SERPINA1 Peptides in Urine as A Potential Marker of Preeclampsia Severity

Abstract

Preeclampsia (PE) is a multisystem disorder associated with pregnancy and its frequency varies from 5 to 20 percent of pregnancies. Although a number of preeclampsia studies have been carried out, there is no consensus about disease etiology and pathogenesis so far. Peptides of SERPINA1 (α1-antitrypsin) in urine remain one of the most promising peptide markers of PE. In this study the diagnostic potential of urinary α1-antitrypsin peptides in PE was evaluated. The urinary peptidome composition of 79 pregnant women with preeclampsia (PE), chronic arterial hypertension (CAH), and a control group was investigated. Mann–Whitney U-test (p < 0.05) revealed seven PE specific SERPINA1 peptides demonstrating 52% sensitivity and 100% specificity. SERPINA1 in urine has been associated with the most severe forms of preeclampsia (p = 0.014), in terms of systolic hypertension (p = 0.01) and proteinuria (p = 0.006). According to Spearman correlation analysis, the normalized intensity of SERPINA1 urinary peptides has a similar diagnostic pattern with known diagnostic PE markers, such as sFLT/PLGF. SERPINA1 peptides were not urinary excreted in superimposed PE (PE with CAH), which is a milder form of PE. An increase in expression of SERPINA1 in the structural elements of the placenta during preeclampsia reflects a protective mechanism against hypoxia. Increased synthesis of SERPINA1 in the trophoblast leads to protein accumulation in fibrinoid deposits. It may block syncytial knots and placenta villi, decreasing trophoblast invasion. Excretion of PE specific SERPINA1 peptides is associated with syncytiotrophoblast membrane destruction degradation and increased SERPINA1 staining. It confirms that the placenta could be the origin of SERPINA1 peptides in urine. Significant correlation (p < 0.05) of SERPINA1 expression in syncytiotrophoblast membrane and cytoplasm with the main clinical parameters of severe PE proves the role of SERPINA1 in PE pathogenesis. Estimation of SERPINA1 peptides in urine can be used as a diagnostic test of the severity of the condition to determine further treatment, particularly the need for urgent surgical delivery.

Alpha-1 Antitrypsin-Induced Endoplasmic Reticulum Stress Promotes Invasion by Extravillous Trophoblasts

“…Furthermore, A1AT-OE or A1AT administration increases the migration and invasion of human umbilical vein endothelial cells from women with PE [ 19 ]. Conversely, it has been reported that A1AT expression is high in placentas from patients with PE [ 24 ] and that the urinary A1AT concentration is high in women with PE [ 5 , 25 , 26 ]. Our data suggest that A1AT regulates cell motility via ER stress and HTRA1 expression in trophoblast cells, and that dysregulation may be associated with complications of pregnancy, including PE ( Table S1 ).…”

“…Previous studies have shown that a reduction of A1AT protein in endometriosis-like lesions exacerbates the inflammatory response in mice [ 4 ]. It has been shown that urinary A1AT may represent a marker of the severity of PE [ 5 ]. Furthermore, A1AT may reduce organ damage in a serine protease activity-independent fashion [ 6 ], although interaction with high-temperature requirement A serine peptidase 1 (HTRA1) may be involved [ 7 ].…”

Proteomic Analysis of Maternal Urine for the Early Detection of Preeclampsia and Fetal Growth Restriction

“…Nineteen of these showed high potential for PE prediction as they were consistently higher or lower in PE, including ceruloplasmin, serpin A1, serpin A5, C3, ALB, TF and HBB. Starodubtseva et al reported that the estimation of serpin A1 peptides in urine was also related to the severity of PE [39]. Placental growth factor (PlGF), a proangiogenic protein commonly used for the prediction of PE and other placentalmediated outcomes of pregnancy is also predictive of PE and PE-related adverse outcomes when measured in urine [17,23,40].…”

A novel peptide promotes human trophoblast proliferation and migration through PI3K/Akt/mTOR signaling pathway

“…At the same time, it has been found that unique peptides derived from α-antitrypsin, type I collagen, type III collagen, and urinary modulin can be used as early diagnostic indicators of PE (21). Furthermore, it has been emphasized that SERPINA1 peptide in urine remains one of the most promising polypeptide markers of PE (21). Taken together, these studies suggest that peptides may be a useful potential target for the prevention and treatment of PE.…”

“…It has been identified that there are 35 statistically different polypeptides in the placentas of PE patients and normal pregnancies (20). At the same time, it has been found that unique peptides derived from α-antitrypsin, type I collagen, type III collagen, and urinary modulin can be used as early diagnostic indicators of PE (21). Furthermore, it has been emphasized that SERPINA1 peptide in urine remains one of the most promising polypeptide markers of PE (21).…”