ATRIAL-NATRIURETIC-PEPTIDE INHIBITS GROWTH OF HEPATOBLASTOMA (HEP-G2)CELLS BY MEANS OF ACTIVATION OF CLEARANCE RECEPTORS

To investigate whether atrial natriuretic factor regulates the growth of hepatocytes and to determine the receptor subtype involved in such modulation, we studied the effect of atrial natriuretic factor 103-126 and clearance receptor binding analogs of atrial natriuretic factor, (des-(Q116, S117, G118, L119, G120) atrial natriuretic factor 102-121 and des-(C105,121) atrial natriuretic factor 104-126) on growth of hum an hepatoblastoma cells. Atrial natriuretic factor 103-126 and des-(Q1 16, S117, G118, L119, G120) atrial natriuretic factor 102-121 inhibite d thymidine incorporation into human hepatoblastoma cells cultured in the presence of bovine serum albumin and epidermal growth factor but n ot in cells cultured in bovine serum albumin alone. Moreover, atrial n atriuretic factor 103-126, des-(Q116, S117, G118, L119, G120) atrial n atriuretic factor 102-121 and des-(C105,121) atrial natriuretic factor 104-126, in a concentration-dependent manner, inhibited thymidine inc orporation and cell proliferation. As monitored by the ability of des- (Q116, S117, G118, L119, G120) atrial natriuretic factor 102-121 to di splace I-125-labeled atrial natriuretic factor, epidermal growth facto r increased the expression of cell surface clearance receptors. Epider mal growth factor also transiently increased the cellular content of a trial natriuretic factor clearance receptor messenger RNA without alte ring the levels of guanylyl cyclase-linked atrial natriuretic factor r eceptor messenger RNA levels. Maximal increase in atrial natriuretic f actor clearance receptor messenger RNA coincided with the maximal incr ease in des-(Q116, S117, G118, L119, G120) atrial natriuretic factor 1 02-121-displaceable I-125-atrial natriuretic factor binding sites. The ability of atrial natriuretic factor clearance receptor-binding ligan ds to inhibit thymidine incorporation and cell proliferation - coupled with the selective upregulation of clearance receptor expression by e pidermal growth factor, which facilitates the growth modulatory action s of atriopeptins-indicates that the atrial natriuretic factor clearan ce receptors mediate the growth regulatory actions of atrial natriuret ic factor. Additionally, the clearance receptor-binding ligands decrea sed cellular cyclic AMP content only under conditions in which clearan ce receptors are expressed, suggesting that modulation of cyclic AMP b y activation of these receptors regulates growth.