Preeclampsia remains a leading cause of maternal and perinatal morbidity and mortality. There have been no material advances in the treatment of preeclampsia for nearly 50 years. Combining in vitro studies and a clinical trial, we aimed to determine whether melatonin could be a useful adjuvant therapy. In a xanthine/xanthine oxidase (X/XO) placental explant model, melatonin reduced oxidative stress (8-isoprostane) and enhanced antioxidant markers (Nrf2 translocation, HO-1), but did not affect explant production of anti-angiogenic factors (sFlt, sEng, activin A). In cultured HUVECs, melatonin mitigated TNFα-induced vascular cell adhesion molecule expression and rescued the subsequent disruption to endothelial monolayer integrity but did not affect other markers for endothelial activation and dysfunction. In a phase I trial of melatonin in 20 women with preeclampsia, we assessed the safety and efficacy of melatonin on (i) preeclampsia progression, (ii) clinical outcomes, and (iii) oxidative stress, matching outcomes with recent historical controls receiving similar care. Melatonin therapy was safe for mothers and their fetuses. Compared to controls, melatonin administration extended the mean ± SEM diagnosis to delivery interval by 6 ± 2.3 days reduced the need for increasing antihypertensive medication on days 3-4 (13% vs 71%), days 6-7 (8% vs 51%), and at delivery (26% vs 75%). All other clinical and biochemical measures of disease severity were unaffected by melatonin. We have shown that melatonin has the potential to mitigate maternal endothelial pro-oxidant injury and could therefore provide effective adjuvant therapy to extend pregnancy duration to deliver improved clinical outcomes for women with severe preeclampsia.

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It has been hypothesized that a reduced nephron endowment exacerbates the hypertensive and renal effects of obesity. We therefore examined the impact of diet-induced obesity on renal structure and function, and arterial pressure in a genetic model of reduced nephron endowment, the GDNF Heterozygous (HET) mouse. 6wk-old male GDNF WT and HET mice were placed on control or high fat (HFF) diet for 20 weeks. 24 hr arterial pressure, heart rate and activity (radiotelemetry), creatinine clearance and albumin excretion were measured, and kidneys collected (histopathology, collagen content). Bodyweights of HFF WT (50.6±1.2 g) and HET (48.8±1.4 g) mice were ∼14 g greater than control mice (37.3±1.3 g, 36.4±1.1 g respectively; Pdiet<0.001). Obesity led to significantly greater 24 hr MAP (Pdiet<0.001), heart rate (Pdiet<0.01) and lower locomotor activity (Pdiet<0.01) in HET and WT mice. Whilst there was no significant impact of genotype on 24 hr MAP response to obesity, night-time MAP of obese HET mice was significantly greater than obese WT mice (122.3±1.6 vs 116.9±1.3 mmHg; P<0.05). 24 hr creatinine clearance was 50%, and albumin excretion 180% greater in obese WT and HET mice compared to controls (Pdiet<0.05) but this response did not differ between genotypes. Obesity induced glomerulomegaly, glomerulosclerosis, tubulointerstitial expansion and increased collagen accumulation (total, collagen I, V and IV; Pdiet<0.001). Obese GDNF HET mice had exacerbated total renal collagen (P<0.01), and greater levels of the collagen I subtype compared to kidneys of obese WT mice. In summary, obese nephron-deficient GDNF HET mice were able to maintain the high creatinine clearances of obese WT mice but at the expense of higher MAP and greater renal fibrosis. Whilst modest, our findings support the hypothesis that a reduced nephron endowment increases the susceptibility to obesity-induced kidney disease and hypertension.

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This study suggests that activin A signaling may contribute to the pathology of bronchopulmonary dysplasia.

This chapter describes the methodologies which may be used in evaluating in vitro endothelial cell dysfunction in preeclampsia.