Heme oxygenase-1 is a potent inhibitor of placental ischemia-mediated endothelin-1 production in cultured human glomerular endothelial cells

Preeclampsia is a pregnancy-specific disorder of maternal hypertension and reduced renal hemodynamics linked to reduced endothelial function. Placental ischemia is thought to be the culprit of this disease, as it causes the release of factors like tumor necrosis factor (TNF)-α that induce vascular endothelin-1 (ET-1) production. Interestingly, placental ischemia-induced hypertension in rats (reduced uterine perfusion pressure, RUPP model) is abolished by ETA receptor blockade, suggesting a critical role for ET-1. While it has been found that systemic induction of heme oxygenase (HO)-1 is associated with reduced ET-1 production and attenuated hypertension, it is unclear whether HO-1 directly modulates the increased ET-1 response to placental factors. We tested the hypothesis that HO-1 or its metabolites inhibit ET-1 production in human glomerular endothelial cells induced by serum of RUPP rats or TNF-α. Serum (5%) from RUPP hypertensive (mean arterial blood pressure 119±9 mmHg) versus normotensive pregnant (NP, 101±6 mmHg, P<0.001) rats increased ET-1 production (RUPP, 168.8±18.1 pg/mL, NP, 80.3±22.7 pg/mL, P<0.001, n=12/group). HO-1 induction (25µM cobalt photoporphyrin; CoPP) abolished RUPP serum-induced ET-1 production (1.6±0.8 pg/mL, P<0.001), while bilirubin (10µM) significantly attenuated ET-1 release (125.3±5.2 pg/mL P=0.005). Furthermore, TNF-α-induced ET-1 production (TNF-α, 31.0±8.4 vs. untreated, 7.5±0.4 pg/mL, P<0.001) was reduced by CoPP (1.5±0.8 pg/mL, P<0.001) and bilirubin (10.5±4.3 pg/mL, P<0.001). These results suggest that circulating factors released during placental ischemia target the maternal glomerular endothelium to increase ET-1, and that pharmacological induction of HO-1 or bilirubin could be a treatment strategy to block this pro-hypertensive pathway in preeclampsia.

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