Molecular Study on Physiological and Clinical Significance of Adrenomedullin

肾上腺髓质素（Adrenomedullin，AM）是一种强有力的血管舒张和利钠肽，在血管系统以及肾小球和肾小管中起着自分泌/旁分泌调节剂的作用，在培养的牛主动脉内皮细胞中，我们发现剪切应力和氧化应激都能显著增加AM的合成和分泌。使用我们制备的特异性抗AM单克隆抗体，我们已经证明，由内皮产生的内源性AM抑制PDGF诱导的细胞增殖，并以自分泌方式强烈下调内皮素分泌，从而潜在地保护血管免受损伤。另一方面，AM能有效地刺激静止的人脐静脉内皮细胞的增殖和迁移。用凝胶塞法和激光多普勒成像，AM刺激血管形成，以及在体内。我们已经证明AM的这些作用是通过cAMP/PKA/PI 3 K途径介导的。此外，我们已经成功地识别了 ...更多信息 小鼠ES细胞血管祖细胞的分离和建立使用这种体外血管生成模型，我们发现AM受体组分RAMP 2和CRLR在血管发育的早期阶段就表达，这表明AM可能在体内血管生成中发挥作用。在肾脏中，我们已经表明，大量的AM是由系膜细胞产生的。我们已经证明，RAMP 2和CRLR显着上调肾纤维化的进展过程中使用阻塞性肾病模型。我们还发现，损伤的肾组织表现出增强的基础和AM刺激的cAMP产生，并且在培养的肾成纤维细胞中加入AM以cAMP依赖的方式抑制增殖和TGF-β刺激的细胞外基质产生。这些结果表明，AM可能通过增强内皮修复和再生以及可能的血管生成在血管系统中发挥保护作用，并且在肾脏中，通过抵消纤维化刺激物如TGF-β。此外，在血管和肾脏损伤过程中，AM及其受体系统的激活（如果有的话）应在调节血管和肾脏重塑过程中发挥作用，对抗疾病的进展。少

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