PHYSIOLOGICAL ROLE OF ADRENOMEDULLIN BY MOLECULAR BIOLOGICAL AND GENE ENGINEERING APPROACH

肾上腺髓质素和PAMP来源于相同的前体蛋白，为了阐明肾上腺髓质素的生理和治疗作用，我们通过在肾上腺髓质素基因的起始密码子插入终止突变来产生肾上腺髓质素敲除小鼠。纯合子是胚胎致死的，我们使用杂合子。我们在2001年曾报道，这种突变体显示血管紧张素II可能通过过度产生氧化应激引起显著的血管损伤。在2002年，我们证明了老年突变体积累氧化应激和胰岛素抵抗，观察到在这个老年突变体。补充肾上腺髓质素或用超氧化物歧化酶治疗成功地逆转了突变体的胰岛素抵抗状态。这些结果表明，肾上腺髓质素是一种内在的抗氧化剂，它的缺乏将导致多种oragan损害。此外，它还将成为预防高血压、糖尿病等常见疾病并发症的新的治疗药物。

Adrenomedullin and PAMP are derived from the same precursor protein and in order to clarify the physiological and therapeutical role of adrenomedullin, we generated adrenomedullin knockout mice by inserting stop mutation in the starting codon of adrenomedullin gene. The homozygous were embryonic lethal and we used heterozygotes. We have reported in 2001 that this mutant showed marked vascular damage by angiotensin II possibly through, overproduction of oxidative stress. In 2002, we demonstrated that aged mutants accumulate oxidative stress and insulin resistance was observed in this aged mutant. Adrenomedullin supplementation or treatment with super oxide dismutase successfully reversed insulin resistant state in the mutants. These results suggest that adrenomedullin is an intrinsic anti-oxidant and its deficiency will cause several oragan damages. Moreover, it will he a new therapeutical agent to prevent complications in common disease such as hypertension, diabetes.