PHYSIOLOGICAL ROLE OF ADRENOMEDULLIN BY MOLECULAR BIOLOGICAL AND GENE ENGINEERING APPROACH

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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.