Invesigation on cellular mechanism of erythropoietin induced hypertension

促红细胞生成素诱发高血压的细胞机制研究

• 批准号: 10671003
• 负责人: KUSANO Eiji
• 金额: $ 0.96万
• 依托单位: Jichi Medical School
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 1998
• 资助国家: 日本
• 起止时间: 1998 至 2000
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-10671003/
• 关键词: hemodialysis; erythropoietin; hypertension; vascular smooth muscle cell; apoptosis; intracellular calcium; nitric oxide; vasoconstrictive substance; 動脈硬化; 血管のリモデリング; 透析患者; サイトカイン; IL-1β; 一酸化窒素合成酵素; 血管平滑筋細胞

Erythropoietin (EPO)-induced hypertension in the patients on maintenance hemodialysis is a matter of paticular interest in clinical nephrology. Although various possibility is indicated on the mechanism of the EPO-induced hypertension, we have examined it with special reference to nitric oxide (NO) metabolism in cultured rat vascular smooth muscle cells (VSMC). We already demonstrated that EPO inhibited interleukin -1β induced iNOS mRNA and protein expression and NO production in VSMC.Recent studies have shown that several cytokines could induce apoptosis to VSMC via the induction of NO.In addition, EPO induces cytosolic free calcium ([Ca^<2+>]i) mobilization and also modulates the sensitivity of the cardiovascular system to vasoconsrictive substances such as angiotensin II (AgII), norepinephrine (NE) or endothelin (ET). Therefore, in the present project, we explored whether EPO has a modulatory effect of apoptosis on IL-1β or NO donor sodium nitroprusside (SNP) induced apoptosis in VS … More MC.Furthermore, we explored the mechanism of EPO induced [Ca^<2+>]i mobilization and its role in the activation of MAP kinase and DNA synthesis and explored the effect of EPO on the responsiveness of AgII, NE or ET induced [Ca^<2+>]i mobilization in VSMC.Our present study demonstrated that rHuEPO inhibited IL-1β or SNP induced VSMC apoptosis. The TK dependent pathway, particularly the PI 3-kinase dependent pathway seems to be critical to the countervailing effect of rHuEPO on IL- 1β and SNP induced VSMC apoptosis.Concerning the effects of EPO on [Ca^<2+>]i, (1) EPO increases [Ca^<2+>]i by both Ca^<2+> influx and Ca^<2+> release from intracellular stores. Tyrosine phosphorylation is critical in the regulation of [Ca^<2+>]i, but PKC activation is important only in the regulation of Ca^<2+> influx. Dihydoropyridine sensitive L-type Ca^<2+> channel seems to be involved in EPO induced Ca^<2+> influx. In addition, increase of [Ca^<2+>]i by EPO stimulates MAP kinase activation and DNA synthesis in VSMC.Furthermore, EPO has synergistic effects on AgII, NE or ET induced [Ca^<2+>]i mobilization, particularly on intracellular Ca^<2+> release, in VSMC.This may be one of the potential mechanisms that contribute to hypertension associated with EPO therapy. However, further investigations were needed to clarify the effect of lower concentaration of EPO on the dynamics of [Ca^<2+>]i. Less

促红细胞生成素（EPO）引起的维持性血液透析患者高血压是临床肾脏病学关注的问题。虽然各种可能性表明EPO诱导的高血压的机制，我们已经研究了它与特别是参考一氧化氮（NO）代谢在培养的大鼠血管平滑肌细胞（VSMC）。我们已经证实EPO可抑制IL-1 β诱导的VSMC中iNOS mRNA和蛋白的表达以及NO的产生，最近的研究表明多种细胞因子可通过诱导NO诱导VSMC凋亡，另外，EPO还可诱导细胞内游离钙离子浓度的升高，（[Ca^<2+>]i）动员，并且还调节心血管系统对血管收缩物质如血管紧张素II（AgII）的敏感性，去甲肾上腺素（NE）或内皮素（ET）。因此，本研究探讨EPO是否对IL-1β或NO供体硝普钠（SNP）诱导的VS细胞凋亡具有调节作用 ...更多信息 本研究进一步探讨了EPO诱导VSMC [Ca^<2+>]i动员的机制及其在MAP激酶激活和DNA合成中的作用，以及EPO对AgII、NE和ET诱导的VSMC [Ca^<2+]i动员反应性的影响。TK依赖性途径，特别是PI 3-激酶依赖性途径似乎对于rHuEPO对抗IL- 1β和SNP诱导的VSMC凋亡的作用至关重要。关于EPO对[Ca^<2+]i的影响，（1）EPO通过Ca^<2 +]i内流和细胞内储存的Ca ^<2+释放增加[Ca^<2 +]i。酪氨酸磷酸化在[Ca^2+]i的调节中是关键的，但PKC激活仅在Ca^2+内流的调节中是重要的。二氢吡啶敏感的L型Ca^2+通道可能参与EPO诱导的Ca^2+内流。此外，EPO增加VSMC [Ca^2+]i，促进MAP激酶激活和DNA合成，并对AgII、NE或ET诱导的VSMC [Ca^2 +]i动员，尤其是胞内Ca^2+释放有协同作用，这可能是EPO治疗高血压的潜在机制之一。然而，需要进一步的研究来阐明低浓度EPO对[Ca^<2+>]i动力学的影响。少

项目成果

Kusano E: "Modulation of endothelin-1 induced cytosolic free calcium mobilization and mitogen-activated protein kinase activation by erythropoietin in vascular smooth muscle cell"Kidney and Blood pressure Res. (in press). (2001)

Kusano E：“血管平滑肌细胞中促红细胞生成素对内皮素-1 诱导的胞浆游离钙动员和有丝分裂原激活蛋白激酶激活的调节”肾脏和血压研究。

Akimot T, Kusano E, Muto S, Fujita N, Okada K, Saito T, Komatsu N, Ono S.Ebata S, Ando Y, Homma S.Asano Y: "The effect of erythropoietin on interleukin- 1b mediated increase in nitric oxide synthesis in vascular smooth muscle cells."J Hypertension. 17. 12

Akimot T、Kusano E、Muto S、Fujita N、Okada K、Saito T、Komatsu N、Ono S.Ebata S、Ando Y、Homma S.Asano Y：“促红细胞生成素对白介素-1b 介导的一氧化氮增加的影响

Kusano E.et al.: "Human recombinant erythropoetin inhibits interleukin-1β-stimulator nitric oxide……" Nephrol.Dial.Transplant.(in press). 14. (1999)

Kusano E. 等人：“人类重组促红细胞生成素抑制白细胞介素 1β 刺激剂一氧化氮……”Nephrol.Dial.Transplant.（出版中）14。

Akimoto T: "Erythropoietin modulates angiotensin II or norepinephrine induced Ca2+ mobilization in cultured rat vascular smooth muscle cells."Nephrol Dial Transplant. (in press). (2001)

Akimoto T：“促红细胞生成素调节培养的大鼠血管平滑肌细胞中血管紧张素 II 或去甲肾上腺素诱导的 Ca2+ 动员。” 肾病拨号移植。

Akimoto T, Kusano E, Ito C, Yanagiba S, Inoue M, Amemiya M, Ando Y, Asano Y: "Involvement of erythropoietin induced cytosolic free calcium mobilization in activation of mitogen-activated protein kinase and DNA synthesis in vascular smooth muscle cells."J

Akimoto T、Kusano E、Ito C、Yanagiba S、Inoue M、Amemiya M、Ando Y、Asano Y：“促红细胞生成素诱导胞质游离钙动员参与血管平滑肌细胞丝裂原激活蛋白激酶的激活和 DNA 合成。