Ludzkie koronawirusy - autor: Krzysztof Pyrć z Zakładu Mikrobiologii, Wydział Biochemii, Biofizyki i Biotechnologii, Uniwersytet Jagielloński, Kraków

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© Borgis - Postępy Nauk Medycznych 2/2014, s. 118-122
*Ewa Koc-Żórawska1, Marcin Żórawski2, Piotr Przybyłowski3, Jolanta Małyszko1
VAP-1 i renalaza u pacjentów po transplantacji narządów unaczynionych
VAP-1 and renalase in solid organ transplant recipients
1Department of Nephrology and Transplantology, Medical University, Białystok
Head of Department: prof. Michał Myśliwiec MD, PhD
2Department of Pharmacology, Medical University, Białystok
Head of Department: prof. Róża Wiśniewska MD, PhD
3Department of Cardiac Surgery and Transplantation, Collegium Medicum of the Jagiellonian University, Kraków
Head of Department: prof. Jerzy Sadowski MD, PhD
Streszczenie
Jedną z metod leczenia schyłkowej niewydolności narządów jest przeszczep narządu pobranego od innej osoby. Wśród pacjentów po przeszczepieniu często obserwuje się dysfunkcję śródbłonka. Jest ona także bardzo powszechna w chorobach układu krążenia i przewlekłej chorobie nerek. VAP-1 (ang. vascular adhesion protein-1 – naczyniowa cząsteczka adhezyjna-1) to glikoproteina o podwójnej roli. Jako cząsteczka adhezyjna bierze udział w rolowaniu, adhezji i migracji leukocytów do miejsca występowania procesu zapalnego oraz pełni funkcję aminooksydazy wrażliwej na semikarbazyd. Jest wydzielany przez szereg komórek: np. śródbłonka, mięśniówki gładkiej naczyń krwionośnych czy adipocytów. Wykazano, podwyższony poziom VAP-1 u pacjentów po przeszczepieniu serca (OHT) i nerek (Ktx). U pacjentów z OHT zależy przede wszystkim od geometrii lewej komory. W obu grupach przeszczepionych VAP-1 był wyższy u chorych na cukrzycę w porównaniu do osób bez cukrzycy. Renalaza należy do klasy oksydaz aminowych. Jest enzymem wydzielanym m.in. przez nerki, adipocyty, śródbłonek. Powoduje degradację krążących we krwi katecholamin, przez co może mieć wpływ na regulację ciśnienia tętniczego. Stężenie renalazy, znacznie zwiększone u chorych po przeszczepieniu nerki i przeszczepieniu serca, w głównym stopniu zależy od funkcji nerek, która pogarsza się z wiekiem i w miarę upływu czasu od przeszczepienia.
Konieczne są więc dalsze badania nad potencjalną rolą VAP-1 i renalazy w patogenezie chorób sercowo-naczyniowych, a także w populacji biorców przeszczepów narządów unaczynionych.
Summary
Transplantation of an organ harvested from another person is one of the methods of treatment of end-stage organ failure. Endothelial dysfunction is a frequent finding in transplant recipients. It is also very common in cardiovascular disorders and chronic kidney disease. Vascular adhesion protein-1 (VAP-1) is a dual-function glycoprotein. As an adhesion molecule, it is involved in rolling, adhesion and migration of leukocytes to the inflammatory site, and is a semicarbazide-sensitive amine oxidase. VAP-1 is secreted by a number of cells, including endothelial cells, vascular smooth muscle cells or adipocytes. Increased VAP-1 levels were shown in cardiac and renal transplant recipients. In cardiac transplant recipients its levels are mainly determined by left ventricular geometry. In both recipient groups VAP-1 was higher in patients with diabetes in comparison with their non-diabetic counterparts. Renalase belongs to a class of amine oxidases – secreted, for example, by the kidneys, adipocytes and endothelium. It causes degradation of bloodstream catecholamines, through which it may be involved in blood pressure regulation. Renalase concentration, markedly increased in renal and cardiac transplant recipients, was predicted by renal function which deteriorates with age and time from transplantation.
Further studies are necessary on the potential role of VAP-1 and renalase in the pathogenesis of cardiovascular disorders, including arterial hypertension, also in the population of organ transplant recipients.
Introduction
Transplantation of an organ harvested from another person is one of the methods of treatment of end-stage failure of vascularised organs (kidneys, heart, liver). Good results obtained with this method derive from advances in the graft rejection prevention treatment. The use of immunosuppressants is associated with numerous complications, such as increased frequency of infections, increased incidence of cancer, bone marrow damage or cardiovascular complications. Normal haemostasis is a result of equilibrium between coagulation factors and their inhibitors. Imbalance in this equilibrium leads to life-threatening bleeding or thrombosis, which is why its maintenance is very important. Studies suggest the presence of hypercoagulability in renal transplant recipients (1, 2). Haemostasis disturbances are inherently correlated with endothelial dysfunction. Early descriptions of endothelial dysfunction focused on structural changes or on the loss of anatomical integrity of this organ. It is currently known that endothelial cells are characterised by highly variable biological activity performing an extremely important role in functioning of the whole body. Małyszko et al. demonstrated impaired haemostasis and endothelial function in dialysed patients and in patients with chronic kidney disease (3, 4). Epithelial damage may contribute to accelerated atherosclerosis development in the group of transplant recipients.
VAP-1
