Editorial Comment
Prostasin, proteases, and preeclampsia
Heather Y. Small, Gemma E. Currie, and Christian Delles
See original paper on page 298
P
reeclampsia is a leading cause of perinatal morbidity
and mortality, affecting between 5 and 8% of preg-
nancies worldwide [1]. The syndrome is character-
ized by development of hypertension (SBP  140 mmHg
and/or DBP  90 mmHg) and proteinuria (300 mg/24 h or
2 on urine dipstick testing) after the 20th gestational
week and its rising incidence is partially attributed to the
increased prevalence of predisposing conditions such as
diabetes and obesity. Preeclampsia is associated with
multiple potentially fatal short-term complications, includ-
ing preterm delivery, hepatic or renal dysfunction, seizures,
and coagulopathy, and is responsible for up to 15% of
maternal deaths worldwide [2]. In addition, the diagnosis
carries important implications for maternal health in the
longer term with greater risk of cardiovascular and renal
disease in later life [3]. Although the consequences for
mother and infant can be disastrous early disease detection
and treatment options remain very limited, partially as a
result of our incomplete understanding of the interplay
between the many complex pathophysiological mechan-
isms underlying the condition.
The fact that the condition resolves with delivery of the
placenta highlights the critical role of the organ in the
development of preeclampsia, and abnormal cytotropho-
blast invasion coupled with failure of spiral artery remod-
elling in early gestation are thought to be a key component
of the disease process [4]. This abnormal placentation is
driven, at least in part, by an imbalance of pro and anti-
angiogenic factors; in particular soluble vascular endo-
thelial growth factor (VEGF) receptor 1 (soluble fms-
related tyrosine kinase 1; sFlt-1) and placental growth factor
(PlGF). A large body of evidence demonstrates elevated
sFlt-1 availability in preeclamptic pregnancies prior to the
onset of the clinical syndrome, with a resultant inhibitory
effect on VEGF and PlGF signalling [5]. In fact, the ratio of
sFlt-1 : PlGF at 34 weeks gestation has been shown to
Journal of Hypertension 2016, 34:193195
BHF Glasgow Cardiovascular Research Centre, Institute of Cardiovascular and Medical
Sciences, University of Glasgow, Glasgow, Scotland, UK
Correspondence to Professor Christian Delles, BHF Glasgow Cardiovascular Research
Centre, Institute of Cardiovascular and Medical Sciences, University of Glasgow, 126
University Place, Glasgow G12 8TA, Scotland, UK. Tel: +44 141 330 2749;
fax: +44 141 330 3360; e-mail: Christian.Delles@glasgow.ac.uk
J Hypertens 34:193195 Copyright 2016 Wolters Kluwer Health, Inc. All rights
reserved.
DOI:10.1097/HJH.0000000000000828
Journal of Hypertension
Copyright 2016 Wolters Kluwer Health, Inc. All rights reserved.
identify women at high risk for adverse pregnancy out-
comes, although evidence for its usefulness as an early
predictive marker of preeclampsia is less compelling.
Recent years have also seen a resurgence of interest in
the role of the reninangiotensinaldosterone system in
development of preeclampsia. Increased concentrations
of agonistic angiotensin II type 1 receptor antibodies
(AT1-AA) are seen in the serum of preeclamptic women,
and experimental studies have shown that injecting rodents
with AT1-AA results in development of many key features
of preeclampsia, including hypertension and abnormal
placentation [6]. It is well documented that pregnancies
complicated by preeclampsia are also characterized by
reduced plasma aldosterone concentration. The resultant
inadequate plasma volume expansion, which contributes
to impaired perfusion of the uteroplacental unit, can be
detected weeks in advance of the onset of the clinical
maternal syndrome [7]. In addition to its effects on maternal
plasma volume, aldosterone availability has been linked to
impaired vasculogenesis and trophoblast proliferation [8].
A number of studies have demonstrated interplay between
these mechanistic pathways: exposure to VEGF has been
shown to stimulate production of aldosterone in H295R
adrenal cells [9]; and studies have implicated AT1-AA in the
increased sFlt-1 production seen in preeclamptic pregnan-
cies [10]. This serves to highlight the complex interaction
between numerous mechanistic pathways underlying the
development of preeclampsia, and offers an insight into
why its pathogenesis remains incompletely understood.
Serine proteases are the most abundant type of protease
in humans making up one-third of all proteases. They
catalyse the cleavage of other proteins dependent upon
the presence of the nucleophilic serine residue in the
enzymes active site. They are functionally diverse and play
important roles in a number of central physiological proc-
esses, including digestion, blood clotting, and immunity
[11]. Research into the role of serine proteases in pre-
eclampsia is a promising new field with targets, such as
corin [12], chymase [13], and serine protease high-tempera-
ture requirement factor A4 [14] shown to be increased in
the disease.
