ENDOTHELINS INHIBIT CYCLIC-AMP INDUCED RENIN GENE-EXPRESSION IN CULTURED MOUSE JUXTAGLOMERULAR CELLS

Endothelins inhibit induced renin gene expression in cultured mouse ju xtaglomerular cells. We have recently described that endothelins-1 to -3 equipotently inhibit cAMP stimulated renin secretion from cultured mouse juxtaglomerular cells by a process involving phospholipase C act ivation. This study examined the influence of endothelin-2 on renin ge ne expression in renal juxtaglomerular cells. To this end we semiquant itated renin mRNA levels by competitive RT-PCR in primary cultures of mouse renal juxtaglomerular cells after 20 hours of incubation. We fou nd that endothelin-2 (0.1 to 100 nmol/liter) did not change basal reni n gene expression. The adenylate cyclase activator forskolin (3 mu mol /liter) increased renin mRNA levels to 400% of the controls and this s timulation was dose-dependently attenuated by ET-2 to 250% of the cont rol value. The effect of ET-2 was mimicked by the ET(B)-receptor agoni st sarafotoxin S6c. The kinase inhibitor staurosporlne (100 nmol/liter ) increased renin secretion and renin mRNA levels. Combination of stau rosporine with forskolin produced the same effects on renin secretion and renin mRNA levels as did staurosporine alone. In the presence of b oth forskolin and staurosporine ET-2 had no significant effect on reni n secretion and renin gene expression. The phorbol ester PMA (30 nmol/ liter), which was used to stimulate protein kinase C activity, attenu ated cAMP stimulated renin secretion and renin mRNA levels. Lowering t he extracellular concentration of calcium by the addition of 1 mmol/li ter EGTA did not inhibit the effect of ET-2 on cAMP induced renin secr etion and renin gene expression. These findings suggest that endotheli ns inhibit cAMP stimulated renin gene expression by an event that is m ediated via ET(B) receptors. This inhibitory effect may in part involv e protein kinase C activation.