Platelet-derived growth factor is a potent inhibitor of angiotensin II-induced aldosterone synthesis.
Platelet-derived growth factor (PDGF) is a potent mitogen for several cell types. In addition, PDGF has vasoconstrictive action and shares some signal transduction mechanisms with angiotensin II (AII). In the present study, we have examined the effects of PDGF on basal and AII-induced aldosterone synthesis in freshly isolated rat adrenal glomerulosa cells. Recombinant human PDGF-BB caused a dose-dependent inhibition of AII-induced aldosterone synthesis being effective at concentrations as low as 10(-12) M. We also investigated possible mechanisms of action of PDGF. We have previously reported that the 12-lipoxygenase (LO) pathway of arachidonic acid plays a key role in AII-induced aldosterone synthesis. We thus examined whether PDGF action is mediated by changes in 12-LO activation. PDGF, at the same doses that blocked AII-induced synthesis also significantly inhibited AII-induced increases in the 12-LO product, 12-hydroxyeicosatetraenoic acid (12-HETE) formation. Further, the addition of 12-HETE completely restored the stimulatory effect of AII during inhibition by PDGF. These results suggest that PDGF could act, at least in part, by inhibition of AII-induced 12-HETE formation. We also examined the role of diacylglycerol (DG) formation since we have previously reported that DG is the source of arachidonic acid for 12-HETE formation. We observed that both AII and PDGF stimulated [3H]arachidonic acid-labeled DG formation. However, PDGF did not alter AII-induced DG formation suggesting that PDGF action is not mediated by affecting AII-induced increases in DG.(ABSTRACT TRUNCATED AT 250 WORDS)
Natarajan
R
R
Department of Diabetes, Endocrinology and Metabolism, City of Hope National Medical Center, Duarte, CA 91010.
Nadler
J
J
D019377:12-Hydroxy-5,8,10,14-eicosatetraenoic Acid; D000324:Adrenocorticotropic Hormone / Q000494:pharmacology; D000450:Aldosterone / Q000096:biosynthesis* / Q000378:metabolism; D000804:Angiotensin II / Q000037:antagonists & inhibitors / Q000502:physiology*; D000818:Animals; D016718:Arachidonic Acid / Q000378:metabolism; D004075:Diglycerides / Q000096:biosynthesis; D004789:Enzyme Activation; D006801:Humans; D006893:Hydroxyeicosatetraenoic Acids / Q000096:biosynthesis; D066298:In Vitro Techniques; D008084:Lipoxygenase / Q000378:metabolism; D008297:Male; D010982:Platelet-Derived Growth Factor / Q000502:physiology*; D011188:Potassium / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains
D004075:Diglycerides; D006893:Hydroxyeicosatetraenoic Acids; D010982:Platelet-Derived Growth Factor; D000804:Angiotensin II; D016718:Arachidonic Acid; D000450:Aldosterone; D019377:12-Hydroxy-5,8,10,14-eicosatetraenoic Acid; D000324:Adrenocorticotropic Hormone; D008084:Lipoxygenase; D011188:Potassium