Abstract
Preeclampsia is a human placental disorder affecting 2–8% of pregnancies worldwide annually, with hypertension and proteinuria appearing after 20 weeks of gestation. The underlying cause is believed to be incomplete trophoblast invasion of the maternal spiral arteries during placentation in the first trimester, resulting in oxidative and nitrative stress as well as maternal inflammation and organ alterations. In the Storkhead box 1 (STOX1) preeclampsia mouse model, pregnant females develop severe and early onset manifestations as seen in human preeclampsia e.g. gestational hypertension, proteinuria, and organ alterations. Here we aimed to evaluate the therapeutic potential of human recombinant alpha-1 microglobulin (rA1M) to alleviate the manifestations observed. Human rA1M significantly reduced the hypertension during gestation and significantly reduced the level of hypoxia and nitrative stress in the placenta. In addition, rA1M treatment reduced cellular damage in both placenta and kidneys, thereby protecting the tissue and improving their function. This study confirms that rA1M has the potential as a therapeutic drug in preeclampsia, and likely also in other pathological conditions associated with oxidative stress, by preserving normal organ function.
Highlights
Preeclampsia is a human placental disorder that clinically presents after 20 weeks of gestation with maternal manifestations including hypertension and proteinuria[1,2]
Our results demonstrate the potential therapeutic capacity of recombinant A1M (rA1M) to alleviate typical manifestations of preeclampsia, such as elevated Blood pressure (BP), proteinuria, and organ damage
Similar protective effects have previously been demonstrated in other animal models of preeclampsia[30,31], with reduced proteinuria, and reverted kidney and placenta damage
Summary
Preeclampsia is a human placental disorder that clinically presents after 20 weeks of gestation with maternal manifestations including hypertension and proteinuria[1,2]. Defective remodeling of the maternal spiral arteries is believed to result in high pressure flow entering the intervillous space, causing physical disruption of the placental villous architecture and fluctuations in oxygen delivery with relative hypoxia in the placenta[4] This leads to increased inflammation[5,6], oxidative stress[7,8], and nitrative stress[9,10]. By mating wildtype (wt) females with STOX1 transgenic males, the transgene expression is restricted to the fetoplacental unit, making this one of the few animal models representing a severe and early onset form of preeclampsia These pregnant females display cardiac hypertrophy and endothelial cell deregulation in gene networks linked to oxidative stress, cell cycle, and hypertrophy[22]. It offers the opportunity to investigate ways of reducing oxidative stress in preeclampsia, as well as testing new therapeutic avenues
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