Adrenomedullin has an antioxidative action and protects organs in various diseases. To clarify the role of adrenomedullin in diabetic nephropathy, we investigated the NADPH oxidase expression, renin-secreting granular cell (GC) hyperplasia, and glomerular matrix expansion in the streptozotocin (STZ)-induced diabetic adrenomedullin gene knockout (AMKO) mice compared with the STZ-diabetic wild mice at 10 weeks. The NADPH oxidase p47phox expression and lipid peroxidation products were enhanced in the glomeruli of the diabetic mice compared with that observed in the controls in both wild and AMKO mice. These changes were more obvious in the AMKO mice than in the wild mice. Glomerular mesangial matrix expansion was more severe in the diabetic AMKO mice than in the diabetic wild mice and exhibited a positive correlation with the degree of lipid peroxidation products in the glomeruli. Proteinuria was significantly higher in the diabetic AMKO mice than in the diabetic wild mice. The GC hyperplasia score and the renal prorenin expression were significantly increased in the diabetic AMKO mice than in the diabetic wild mice, and a positive correlation was observed with the NADPH oxidase expression in the macula densa. The endogenous adrenomedullin gene exhibits an antioxidant action via the inhibition of NADPH oxidase probably by suppressing the local renin-angiotensin system. 1. Introduction Adrenomedullin is a potent vasodilating peptide that is upregulated in cardiovascular diseases to counteract the disease process with its diverse physiological actions including antioxidative stress actions [1–6]. The plasma concentration of adrenomedullin also increased in the diabetic patients, and hyperglycemia increases the production of adrenomedullin in the vasculature [7, 8]. The receptors for adrenomedullin are expressed in the kidneys, especially in the glomerulus and distal nephron, and the local action of adrenomedullin is increased in diabetic rats [9], thus suggesting that adrenomedullin may contribute to the dilatation of the glomerular capillary in the early phase of diabetic nephropathy. Although the organoprotective effects of adrenomedullin have been demonstrated in various cardiovascular diseases, the mechanisms underlying its renoprotection in diabetic nephropathy are still unclear. Hyperglycemia accelerates the formation of advanced glycation end products (AGE), while also upregulating the protein kinase C (PKC) activity, accelerating the polyol pathway, and promoting sorbitol deposition [10]. These pathways are related to the increased oxidative stress,
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