In this issue, Frederiksen-Mller et al. [15] present novel
data showing that levels of prostasin, a serine protease, are
increased in the urine of women with preeclampsia. The
authors provide evidence for prostasin as a relevant mol-
ecule to preeclampsia, in keeping with previous data where
its increase has been related to abnormal placental
www.jhypertension.com 193
Small et al.
development in a mouse model [16] and kidney dysfunc-
tion, and hypertension in humans [11]. Prostasin has been
shown to be upregulated by aldosterone and can be nega-
tively regulated by protease inhibitors HA-1, HA-2, or
nexin-1. In some forms of human hypertension aldosterone
levels are increased, and it has been shown that HA-1, HA-2,
and nexin-1 are decreased. This can result in upregulated
expression of prostasin in the kidney where prostasin
increases the rate of sodium reabsorption through the
epithelial sodium channel [17]. Frederiksen-Mller et al.
[15] present findings, which show that levels of the serine
protease prostasin are increased in urine from women with
preeclampsia relative to normotensive women and that this
increase is correlated with urinary albumin. However, there
was no correlation between prostasin and aldosterone
which has been reported in patients with essential hyper-
tension elsewhere [18]. The authors did not find any
changes at mRNA or protein level in prostasin or its associ-
ated inhibitory molecules, HA-1, HA-2, or nexin-1, in pla-
cental samples taken at point of delivery.
The absence of animal models that cover all aspects of
the human-specific disease of preeclampsia is a major
challenge to studying the underlying mechanisms of this
condition as reviewed elsewhere [19]. Frederiksen-Mller
and colleagues [15] should be congratulated on translating
the work on prostasin in a preclinical model [16] to human
samples. Furthermore, they present a complete evaluation
of the prostasin/aldosterone pathway in plasma and urine
as well as tissue work in placental samples. Preeclampsia
research using human samples is not straightforward as the
disease itself presents as a continuum of subclinical abnor-
malities from the very early stages of pregnancy to the
clinical presentation which can broadly be defined into
early and late onset. In this study, preeclamptic and normo-
tensive individuals were matched for gestational age
at delivery. Therefore, the exploration of prostasin in
women with severe early onset preeclampsia (<34 weeks
gestation) is warranted. Women in the preeclampsia group
were also clinically obese, which could be a confounding
factor as urinary prostasin has been found to correlate with
increased adiposity in adolescents [20]. There are technical
issues associated with the use of placental tissue collected at
parturition as the mature placenta may not reflect earlier
subclinical abnormalities which have led to abnormal
placentation in the first instance. Prostasin has been shown
to affect trophoblast invasion which takes place in the very
early stages of maternal spiral artery remodelling [21];
therefore, prostasin is an intriguing candidate for further
study at an earlier gestational time point even if no change
was detected in this study [15] in term placenta.
Although some of the results in the paper by Freder-
iksen-Mller et al. [15] may be counterintuitive or nega-
tive and some of the increased levels of prostasin in urine
could simply be the result of general leakage of protein
through the damaged glomerular barrier the study draws
our attention to a fascinating potential player in the
complex pathogenesis of preeclampsia. The beauty of
this molecule lies in its involvement in many of the key
mechanisms that are dysregulated in the development of
preeclampsia, including trophoblast invasion, arterial
remodelling, and sodium and volume balance. In light
194 www.jhypertension.com
Copyright 2016 Wolters Kluwer Health, Inc. All rights reserved.
of the strong preclinical data and a first and somehow
promising translation to human pathology in the present
study [15] it is more than justified to continue research on
the role of prostasin and other serine proteases in the
pathogenesis of preeclampsia. We need to learn more
about its regulation on a genetic (and as the present data
suggest, particularly on an epigenetic) level, and whether
it has a causal role in the development of preeclampsia, or
if changes in prostasin levels are secondary to other
phenomena in this multifactorial condition.
ACKNOWLEDGEMENTS
Work in our group is funded by grants from the European
Commission (grant agreements 278249 EU-MASCARA and
603288 sysVASC). H.Y.S. is funded by a British Heart
Foundation PhD Fellowship and G.E.C. by a European
Commission grant (grant agreement 279277 PRIORITY).
Conflicts of interest
There are no conflicts of interest.
REFERENCES
1. Steegers EA, von Dadelszen P, Duvekot JJ, Pijnenborg R. Preeclampsia.
Lancet 2010; 376:631644.
2. Khan KS, Wojdyla D, Say L, Gulmezoglu AM, Van Look PF. WHO
analysis of causes of maternal death: a systematic review. Lancet 2006;
367:10661074.
