|Budget Amount *help
¥2,900,000 (Direct Cost : ¥2,900,000)
Fiscal Year 1998 : ¥1,100,000 (Direct Cost : ¥1,100,000)
Fiscal Year 1997 : ¥1,800,000 (Direct Cost : ¥1,800,000)
Cardiovascular hormones may be implicated in various renal and cardiovascular disorders such as chronic renal failure, glomerulonephritis, and hypertension. To explore their roles, we studied the renal renin-angiotensin system (RAS), adrenomedullin (AM) system, and natriuretic peptide system (NPS) using experimental disease models.
Angiotensin II type 2 (AT_2) receptor is abundantly expressed in the fetus and markedly down-regulated after birth, but reexpressed in various disease states. In cultured rat mesangial cells (MC), the AT_2 receptor was markedly induced upon confluence and exerted antiproliferative and proapoptotic effects counteracting the AT_1 receptor, and inhibited the MAP kinase cascade. Lower expression of the AT_2 receptor in glomeruli at the younger period from spontaneously hypertensive rats (SHRSP) as well as in MC of SHRSP with highly proliferative nature, suggested its implication in pathogenesis of glomerular injury and hypertension.
To clarify a role of AM as a lo
cal regulator, we examined its secretion and action in cultured mesangial and endothelial cells (EC) using a monoclonal antibody (MAb) prepared against AM.We found secretion of AM, with a potent antigrowth property, from cultured MC as abundantly as from EC, and neutralization of endogenous AM by MAb markedly reduced basal cAMP levels and stimulated growth of EC.MC from SHRSP secreted less AM compared to WKY.These findings suggested a role of endogenous AM as an autocrine/paracrine regulator in these cells.
We have previously established the transgenic mice overexpressing brain natriuretic peptide (BNP-Tg) with low blood pressure. To assess the renal RAS-NPS interaction, we examined the effect of excess of BNP, using mouse models of renal diseases with chronic RAS activation, i.e. subtotal nephrectomy and anti-GBM nephritis. We found significant renoprotective effects of BNP, suggesting that NPS acts against RAS in vivo, perhaps at cellular and molecular levels including MAP kinase and TGF-beta expression. In another model of renal RAS activation, unilateral ureteral obstruction, renal expression of AM was significantly reduced along with development of interstitial fibrosis, suggesting that AM may normally act against renal fibrosis. Less