Eicosanoids (prostaglandins) can alter renin secretion and angiotensin (ANG) II action. We have studied the effects of both prostacyclin and a lipoxygenase (LO) product, 12-hydroxyeicosatetraenoic acid (12-HETE), on renin in normal and streptozotocin-induced diabetic rats. 12-HETE is not only a potent inhibitor of basal renin secretion but also a key mediator of ANG II-induced renin inhibition. We have also examined the effects of ANG II on 12-HETE formation in normal and diabetic animals. Both plasma (3.9 ± 0.9 vs. 0.8 ± 0.1 ng ANG I ç ml−1 + h−1, P < 0.01) and tissue (38 ± 6 vs. 21 ± 2 ng ANG I + mg tissue−1 + h−1, P < 0.05) renin activity levels were markedly reduced in diabetic animals. Iloprost (10−6 mol/l), a stable analog of prostacyclin, had similar stimulatory effects on renin secretion in both normal and diabetic tissues, but the response was enhanced by LO inhibition in diabetic tissue. 12-HETE (10−7 mol/l) had an exaggerated effect on renin inhibition in diabetic tissue (78 ± 2% normal vs. 65 ± 4% diabetic, P < 0.05). Similarly, ANG II (10−8 mol/l) inhibition of renin was significantly enhanced in diabetic rats (P < 0.001). However, ANG II did not produce an exaggerated increase in 12-HETE in diabetic renal tissue. Insulin reversed the inhibitory effects of ANG II on renin in normal rats, but it blunted the effect of ANG II in diabetic rats. These studies suggest that, while the capacity of renal cortical tissue to synthesize 12-HETE in response to ANG II is not altered, 12-HETE and ANG II actions are exaggerated in diabetes, and this may contribute to reduced renin production.