Molecular Study on Physiological and Clinical Significance of Adrenomedullin

肾上腺髓质素生理和临床意义的分子研究

基本信息

批准号：
10218204
负责人：
NAKAO Kazuwa
金额：
$ 39.81万
依托单位：
Kyoto University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research on Priority Areas
财政年份：
1998
资助国家：
日本
起止时间：
1998 至 2002
项目状态：
已结题

项目摘要

Adrenomedullin (AM), a potent vasorelaxing and natriuretic peptide, is thought to act as an autocrine/paracrine regulator in the vasculature as well as in renal glomeruli and tubules.In cultured bovine aortic endothelial cells, we have shown that both shear stress and oxidative stress markedly augment the synthesis and secretion of AM. Using specific anti-AM monoclonal antibody we prepared, we have demonstrated that endogenous AM produced by the endothelium inhibits PDGF-induced cell proliferation and strongly downregulates the endothelin secretion in an autocrine manner, thereby potentially protecting against vascular insults. On the other hand, AM potently stimulated the proliferation and migration of quiescent human umbilical vein endothelial cells. Using gel plug assay and laser Doppler imaging, AM stimulated vascular formation in vivo as well. We have shown that these effects of AM are mediated via the cAMP/PKA/PI3K pathway. Furthermore, we have already succeeded in the identifica … More tion and establishment of vascular progenitor cells from mouse ES cells. Using this in vitro vasculogenesis model, we found that AM receptor components, RAMP2 and CRLR, are expressed from an early stages of vascular development, suggesting that AM may play a role in vasculogenesis in vivo.In the kidney, We have shown that a significant amount of AM is produced from mesangial cells. We have demonstrated that RAMP2 and CRLR are markedly upregulated during the progression of renal fibrosis using an obstructive nephropathy model. We also showed that injured renal tissues exhibited enhanced basal and AM-stimulated cAMP production, and addition of AM in cultured renal fibroblasts inhibited proliferation and TGF-β-stimulated extracellular matrix production in a cAMP-dependent fashion.These results suggest that AM potentially exerts protective effects in the vasculature, by enhancing endothelial repair and regeneration as well as probably angiogenesis, and in the kidney, by counteracting the fibrogenic stimuli such as TGF-β. In addition, the activation of AM and its receptor system during vascular and renal injury, if any, should play a role in modulating the process of vascular and renal remodeling, against the disease progression. Less

肾上腺囊肿（AM）是一种潜在的血管长期和纳地酸肽，被认为是脉管系统中的自分泌/旁分泌调节剂，以及肾肾小球和肾小管肾小球和肾小管植物。在培养的牛主动脉主动脉细胞中，我们已经表现出了剪切应力和氧化度的分泌。使用我们制备的特定抗AM单克隆抗体，我们证明了内源性由内皮产生的内源性抑制PDGF诱导的细胞增殖，并以自分泌的方式强烈下调内皮素分泌，从而潜在地保护侵害血管感染。另一方面，AM可能刺激了静止的人脐静脉内皮细胞的增殖和迁移。使用凝胶塞分析和激光多普勒成像，还可以在体内刺激的血管形成。我们已经表明，AM的这些作用是通过CAMP/PKA/PI3K途径介导的。此外，我们已经成功地识别了……更多的和从小鼠ES细胞中建立血管祖细胞。使用这种体外血管生成模型，我们发现AM受体成分RAMP2和CRLR是从血管发育的早期阶段表达的，这表明AM可能在体内在血管生成中起作用。在肾脏中，我们表明，我们的AM大量AM是由Messianical细胞产生的。我们已经证明，使用阻塞性肾病模型，在肾纤维化进展过程中，RAMP2和CRLR显着上调。我们还表明，受伤的肾脏组织暴露了增强的基本和AM刺激的营地生产，并且在培养的肾成纤维细胞中添加AM抑制了增殖和TGF-β刺激的细胞外基质的产生。这些结果表明，通过增强内皮修复和再生以及可能的血管生成，以及通过抵消诸如TGF-β之类的纤维纤维刺激，可能会在脉管系统中发挥保护作用，并可能在肾脏中发挥保护作用。此外，在血管和肾脏损伤期间，AM及其受体系统的激活（如果有）应在调节疾病进展的血管和肾脏重塑过程中发挥作用。