Vascular Adhesion Protein-1 (VAP-1) is a multi-function protein, which mediates lymphocyte adhesion to the vascular endothelium (5-9). Biochemically, VAP-1 is a homodimeric transmembrane glycoprotein with a molecular mass of 170-180 kDa, made of 764 amino acids, with a short N-terminal cytoplasmic part, a single transmembrane domain and a large extracellular C-terminal domain (5-9). Each subunit has six N-glycosylation sites (10). N-glycoside chains of VAP-1, ended with sialic acid, differ depending on the tissue in which they occur. This differentiation suggests their functional differences (11). The structure of DNA coding the VAP-1 molecule displays high homology with enzymes of the semicarbazide-sensitive amine oxidase (SSAO) class (12). VAP-1 also displays enzymatic activity of a semicarbazide-sensitive amine oxidase. Its active centre contains a copper atom (9, 13). SSAO/VAP-1 catalyses a reaction of two-stage deamination of primary amine groups (methylamine, aminoacetone, benzylamine) leading to the formation of aldehydes and additionally hydrogen peroxide and ammonia (14). On one hand, the activity of VAP-1 provides protection from amines of endo- and exogenous origins, and on the other hand, high concentration of the products formed increases the quantity of other adhesion molecules, leading to escalation of the inflammatory process. Increased concentration of toxic aldehydes and oxygen radicals, which are the source of oxidative stress, in the endothelial environment may result in endothelial damage and may contribute to the development of atherosclerosis and vascular damage in diabetic patients (15-17). Elevated activity of SSAO is observed in atherosclerosis, diabetes and obesity (18-20). VAP-1 concentration, SSAO activity and SSAO activity products are elevated in congestive heart failure and hepatitis (21). Elevated VAP-1 levels were found in persons with chronic kidney disease, which suggests that it may be excreted via the kidneys (22). Moreover, recently Li et al. have demonstrated that VAP-1 may be a good predictor of cardiovascular death in persons with type 2 diabetes (21). Constant expression of VAP-1 is observed in high endothelial venules (HEV), which physiologically are present in lymphoid organs, in the liver and in dendritic cells of lymph node proliferation centres (6). VAP-1 is also present in vascular smooth muscle cells and in adipocytes. Physiologically, soluble VAP-1 (sVAP-1) is present in the serum of healthy persons. It is probably released as a result of enzymatic proteolysis or is formed directly on messenger RNA devoid of the membrane region-coding fragment (12). Metalloproteinases may release VAP-1 from adipocytes and this process is intensified in hyperglycaemia (23). sVAP possesses immunomodulatory function causing much stronger binding of T-cells to endothelial cells, which may play an important role in the graft rejection process (24). In the case of kidney transplant, in which rejection signs were found, high expression of VAP-1 was detected in the endothelium of peritubular vessels that became morphologically similar to HEV (25). SSAO oxidates dopamine and, to a lower extent, norepinephrine, and does not oxidate epinephrine. SSAO/VAP-1 is insensitive to MAO inhibitors (26). In view of its monoamine oxidase activity, like renalase, VAP-1 may be a factor regulating blood pressure.
Renalase
Renalase belongs to a class of amine oxidases containing flavin adenine dinucleotide (FAD). It is coded by a gene of approximately 311 kb, comprising 10 exons located on chromosome X (27). It consists of 342 amino acids forming a peptide containing the FAD domain (amino acids 4-35) and an amine oxidase domain (amino acids 75-339). Renalase is synthesised in the kidneys, secreted to the bloodstream, and subsequently excreted in the urine where it exerts ca. 100 times its activity in the blood in standard conditions (28). It is secreted into the bloodstream in the form of biologically inactive prorenalase. Renalase undergoes preferential expression in proximal tubules but is also observed in distal glomeruli and tubules and in cardiomyocytes, hepatocytes, skeletal muscle cells and the epithelium, and also in adrenals, peripheral nerves, the central nervous system and human adipose tissue (29). In 2005, Xu et al. described the probable role of renalase in hypertension. They evidenced significant decrease in plasma renalase activity in patients with chronic kidney disease (which may contribute to the development of arterial hypertension) (30). By metabolising catecholamines (dopamine, norepinephrine, epinephrine), renalase probably participates in blood pressure regulation. It is insensitive to MAO inhibitors (30). Renalase deficiency in patients with chronic kidney disease causes an increase in blood pressure at least in patients with GG (rs 2576 178) and CC (rs 229 8545) polymorphisms. Recombinant renalase is hypotensive and cardioprotective in patients with coronary insufficiency (28). Blockade of this enzyme with the use of antisense RNA causes blood pressure elevation in animals (31). Chinese studies demonstrated a correlation between rs 2576178 GG and rs 2296545 CC mutations of the renalase gene and the occurrence of arterial hypertension (32). Similarly, Stec et al. found a relationship between renalase gene polymorphism and the presence of arterial hypertension in dialysed patients (33).
VAP-1 and renalase in renal or cardiac transplant recipients

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otrzymano: 2013-11-20
zaakceptowano do druku: 2014-01-08

Adres do korespondencji:
*Ewa Koc-Żórawska
Department of Nephrology and Transplantology Medical University
ul. Żurawia 14, 15-540 Białystok
tel. +48 (85) 740-95-48
ewakoczorawska@wp.pl

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