Leptin is enhanced in animal models of obesity. The role of leptin in hypertension is unclear with some studies showing antihypertensive actions and others showing a pro-hypertensive role. In normotensive, non-obese, animals, infusion of leptin induces natriuresis. However, in animal models of enhanced oxidative stress, obesity, or activated renin-angiotensin system, infusion of leptin tends to increase blood pressure. Renin is a critical mediator of angiotensin-II formation, and thus blood pressure control. However, the direct effect of leptin on the release of renin from juxtaglomerular (JG) cells has not been studied. We hypothesize that under normal conditions leptin does not affect renin release whereas during high oxidative stress leptin stimulates renin release. We isolated primary cultures of mouse juxtaglomerular (JG) cells. After treatment with different agonists, renin released to the supernatant was measured by radioimmunoassay. We first tested the direct effect of murine leptin on renin release. We found that 1 hr treatment with leptin (0.1-1 uM) decreased basal renin by 20 ± 5% (p<0.05; n=8). Treatment of JG cells for longer periods (4 and 24 hrs) did not affect renin release (n=6) or total renin expression (n=4). We then tested whether oxidative stress modified the effect of leptin on renin release. For this we pre-incubated JG cells with 10 uM hydrogen peroxide (H2O2) for 1 hr. After this, the medium was removed and H2O2 was completely washed out from JG cells followed by treatment with vehicle (cont) or 10 uM leptin. We found that, in cells pre-treated with H2O2, leptin increased renin release by 49.2 ±16 %(P<0.05 vs vehicle). By Western blot, we detected the expression of the leptin receptor in lysates from JG cells. We concluded that under normal conditions leptin inhibits renin release from JG cells. However, after exposure to H2O2, leptin stimulates renin release. Our data suggest the hypothesis that oxidative stress reverses the inhibitory effect of leptin on renin release and supports a pro-hypertensive role for leptin during chronic inflammatory conditions that induces oxidative stress.
Sex, Oxidative Stress, and Hypertension: Insights From Animal Models
