A 12-lipoxygenase product of arachidonate metabolism is involved in angiotensin action on renin release.
Angiotensin II (AII) action is coupled to the hydrolysis of phospholipids resulting in the formation of arachidonic acid, the precursor of both prostaglandins, and hydroxyeicosatetraenoic acids (HETEs). Since 12-HETE is not only a major arachidonate lipoxygenase (LO) product in the kidney, but is also a potent inhibitor of renin release, we studied the role of AII on renin inhibition and 12-HETE formation using rat renal cortical slices and isolated juxtaglomerular-like cells. In both preparations, 12-HETE was produced in a basal state. AII significantly inhibited renin release (control 100 +/- 3%, AII (10(8) M) 79 + 4%, P less than 0.01) and stimulated 12-HETE formation in slices (control 106 +/- 6%, AII 10(-8) M 177 +/- 18%, P less than 0.01) and in an enriched juxtaglomular cell preparation (control 96 +/- 3%, AII 10(-8) M 130 +/- 6%, P less than 0.001). A specific cyclooxygenase blocker, meclofenomate, or 5-LO blocker, U60,257, did not alter basal or AII-induced renin inhibition or 12-HETE formation by slices. The LO blockers BW755c, at 10(-5) M, or baicalein, 10(-6) M, did not significantly alter basal renin or 12-HETE levels, but BW755c at 10(-4) M, significantly stimulated basal renin (131 +/- 4%) and decreased basal 12-HETE levels (72 +/- 5%). However, both BW755c and baicalein blunted AII-induced renin inhibition (AII, 10(-8) M 70 +/- 3%, AII + BW755c, 10(-5) M 85 +/- 4%, P less than 0.02, AII + baicalein, 10(-6) M, 90 +/- 4%, P less than 0.005) and AII mediated 12-HETE formation (AII, 10(-8) M 150 +/- 5%, AII + BW755c, 10(-5) M 117 +/- 8%, P less than 0.02, AII + baicalein, 10(-6) M 110 +/- 3%, P less than 0.005). These results suggest that AII inhibition of renin is not mediated by the cyclooxygenase or 5-LO pathway, but rather by the 12-LO pathway. These findings reveal a new action for 12-LO products which may play a pivotal role in stimulus secretion coupling of renin secretion.
Antonipillai
I
I
University of Southern California Medical Center, Section of Endocrinology, Los Angeles 90033.
Horton
R
R
Natarajan
R
R
Nadler
J
J
D019377:12-Hydroxy-5,8,10,14-eicosatetraenoic Acid; D000804:Angiotensin II / Q000494:pharmacology*; D000818:Animals; D001092:Arachidonate 12-Lipoxygenase / Q000096:biosynthesis*; D001091:Arachidonate Lipoxygenases / Q000096:biosynthesis*; D016718:Arachidonic Acid; D001095:Arachidonic Acids / Q000378:metabolism*; D016861:Cyclooxygenase Inhibitors; D006893:Hydroxyeicosatetraenoic Acids; D066298:In Vitro Techniques; D007672:Kidney Cortex / Q000378:metabolism; D008084:Lipoxygenase / Q000378:metabolism; D008297:Male; D051381:Rats; D011919:Rats, Inbred Strains; D012083:Renin / Q000378:metabolism*; D000092502:Renin Inhibitors
D019377:12-Hydroxy-5,8,10,14-eicosatetraenoic Acid; D000804:Angiotensin II; D001092:Arachidonate 12-Lipoxygenase; D001091:Arachidonate Lipoxygenases; D016718:Arachidonic Acid; D001095:Arachidonic Acids; D016861:Cyclooxygenase Inhibitors; D006893:Hydroxyeicosatetraenoic Acids; D008084:Lipoxygenase; D012083:Renin; D000092502:Renin Inhibitors