The peptide hormone angiotensin-II (All) is a potent vasoconstrictor and major regulator of aldosterone synthesis. In addition, All also has growth-promoting effects. We have recently shown that the lipoxygenase (LO) pathway of arachidonic acid plays a major role in All-induced aldosterone synthesis in adrenal glomerulosa cells. The LO pathway is also involved in the vasopressor and renin-inhibitory effects of AIL However, the role of LO products in All-induced mitogenic effects have not yet been investigated. In the present studies we have evaluated the role of the LO pathway in All-induced proliferative responses in a bovine adrenocortical cell clone termed AC1 cells. In addition, the potential receptor type and mechanism of All-induced proliferation was studied by evaluating the effect of specific nonpeptide type 1 and type 2 All receptor antagonists and the role of protein kinase-C (PKC). All-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 All-mediated mitogenesis. Allinduced proliferative responses were blocked by the type 1 All receptor antagonist. Both All- and 12-HETE-induced increases in DNA synthesis were markedly inhibited by two PKC blockers, staurosporine and sangivamycin. Further, both All 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 All-induced adrenal cell proliferation.
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