Adrenomedullin inhibits transmural pressure induced mesangial cell proliferation through activation of protein kinase A

Adrenomedullin (AM), a hypotensive peptide isolated from human pheochromocy toma, inhibits the proliferation of mesangial cells (MC) induced by mitogen s such as platelet-derived growth factor. Quite recently, we have demonstra ted that transmural pressure applied to cultured MC increased DNA synthesis and cell proliferation through protein kinase C and tyrosine kinase pathwa ys. However, the modulatory effect of AM on pressure-induced cell prolifera tion is as yet unknown. In the present study, we examined the effect of AM on transmural pressure-induced DNA synthesis in cultured rat MC. Pressure w as applied to cells placed in a sealed chamber using compressed helium. App lication of pressure resulted in an increase in [H-3]thymidine incorporatio n (approximately 2.0-fold). AM clearly inhibited pressure-induced DNA synth esis in a concentration-dependent manner. This inhibition was paralleled by an increase in cellular cAMP levels evoked by AM. Forskolin and dibutyryl cAMP mimicked the inhibitory effect of AM. The protein kinase A inhibitor H -89 significantly attenuated the effect of AM, Human AM(22-52)-NH2, a putat ive AM receptor antagonist, reversed the inhibitory effects of AM more pote ntly than did human CGRP(8-37), a calcitonin gene related peptide receptor antagonist. Our results suggest that AM, by acting mainly on AM-sensitive r eceptors, inhibits pressure-induced DNA synthesis in cultured rat MC throug h activation of protein kinase A, AM may play a protective role against MC proliferation in certain pathological conditions. Copyright (C) 1999 S. Kar ger AG, Basel.