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Pregnancy-Associated Plasma Protein A: Spotlight on Kidney Diseases

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Pregnancy-Associated Plasma Protein A: Spotlight on Kidney Diseases Clin Chem Lab Med 2012;50(7):1183–1190 © 2012 by Walter de Gruyter • Berlin • Boston. DOI 10.1515/cclm-2011-0640 Review Pregnancy-associated plasma protein A: spotlight on kidney diseases Marta Kalousov á 1, *, Vladim í r Tesa r˘ 2 , Introduction Alexandra Muravsk á 1 and Tom á š Zima 1 Pregnancy-associated plasma protein A (PAPP-A) is a bio- 1 Institute of Medical Biochemistry and Laboratory marker routinely used in screening for Down syndrome in the Diagnostics , First Faculty of Medicine, Charles University in fi rst trimester of pregnancy. Despite its name “ pregnancy pro- Prague and General University Hospital in Prague, Prague , tein ” it is also present in very small amounts in non-pregnant Czech Republic individuals, both men and women and is implicated in various 2 Department of Nephrology , First Faculty of Medicine, processes, such as wound healing, bone remodeling or ath- Charles University in Prague and General University erosclerosis. Measurement of circulating PAPP-A can provide Hospital in Prague, Prague , Czech Republic valuable information not only in pregnant women but also in patients with coronary artery disease and in patients with Abstract kidney diseases. In this review we would like to summarize basic informa- Pregnancy-associated plasma protein A (PAPP-A) is a bio- tion about PAPP-A and focus on the signifi cance of PAPP-A marker routinely used in screening for Down syndrome in the in renal diseases – what was demonstrated in experimental, fi rst trimester of pregnancy. It is also present in very small genetic, laboratory, clinical and pharmacological studies. amounts in men and non-pregnant women. PAPP-A is a key regulator of local insulin-like growth factor (IGF) bioavail- ability – IGFs are essential for normal body size during fetal History of PAPP-A in laboratory medicine development, but they are associated with aging and age- related diseases. Measurement of circulating PAPP-A can PAPP-A was originally isolated in 1974 as one of four pla- provide valuable information not only in pregnant women cental proteins circulating in high concentrations in pregnant (chromosomal anomalies and adverse pregnancy outcomes) women (1) . In 1990 it was shown that low maternal serum but also in patients with coronary artery disease (contribution level of PAPP-A in the fi rst trimester of pregnancy is char- to diagnosis, prognostic value) and in patients with kidney dis- acteristic for Down syndrome fetus development (2) , and eases. PAPP-A is associated with renal function and proteinu- measurement of PAPP-A was introduced in the fi rst trimester ria, is increased mainly in dialysis patients and decreases after screening of chromosomal anomalies (3) . There is increas- kidney transplantation. It is an independent mortality predic- ing evidence that low levels of PAPP-A in the fi rst trimester tor of hemodialysis patients and indicator of adverse outcome are associated with adverse outcomes, such as preterm deliv- of transplanted patients. PAPP-A levels can be infl uenced by ery, intrauterine growth retardation, preeclampsia, and still- various chemicals and drugs, among them mainly heparin. birth (4) . In the third trimester in preeclamptic pregnancies, Various assays for PAPP-A exist and the type of assay used PAPP-A is increased (5) . in a study should be considered. This article reviews the data In 2001, PAPP-A was found in eroded and ruptured ath- summarizing basic information about PAPP-A with a particu- erosclerotic plaques and its serum levels were increased in lar focus on the signifi cance of PAPP-A in renal diseases. patients with acute coronary syndromes (6) . Many studies regarding the usefulness of PAPP-A screening in cardiology were performed. PAPP-A was demonstrated as a marker of Keywords: dialysis; kidney; polymorphism; predictive value; the presence and extent of atherosclerosis in coronary and pregnancy-associated plasma protein A; transplantation. peripheral arterial diseases, a marker of outcome in stable atherosclerotic disease and in some studies as a marker of *Corresponding author: Prof. Marta Kalousova, MD, PhD, Institute worst prognosis in acute coronary syndrome and as a marker of Medical Biochemistry and Laboratory Diagnostics, 1st Faculty of that might help in the diagnosis of acute coronary syndrome Medicine, Charles University and General University Hospital, Na [reviewed in (7) ]. Controversy exists due to different assays Boji š ti 3, 121 08 Prague 2, Czech Republic Phone: + 420 224964212, Fax: + 420 224962848 , used in the studies. E-mail: [email protected]; [email protected]; In 2003, we fi rst described elevation of PAPP-A in patients [email protected] with end-stage renal disease treated with hemodialysis (8) , Received September 11, 