Key role of diacylglycerol-mediated 12-lipoxygenase product formation in angiotensin II-induced aldosterone synthesis.
We have shown earlier that the 12-lipoxygenase product of arachidonic acid (AA), 12-hydroxyeicosatetraenoic acid (12-HETE), plays an important role in mediating angiotensin II (AII)-induced aldosterone secretion (J. Clin. Invest. (1987) 80, 1763). In the present study, we have evaluated whether diacylglycerol (DG) is the source of arachidonic acid giving rise to this 12-HETE. Treatment of rat adrenal glomerulosa cells with a DG lipase inhibitor, RHC 80267, which prevents conversion of DG to AA and HETEs, blocked AII-induced aldosterone and 12-HETE formation. In contrast, a DG kinase inhibitor, R59022, which prevents conversion of DG to phosphatidic acid, potentiated AII-induced aldosterone and 12-HETE formation. These two inhibitors block DG metabolism which would be expected to lead to increased DG levels and protein kinase C activity and AII-induced steroidogenesis. However, only R59022 potentiated AII action while RHC 80267 was inhibitory. This suggests that conversion of DG to AA and 12-HETE is important for AII action. Further proof for this was obtained by measuring [3H]AA-labeled DG levels. The combination of the inhibitors significantly potentiated AII-induced DG formation even though this same combination was inhibitory on AII-induced aldosterone and 12-HETE. Thus, the inhibitory effect of RHC 80267 is due to blockade of AA release and not of DG formation. These results suggest that DG plays a dual role in AII action, both as an activator of protein kinase C and as a source of AA for 12-HETE formation.
Natarajan
R
R
Section of Endocrinology, University of Southern California Medical Center, Los Angeles 90033.
Dunn
W D
WD
Stern
N
N
Nadler
J
J
D019377:12-Hydroxy-5,8,10,14-eicosatetraenoic Acid; D000450:Aldosterone / Q000096:biosynthesis*; D000804:Angiotensin II / Q000494:pharmacology*; D000818:Animals; D001092:Arachidonate 12-Lipoxygenase / Q000378:metabolism*; D016718:Arachidonic Acid; D001095:Arachidonic Acids / Q000378:metabolism; D003512:Cyclohexanones / Q000494:pharmacology; D019852:Diacylglycerol Kinase; D004075:Diglycerides / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006893:Hydroxyeicosatetraenoic Acids / Q000378:metabolism; D008071:Lipoprotein Lipase / Q000037:antagonists & inhibitors; D008297:Male; D010770:Phosphotransferases / Q000037:antagonists & inhibitors; D011744:Pyrimidinones / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D013844:Thiazoles / Q000494:pharmacology; D015384:Zona Glomerulosa / Q000187:drug effects / Q000378:metabolism*
D001095:Arachidonic Acids; D003512:Cyclohexanones; D004075:Diglycerides; D006893:Hydroxyeicosatetraenoic Acids; D011744:Pyrimidinones; D013844:Thiazoles; D000804:Angiotensin II; D016718:Arachidonic Acid; D000450:Aldosterone; D019377:12-Hydroxy-5,8,10,14-eicosatetraenoic Acid; C036535:1,6-bis(cyclohexyloximinocarbonyl)hexane; C047505:R 59022; D001092:Arachidonate 12-Lipoxygenase; D010770:Phosphotransferases; D019852:Diacylglycerol Kinase; D008071:Lipoprotein Lipase