ATRIAL-NATRIURETIC-PEPTIDE INHIBITS ENDOTHELIN-1-INDUCED ACTIVATION OF JNK IN GLOMERULAR MESANGIAL CELLS

Atrial natriuretic peptide (ANP) has been shown to counteract various actions of endothelin-1 (ET-1) in mesangial cells. We have reported th at both extracellular signal-regulated kinase (ERK) and c-Jun NH2-term inal kinase (JNK) are activated by ET-1 and ET-1-induced activation of ERK is inhibited by ANP. To further clarify the action of ANP, we exa mined the effect of ANP on ET-1-induced activation of JNK. ANP inhibit ed ET-1-induced activation of JNK in a dose-dependent manner. This inh ibitory effect of ANP was reversed by HS-147-1, an antagonist for biol ogical receptors of ANP, while C-ANP, an analog specific to clearance receptors of ANP, failed to inhibit ET-1-induced activation of JNK. 8- Bromo-cGMP and sodium nitroprusside were also able ro inhibit ET-1-ind uced activation of JNK, suggesting cGMP-dependent action of ANP. In co ntrast, ANP failed to inhibit interleukin-1 beta (IL-1 beta)-induced a ctivation of JNK. Since an increase in intracellular calcium ([Ca2+](i )) was shown to be necessary for ET-1-induced activation of JNR in mes angial cells, we measured [Ca2+](i) using fura-2. ANP attenuated the E T-1-induced increase in [Ca2+](i) in concentrations enough to inhibit ET-1-induced activation of JNK. Finally, ANP was able to inhibit ET-1- , but not IL-1 beta-induced increase in DMA-binding activity of AP-1 b y gel shift assay. These results indicate that ANP is able to inhibit ET-1-induced activation of AP-1 by inhibiting both ERK and JNK, sugges ting that ANP might be able to counteract the expression of AP-1-depen dent genes induced by ET-1.