2011; accepted February 8, 2012 ; and subsequently its relationship to renal function (9) and its previously published online March 24, 2012 possible prognostic role in long-term hemodialysis patients 1184 Kalousová et al.: PAPP-A and kidney diseases (10) . Elevation of PAPP-A measured by a different method the metzincin superfamily of metalloproteinases. PAPP-A2 with lower reference range was also confi rmed by Coskun shares 45 % homology with PAPP-A and unlike PAPP-A it is et al. (11) . unable to bind to cells. Ulilysin was found in archebacteria PAPP-A has been studied in a variety of diseases, e.g., in Methanosarcina acetotivorans (26) . PAPP-A is responsible diabetes mellitus, allergy and obesity. In diabetic patients, for proteolytic cleavage of IGFs, mainly IGFBP-4 but also -2 no difference in PAPP-A levels in DM1 or DM2 and healthy and -5 and so acts as a positive regulator of IGF availability subjects was found (12) and another group did not fi nd its (27 – 29) . PAPP-A is a key regulator of IGF-II bioavailability usefulness as a biomarker of carotid atherosclerosis in type during early embryogenesis and plays a similar role regulat- 2 diabetics (13) . Conversely, PAPP-A was associated with ing IGF-I bioavailability postnatally (21) . PAPP-A like other increased mortality in type 1 diabetic patients with nephropa- metzincins has the ability to cleave itself resulting in frag- thy but only in unadjusted analysis; after adjustment for tra- ments of 150 kDa and 50 kDa (30) . ditional risk factors the prognostic value of PAPP-A was no PAPP-A is present in healthy individuals in very low con- longer signifi cant (14) . PAPP-A was signifi cantly elevated in centration (6, 8) . During normal pregnancy it rises linearly and allergic rhinitis (15) and in asthma and correlated with asthma after labor it disappears from circulation with a half-life of 3 – 4 severity (16) . In children there was no difference between days (31) . In acute coronary syndromes it is increased early obese and lean subjects but a correlation with other cardio- after the onset of symptoms (fi rst ca 7 h) (32) . vascular risk factors was found (17) . Experimental studies Biology of PAPP-A: gene structure and function PAPP-A is a key regulator of local IGF bioavailability. IGFs The gene for PAPP-A in humans is located on chromosome are essential for normal body size during fetal development, 9q33.1 (18) , spans over 200 kb of DNA, and contains 22 however, IGFs are associated with aging and age-related dis- exons with a length from 72 to 1063 nucleotides separated eases. That is why loss of PAPP-A or inhibition of PAPP-A by 21 introns of various length (19) . PAPP-A is synthesized activity should have negative effects early in life and benefi - as a 1627-residue precursor preproprotein with a 22-residue cial effects later in life (33) . putative signal peptide and a propeptide of 58 residues, so PAPP-A knockout mice are smaller in body size but have that the mature protein then contains 1547 amino acids. signifi cantly increased life span compared with wild-type PreproPAPP-A mRNA has an unusually long 5 ′ untranslated littermates. Incidence of neoplastic disease was not signifi - region that contains several ORF (20) . The PAPP-A amino cantly different in wild-type and PAPP-A knockout mice; acid sequence is, to a high extent, identical with other mam- however, it did occur in older aged PAPP-A knockout mice mals which suggests its essential function. Additionally, compared to wild-type mice. Additionally, PAPP-A knockout PAPP-A was also found in non-mammalian vertebrates but mice were less likely to show degenerative changes of aging. not in invertebrates (21) . Nephropathy was more evident and more severe in wild-type The PAPP-A protein (PAPP-A monomer) containing 1547 than in PAPP-A knockout mice. The kidney, an organ with the amino acids has pI 5.4 and molecular weight 200 kDa. It highest PAPP-A expression levels in wild-type mice, had the is composed of fi ve domains: the N-terminal laminin like most marked changes in gene expression in PAPP-A knockout domain, the metzincin proteolytic domain which is respon- mice (34) . Swindel et al. (35) demonstrated higher expression sible for insulin-like growth factor binding proteins (IGFBPs) of IGFBPs-1 and 2, decreased expression of IGFBPs-3 and 5 cleavage, a central domain of unknown identity, a domain and no change of IGFBP-4 expression in PAPP-A knockout defi ned by fi ve complement control protein modules which mice compared to wild-type mice. is responsible for binding to the cell surface and a C-terminal In contrast, transgenic mice with over expression of domain (21) . PAPP-A exists as a homodimer of 400 kDa PAPP-A in arterial smooth muscle show accelerated athero- which is proteolytically active and as a proteolytically inac- sclerotic lesion development (36) . tive PAPP-A/pro major basic protein (MBP) heterotetra- meric complex of 500 kDa (21) .
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