Pathological role of endothelin ET_B receptors

内皮素ET_B受体的病理作用

• 批准号: 12670098
• 负责人: MATSUMURA Yasuo
• 金额: $ 2.18万
• 依托单位: Osaka University of pharmaceutical Sciences, Assistant
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2000
• 资助国家: 日本
• 起止时间: 2000 至 2001
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-12670098/
• 关键词: endothelin-1; ET_B receptor; hypertension; renal failure; 腎障害

We evaluated the pathological role of ET_B receptors in DOCA-salt-induced hypertension, cardiovascular hypertrophy and renal damage, using the spotting-lethal (sl) rat which carries a naturally occurring deletion in ET_B receptor gene. When homozygous (sl/sl) and wild-type (+/+) rats were treated with DOCA-salt, homozygous rats exhibited earlier and higher increases in systolic blood pressure than wild-type rats. Chronic treatment with ABT-627, an ET_A receptor antagonist, completely suppressed DOCA-salt-induced hypertension in both groups. Renal dysfunction and histologial damage were more severe in homozygous than in wild-type rats. Marked vascular hypertrophy was observed in homozygous, compared with wild-type rats. Renal and vaslcular injuries were significantly improved by ABT-627. In DOCA-salt-induced hypertension. Enhanced ET-1 production and ET_A-mediated actions are responsible for the increased susceptivity to DOCA-salt hypertention and tissue injuries in ET_B receptor-defici … More ent ratsUsing same animals, we also evaluated the role of endothelin ET\B-receptor-mediated action in the development and maintenance of ischemic acute renal failure (ARF). Animals were subjected to ischemic ARF by clamping the renal pedicle for 45 min followed by reperfusion. At 24 h after the reperfusion, renal glomerular dysfunction and histological damage were markedly and equally observed both in homozygous and wild-type groups, and these renal njury gradually recovered. When the ischemia/reperfusion-induced renal injury was examined at 7 days after the reperfusion, the recovery in homozygous ARF rats obviously delayed compared with the cases in wild-type animals. Increment of renal endothelin-1 content after the ischemia/reperfusion was more marked in homozygous than in wild-type rats. Thus, ET_B-receptor-mediated actoins do not play an important role in the development of ischemic ARF, but may be involoved in the recovery process from the ischemia/reperfusion-induced renal injury Less

我们使用斑点致死（SL）大鼠评估了ET_B受体在DOCA盐诱导的高血压，心血管肥大和肾损伤中的病理作用，该斑点（SL）大鼠携带ET_B受体基因中自然存在的缺失。当纯合子（SL/SL）和野生型（+/+）大鼠用DOCA-SALT治疗时，比野生型大鼠更早地暴露于收缩压的纯合大鼠，并且收缩压的升高更高。 ET_A接收器拮抗剂ABT-627的慢性治疗完全抑制了两组DOCA盐诱导的高血压。在纯合子中，肾功能障碍和组织学损害比野生型大鼠更严重。与野生型大鼠相比，在纯合子中观察到了明显的血管肥大。 ABT-627可显着改善肾脏和血管损伤。在DOCA盐引起的高血压中。增强的ET-1产生和ET_A介导的作用是造成ET_B受体 - 受体 - 造成同一动物的更大剂量的DOCA-SALT高血压和组织损伤的易感性，我们还评估了内皮素ET \ B受体介导的作用在缺血性急性肾脏肾脏失败（ARF）中的作用。通过夹紧肾脏椎弓根45分钟，然后再灌注，对动物进行缺血ARF。再灌注后24小时，在纯合子和野生型基团中明显观察到肾肾小球功能障碍和组织学损害，并且这些肾脏NJury逐渐恢复。当再灌注后7天检查缺血/再灌注引起的肾损伤时，与野生型动物的病例相比，纯合ARF大鼠的恢复显然延迟了。缺血/再灌注后肾脏内皮素-1含量的增加在纯合子中比野生型大鼠更明显。这是，ET_B受体介导的actons在缺血性ARF的发展中不起作用，但可能参与缺血/再灌注引起的肾脏损伤的恢复过程。

项目成果

西田昌広: "Role of Endothelia ET_B receptor in the pathogenesis of ischemic acute renal failure"J. Cardiovasc. Pharmacol. (印刷中). (2002)

Masahiro Nishida：“内皮细胞 ET_B 受体在缺血性急性肾衰竭发病机制中的作用”J. Cardiovasc（正在出版）。

松村靖夫: "エンドセリン受容体拮抗薬と内皮機能"血圧. 8. 67-74 (2001)

Yasuo Matsumura：“内皮素受体拮抗剂和内皮功能”血压。8. 67-74 (2001)

松村靖夫: "Exaggerated vascular and renal pathology in deoxycorticosterone acetate-salt, endothelin-B receptor-deficient rats"Circulation. 102. 2765-2773 (2000)

Yasuo Matsumura：“醋酸脱氧皮质酮盐、内皮素 B 受体缺陷大鼠的血管和肾脏病理学夸大”循环。 102. 2765-2773 (2000)

MATSUMURA Yasuo, KURO Toshihiko, KOBAYASHI Yutaka, KONISHI Fumiko, TAKAOKA Masanori, WESSALE Jerry L., OPGENORTH Terry j., GARIEPY Cheryl E. and YANAGISAWA Masashi: "Increased susceptivity to deoxycorticosterone acetate-salt-induce hypertension in endothe

MATSUMURA​​ Yasuo、KURO Toshihiko、KOBAYASHI Yutaka、KONISHI Fumiko、TAKAOKA Masanori、WESSALE Jerry L.、OPGENORTH Terry j.、GARIEPY Cheryl E. 和 YANAGISAWA Masashi：“内皮细胞对醋酸脱氧皮质酮盐的敏感性增加可诱发高血压

NISHIDA Masahiro, IESHIMA Miyuki, KONISHI Fuimko, YAMASHITA Junji, TAKAOKA Masanori and MATSUMURA Yasuo: "Role of Endothelia ET_B receptor in the pathogenesis of ischemic acute renal failure"J. Cardiovasc. Pharmacol.. (in press). (2002)

NISHIDA Masahiro、IESHIMA Miyuki、KONISHI Fuimko、YAMASHITA Junji、TAKAOKA Masanori 和 MATSUMURA​​ Yasuo：“内皮 ET_B 受体在缺血性急性肾衰竭发病机制中的作用”J。