| Co-Investigator(Kenkyū-buntansha) |
SOGABE Keizo Fujisawa Pharmaceutical Company, 探索研究所, 主任研究員
NONOGUCHI Hiroshi Kumamoto University, Internal Medicine, Associate Professor, 医学部・附属病院, 講師 (30218341)
IWAOKA Taisuke Kumamoto University, Internal Medicine, Associate Professor, 医学部・附属病院, 講師 (30184857)
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| Budget Amount *help |
¥4,800,000 (Direct Cost: ¥4,800,000)
Fiscal Year 1998: ¥4,800,000 (Direct Cost: ¥4,800,000)
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| Research Abstract |
Endothelin-1 (FT-1) has a pathophysiological potential in the development of hypertension. Synthesis of bioactive FT-1 requires endothelin converting enzyme-1 (ECE-1). To investigate the role of ECE-1 in the pathodenesis of hypertension in SHR, ECE-I gene expression was studied in the kidneys of both 4 and 12 week-old SHR.In 4 week-old SHR, ECE-l mRNA was significantly increased in the proximal straight tubule, medullary thick ascending limb, corticalthick ascending limb, and inner medullary collecting duct. In 12 week-old SHR, BCE-I mRNA was significantly increased in the proximal straight tubule, medullary thick ascending limb, and also in the glomeruli. These result suggest that high ECE-1 gene expression in the nephron, via generation of FT-1, may promote Na reabsorption that contributes to the development and/or maintenance of hypertension in SHR.The reason of increased ECE-1 gene expression in SHR is not known. To investigate the mechanism of regulation, the effects of ET-1 on ECE-1 mRNA was studied in cultured endothelial cells. Incubation of ET-1 for 6 hours caused a significant decrease in ECE-1 mRNA expression. This effect was was abolished by co-incubation with BQ788, a specific ETB receptor antagonist, but not by co-incubation with BQ123, a specific ETA receptor antagonist. These results suggested that ET-1 suppressed ECE-1 expression through ETB receptor, indicating the existence of a feedback mechanism of FT-1 on ECE-1 in endothelial cells. In SHR, this feedback mechanismwas disturbed, therefore, overproduction of ET-1 by ECE-1 may contribute to develop the hypertention in SHR.
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