol.. 437. 79-84 (2002)

粕谷 豊 他: "NEW薬理学(改訂第4版)"南江堂. 670 (2002)

Yutaka Kasuya 等人：“NEW Pharmacology（修订第 4 版）”Nankodo 670（2002）。