Mechanism of angiotensin II-induced proliferation in bovine adrenocortical cells.
The peptide hormone angiotensin-II (AII) is a potent vasoconstrictor and major regulator of aldosterone synthesis. In addition, AII also has growth-promoting effects. We have recently shown that the lipoxygenase (LO) pathway of arachidonic acid plays a major role in AII-induced aldosterone synthesis in adrenal glomerulosa cells. The LO pathway is also involved in the vasopressor and renin-inhibitory effects of AII. However, the role of LO products in AII-induced mitogenic effects have not yet been investigated. In the present studies we have evaluated the role of the LO pathway in AII-induced proliferative responses in a bovine adrenocortical cell clone termed AC1 cells. In addition, the potential receptor type and mechanism of AII-induced proliferation was studied by evaluating the effect of specific nonpeptide type 1 and type 2 AII receptor antagonists and the role of protein kinase-C (PKC). AII-induced DNA synthesis was significantly attenuated by two structurally dissimilar LO inhibitors, baicalein and phenidone. In addition, the LO product 12-hydroxyeicosatetraenoic acid (12-HETE) itself caused a significant increase in DNA synthesis, suggesting that the 12-LO pathway in part plays a role in AII-mediated mitogenesis. AII-induced proliferative responses were blocked by the type 1 AII receptor antagonist. Both AII- and 12-HETE-induced increases in DNA synthesis were markedly inhibited by two PKC blockers, staurosporine and sangivamycin. Further, both AII and 12-HETE could activate PKC by translocating it from the cytosol to the membrane fraction, as determined by Western immunoblotting. These results suggest that both 12-LO activation and protein kinase-C have an important role in AII-induced adrenal cell proliferation.
Natarajan
R
R
Department of Diabetes, Endocrinology, and Metabolism, City of Hope Medical Center, Duarte, California 91010.
Gonzales
N
N
Hornsby
P J
PJ
Nadler
J
J
D019377:12-Hydroxy-5,8,10,14-eicosatetraenoic Acid; D000302:Adrenal Cortex / Q000166:cytology* / Q000187:drug effects / Q000502:physiology; D000804:Angiotensin II / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D057911:Angiotensin Receptor Antagonists; D001713:Biphenyl Compounds / Q000494:pharmacology; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D004261:DNA Replication / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D044950:Flavanones; D005419:Flavonoids / Q000494:pharmacology; D006801:Humans; D006893:Hydroxyeicosatetraenoic Acids / Q000378:metabolism; D007093:Imidazoles / Q000494:pharmacology; D019808:Losartan; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism; D011720:Pyrazoles / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D011741:Pyrimidine Nucleosides / Q000494:pharmacology; D013777:Tetrazoles / Q000494:pharmacology; D013936:Thymidine / Q000378:metabolism
D057911:Angiotensin Receptor Antagonists; D001713:Biphenyl Compounds; D044950:Flavanones; D005419:Flavonoids; D006893:Hydroxyeicosatetraenoic Acids; D007093:Imidazoles; D011720:Pyrazoles; D011725:Pyridines; D011741:Pyrimidine Nucleosides; D013777:Tetrazoles; D000804:Angiotensin II; C066253:PD 123177; C005699:sangivamycin; C006680:baicalein; D019377:12-Hydroxy-5,8,10,14-eicosatetraenoic Acid; C025984:15-hydroxy-5,8,11,13-eicosatetraenoic acid; D011493:Protein Kinase C; C015429:phenidone; D019808:Losartan; D013936:Thymidine