腎糸球体メサンギウム細胞に於けるアンジオテンシソIIの抗ANP作用について

―細胞内cyclic GMP蓄積の抑制―

抄録

Glomerular mesangial cells are believed to contribute to regulation of glomerular filtration rate through their contractility, which is regulated by various vasoactive hormones such as angiotensin II (A II), and atrial natriuretic peptide (ANP). A II has been recently reported to inhibit ANP-induced cyclic GMP (cGMP) accumulation in vascular smooth musucle cells, and other types of cells, but the mechanism of this inhibitory effect of A II is still unclear. In order to know the interaction between A II and ANP in glomerular mesangial cells and to know the mechanism of the interaction, I examined the effects of A II on ANP-induced cGMP accumulation in cultured rat glomerular mesangial cells. ANP produced rapid increase in cellular cGMP in cultured rat glomerular mesangial cells, which was significantly inhibited by co-incubation with A II. A II also inhibited cGMP accumulation produced by sodium nitroprusside, soluble guanylate cyclase activator. This inhibitory effect of A II was completely blocked by 1 mM of 3-isobutyl-1-methylx-anthine (IBMX), a cyclic nucleotide phosphodiesterase inhibitor. Thus, it seems that A II inhibits ANP-induced cGMP accumulation by activating phosphodiesterase rather than by inhibiting guanylate cyclase. Since the action of A II has been reported to be mediated by increase of cytosolic free Ca²⁺ secondary to inositol 1, 4, 5-trisphosphate (IP₃) generation and activation of pro-tein kinase C secondary to diacylglycerol (DG) generation, I investigated the effects of Ca ionophore (A23187), and 12-O-tetradecanoyl phorbol-l3-acetate (TPA), protein kinase C activator, on ANP-induced cGMP acumulatian. Ca ionophore (A23187) inhibited cellular cGMP accumulation produced by ANP similarly to A II, whereas TPA had no effect upon ANP-induced cGMP accumulation. These results suggest that, at least in short term experiment, A II inhibits the ANP-induced cGMP accumulation by stimulating cGMP hydrolysis via an activation of Ca²⁺dependent cyclic nucleotide phosphodiesterase.