New Treatment for Nephropathy with the Normalization of Tubulo-Glomerular Feedback Mechanisms

肾小管肾小球反馈机制正常化的新疗法

• 批准号: 16390158
• 负责人: ABE Youichi
• 金额: $ 8.45万
• 依托单位: Kagawa University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 2004
• 资助国家: 日本
• 起止时间: 2004 至 2005
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-16390158/
• 关键词: Tubulo-glomerular feedback; Afferent arteriole; Nephropathy; Hypertension; Dahl salt-sensitive rats; ATP; P2 receptor; Suramin; P2受容体

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. In addition, the transmitters from macula densa cells to afferent arterioles have not been determined yet. We have fortunately solved the first problem by introducing the in vivo dynamic method to evaluate TGF activity. So, the purposes of this project are to determine the transmitter in TGF mechanisms and to develop the new strategy for the treatment of nephropathy by the normalization of TGF activity.1.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 pick up ATP for the candidate of TGF mediator.2.TGF activity in Dahl salt -sensitive (DS) rats : DS rars were ma … More intained on low(L:0.3% NaCl) or high salt(H:8% NaCl) diets for 4 weeks. Using in vivo dynamic method described above, superficial afferent arteriolar diameter (AAD) was measured before and during enhanced TGF activity induced by acetazolamide(ACZ). Compared to DS・L rats, DS・H rats showed smaller basal AAD. ACZ significantly decreased, AAD in DS・L rats, but did not change AAD in DS・H rats. Furosemide increased AADs in both rats. These findings indicate an enhancement of TGF activity in DS・H rats.3.Effect of P2 receptor antagonist, suramin, on TGF activity in DS・H rats : Treatment of suramin significantly increased basal AAD, but AAD did not change during administration of ACD and furosemide, indicating suramin normalized the enhanced TGF activity in DS・H rats.4.Effects of suramin on blood pressure and urinary excretion of protein : Suramin markedly attenuated the development of hypertension and decreased the urinary protein excretion in DS・H rats.The result indicates that the development of nephropathy and hypertension is associated with an enhancement of TGF activity in DS・H rats. P2 receptor antagonist should be a good agent 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。此外，致密斑细胞到传入小动脉的递质尚未确定。我们已经幸运地解决了第一个问题，通过引入体内动态方法来评估TGF活性。因此，本课题的研究目的是确定TGF机制中的递质，并通过TGF活性的正常化为肾病的治疗提供新的策略。1. TGF机制中介质的测定：肾间质腺苷、ATP和NO代谢产物的浓度。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。2.Dahl盐敏感（DS）大鼠的TGF活性：DS组大鼠的TGF活性显著高于对照组（P < 0.05），而对照组大鼠的TGF活性显著低于对照组（P < 0.05）。 ...更多信息 分别饲喂低盐（L：0.3%NaCl）和高盐（H：8%NaCl）日粮4周。采用上述体内动力学方法，在乙酰唑胺（ACZ）诱导TGF活性增强之前和期间测量浅表传入小动脉直径（AAD）。与DS·L大鼠相比，DS·H大鼠的基础AAD较小。ACZ可显著降低DS·L大鼠的AAD，但对DS·H大鼠的AAD无明显影响。速尿增加AAD在这两个大鼠。3. P2受体拮抗剂苏拉明对DS·H大鼠TGF活性的影响：苏拉明治疗显著增加基础AAD，但ACD和速尿给药期间AAD无变化，表明苏拉明使DS·H大鼠TGF活性升高正常化。4.苏拉明对血压和尿蛋白排泄的影响：苏拉明可明显减轻DS·H大鼠高血压的发生，减少尿蛋白排泄，提示DS·H大鼠肾脏病变和高血压的发生与TGF活性增高有关。P2受体拮抗剂应该是治疗肾病的良好药物。少

项目成果

D-allose, an all-cis aldo-hexose, suppresses development of salt-induced hypertension in Dahl rats

• DOI: 10.1097/01.hjh.0000182523.29193.e3
• 发表时间: 2005-10-01
• 期刊: JOURNAL OF HYPERTENSION
• 影响因子: 4.9
• 作者: Kimura, S;Zhang, GX;Abe, Y
• 通讯作者: Abe, Y

Temporary angiotensin blockade at the prediabetic stage attnuates the development of type 2 diabetic nephropathy

糖尿病前期阶段的暂时血管紧张素阻断可减弱 2 型糖尿病肾病的发展

• 发表时间: 2005
• 期刊: J.Am.Soc.Nephrol. 16
• 作者: Hidemichi;Suyama;Takao;Yamanoue;et. al.;Nishiyama Akara;Kimura Shoji;山野上 敬夫;Nagai Yukiko
• 通讯作者: Nagai Yukiko

Temporary angiotensin II blockade at the prediabetic stage attnuates the development of renal injury in type 2 diabetic rats.

在糖尿病前期阶段暂时阻断血管紧张素 II 可减轻 2 型糖尿病大鼠肾损伤的发展。

• 发表时间: 2005
• 期刊: J.Am.Soc.Nephrol. 16
• 作者: Hidemichi;Suyama;Takao;Yamanoue;et. al.;Nishiyama Akara;Kimura Shoji;山野上 敬夫;Nagai Yukiko;Nishiyama Akira;Kimura Shoji;Nagai Yukiko
• 通讯作者: Nagai Yukiko

The SOD mimetic tempol ameliorates glomerular injury and reduces mitogen-activated protein kinase activity in Dahl salt-sensitive rats

• DOI: 10.1097/01.asn.0000108523.02100.e0
• 发表时间: 2004-02-01
• 期刊: JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY
• 影响因子: 13.6
• 作者: Nishiyama, A;Yoshizumi, M;Abe, Y
• 通讯作者: Abe, Y

Time dependent transition of tempol sensitive reduction of blood pressure in angiotensin II induced hypertension.

血管紧张素 II 诱导的高血压中时间依赖性血压降低的时间依赖性转变。

• 发表时间: 2004
• 期刊: J.Hypertens. 22
• 作者: 田熊;一敞;Kamide K et al.;Miwa Y et al.;Miwa Y et al.;Shoji Kimura;Shoji Kimura
• 通讯作者: Shoji Kimura