Adrenomedullin-sensitive receptors are preferentially expressed in cultured rat mesangial cells.

By using cultured rat mesangial cells, we compared the effects on cyclic nucleotide levels of adrenomedullin with those of the structurally related peptides, calcitonin gene-related peptide (CGRP) and amylin. Adrenomedullin potently increased cAMP levels 7-fold in a time- and concentration-dependent manner. Its EC50 was 3 x 10(-9) M. CGRP was less potent (2-fold) with an EC50 of 10(-7) M, and amylin had no effect on cAMP levels. All three peptides failed to increase cGMP levels. Treatment of cells with near maximal concentrations of adrenomedullin (10(-7) M) and CGRP (10(-6) M) had no additive effect on cAMP levels. Human adrenomedullin-(22-52)-NH2, a putative adrenomedullin receptor antagonist, inhibited the production of cAMP elicited by adrenomedullin (IC50: 7 x 10(-8) M) and CGRP (IC50: 5 x 10(-8) M). Human CGRP-(8-37), a CGRP receptor antagonist, conversely, reduced the cAMP elevation caused by these peptides with a lower potency (IC50: 10(-6) M for both peptides). This demonstrated that human adrenomedullin-(22-52)-NH2 was a more effective antagonist for adrenomedullin- and CGRP-specific receptors than human CGRP-(8-37). Results suggest that receptors sensitive to adrenomedullin are preferentially expressed in cultured rat mesangial cells. Immunohistochemical study showed almost no immunoreactive adrenomedullin and CGRP, if any, in the cells. Adrenomedullin may regulate mesangial function as either a paracrine or circulating hormone via a cAMP- but not a cGMP-dependent mechanism.