3. Carty DM, Delles C, Dominiczak AF. Preeclampsia and future maternal
health. J Hypertens 2010; 28:13491355.
4. Hladunewich M, Karumanchi SA, Lafayette R. Pathophysiology of the
clinical manifestations of preeclampsia. Clin J Am Soc Nephrol 2007;
2:543549.
5. Maynard SE, Min JY, Merchan J, Lim KH, Li J, Mondal S, et al. Excess
placental soluble fms-like tyrosine kinase 1 (sFlt1) may contribute to
endothelial dysfunction, hypertension, and proteinuria in preeclamp-
sia. J Clin Invest 2003; 111:649658.
6. Xia Y, Kellems RE. Angiotensin receptor agonistic autoantibodies and
hypertension: preeclampsia and beyond. Circ Res 2013; 113:7887.
7. Salas SP, Marshall G, Gutierrez BL, Rosso P. Time course of maternal
plasma volume and hormonal changes in women with preeclampsia or
fetal growth restriction. Hypertension 2006; 47:203208.
8. Gennari-Moser C, Khankin EV, Schuller S, Escher G, Frey BM, Port-
mann CB, et al. Regulation of placental growth by aldosterone and
cortisol. Endocrinology 2011; 152:263271.
9. Gennari-Moser C, Khankin EV, Escher G, Burkhard F, Frey BM,
Karumanchi SA, et al. Vascular endothelial growth factor-A and
aldosterone: relevance to normal pregnancy and preeclampsia. Hyper-
tension 2013; 61:11111117.
10. Zhou CC, Ahmad S, Mi T, Abbasi S, Xia L, Day MC, et al. Autoantibody
from women with preeclampsia induces soluble Fms-like tyrosine
kinase-1 production via angiotensin type 1 receptor and calci-
neurin/nuclear factor of activated T-cells signaling. Hypertension
2008; 51:10101019.
11. Aggarwal S, Dabla PK, Arora S. Prostasin: an epithelial sodium channel
regulator. J Biomark 2013; 2013:179864.
12. Zhou Y, Wu Q. Role of corin and atrial natriuretic peptide in pre-
eclampsia. Placenta 2013; 34:8994.
13. Wang Y, Alexander JS. Role of chymase in preeclampsia. Curr Vasc
Pharmacol 2013; 11:606615.
14. Singh H, Zhao M, Chen Q, Wang Y, Li Y, Kaituu-Lino TJ, et al. Human
HtrA4 expression is restricted to the placenta, is significantly up-
regulated in early-onset preeclampsia, and high levels of HtrA4 cause
endothelial dysfunction. J Clin Endocrinol Metab 2015; 100:E936
E945.
15. Frederiksen-Mller B, Jrgensen JS, Hansen MR, Krigslund O, Vogel
LK, Andersen LB, Jensen BL. Prostasin and matriptase (ST14) in
placenta from preeclamptic and healthy pregnant women. J Hypertens
2016; 34:298306.
Volume 34  Number 2  February 2016

16. Szabo R, Uzzun Sales K, Kosa P, Shylo NA, Godiksen S, Hansen KK,
et al. Reduced prostasin (CAP1/PRSS8) activity eliminates HAI-1 and
HAI-2 deficiency-associated developmental defects by preventing
matriptase activation. PLoS Genet 2012; 8:e1002937.
17. Olivieri O, Castagna A, Guarini P, Chiecchi L, Sabaini G, Pizzolo F, et al.
Urinary prostasin: a candidate marker of epithelial sodium channel
activation in humans. Hypertension 2005; 46:683688.
18. Koda A, Wakida N, Toriyama K, Yamamoto K, Iijima H, Tomita K,
Kitamura K. Urinary prostasin in humans: relationships among pros-
tasin, aldosterone and epithelial sodium channel activity. Hypertens Res
2009; 32:276281.
Journal of Hypertension
Copyright 2016 Wolters Kluwer Health, Inc. All rights reserved.
Prostasin, proteases, and preeclampsia
19. McCarthy FP, Kingdom JC, Kenny LC, Walsh SK. Animal models
of preeclampsia; uses and limitations. Placenta 2011; 32:413
419.
20. Guo DH, Parikh SJ, Chao J, Pollock NK, Wang X, Snieder H, et al.
Urinary prostasin excretion is associated with adiposity in
nonhypertensive African-American adolescents. Pediatr Res 2013;
74:206210.
21. Yang Y, Zhang J, Gong Y, Liu X, Bai Y, Xu W, Zhou R. Increased
expression of prostasin contributes to early-onset severe
preeclampsia through inhibiting trophoblast invasion. J Perinatol
2015; 35:1622.
www.jhypertension.com 195