Hypertension and kidney disease

Review Hypertension and kidney disease: is renalase a new player or an innocent bystander? Jolanta Malyszko a, Jacek S. Malyszko a, Dimitri P. Mikhailidis b, Jacek Rysz c, Marcin Zorawski d, and Maciej Banach e Most patients on dialysis are hypertensive and their blood pressure (BP) control is often poor. Renalase is preferentially expressed in proximal tubules, but it is also present in glomeruli and distant tubules, as well as in cardiomyocytes, liver, and skeletal muscle. It had been proposed that renalase had a flavin adenine dinucleotide (FAD)-binding domain and that FAD was an essential cofactor for its stability and monoamine oxidase activity. It was reported that renalase, secreted by the kidney and circulating in the blood, degraded catecholamines and might play a role in the regulation of sympathetic tone and BP. It has been also proposed that renalase-coding gene is a novel susceptibility gene for essential hypertension and its variations may influence BP. In addition, polymorphisms of the renalase gene in hemodialysed patients were associated with hypertension. However, several unresolved and controversial issues still remain such as how to measure renalase and its physiological activity. Furthermore, there are few data on possible activators and/or inhibitors of renalase. We are at the very beginning of solving the problem of whether renalase is a causative factor of hypertension in kidney disease or just an innocent bystander. Therefore, more research is needed to establish whether renalase can become a useful therapeutic target. Keywords: blood pressure, hypertension, kidney diseases, renalase Abbreviations: BP, blood pressure; CKD, chronic kidney disease; CVD, cardiovascular disease; ESRD, end-stage renal disease; FAD, flavin adenine dinucleotide; LAD, left anterior descending coronary artery; MAO, monoamine oxidase; SSAO, semicarbazide-sensitive amine oxidase INTRODUCTION Hypertension and the sympathetic nervous system in end-stage kidney disease M ost patients starting dialysis are hypertensive, suggesting that blood pressure (BP) control is an important target to reduce cardiovascular mortality [1]. The relationships between elevated BP and cardiovascular mortality in patients with end-stage renal disease (ESRD) are complex due to the high prevalence of comorbid conditions and underlying vascular abnormalities [1,2]. The rate of cardiovascular disease (CVD) is six to Journal of Hypertension 10 times higher in that population compared with those not undergoing dialysis [3,4]. Worldwide, chronic renal failure and ESRD is increasingly becoming a global public health problem [5,6]. It is known that major established vascular risk factors (e.g. hypertension, diabetes, dyslipidemia) occur more frequently and with greater severity in those with a decreased glomerular filtration rate [7]. Hypertension, the most prevalent controllable disease in developing countries, contributes to about 62% of all strokes and 49% of all causes of heart disease in the adult population [8,9]. Most patients on dialysis have hypertension, and BP control is often very poor [10,11]. Several factors are involved in BP control and in CVD that develops in ESRD [4,10]. These include sodium and volume excess, activation of the renin–angiotensin– aldosterone system, an overactive sympathetic nervous system, increased activity of vasoconstrictive systems and decreased activity of vasodilator systems, increased intracellular calcium, increased arterial stiffness, oxidative stress, hyperparathyroidism, the administration of erythropoiesisstimulating agents, inflammation, sleep apnea, renovascular disease, and pre-existing hypertension [1,10–12]. Enhanced sympathetic activity is frequently reported in ESRD [13] and correlates with the increase in both vascular resistance and systemic BP [14] through unknown mechanisms. It seems that the afferent signal may arise within the kidney, as sympathetic activation is not seen in anephric patients [14]. Such activation declines, but does not normalize, after successful kidney transplantation [15]. Thus, it has been proposed that activation of chemoreceptors within the kidney by uremic metabolites leads to a neural reflex that through afferent pathways reached the central nervous Journal of Hypertension 2012, 30:457–462 a Department of Nephrology and Transplantology, Medical University, Bialystok, Poland, bDepartment of Clinical Biochemistry, University College London Medical School, University College London (UCL), London, UK, cDepartment of Nephrology, Hypertension and Family Medicine, Medical University of Lodz, Lodz, dDepartment of Pharmacology, Medical University, Bialystok and eDepartment of Hypertension, Medical University of Lodz, Lodz, Poland Correspondence to Maciej Banach, MD, PhD, FAHA, FESC, FASA, FRSPH, Head, Department of Hypertension, Chair of Nephrology and Hypertension, WAM University Hospital in Lodz, Medical University of Lodz, Zeromskiego 113, 90-549 Lodz, Poland. Tel: +48 42 639 3771; fax: +48 42 639 3782; e-mail: maciejbanach@aol.co.uk Received 23 August 2011 Revised 2 October 2011 Accepted 9 November 2011 J Hypertens 30:457–462 ß 2012 Wolters Kluwer Health | Lippincott Williams & Wilkins. DOI:10.1097/HJH.0b013e32834f0bb7 www.jhypertension.com 457 Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. Malyszko et al. system, resulting in increased efferent sympathetic tone [15]. Sympathetic nervous system activation in chronic kidney disease (CKD) is an early event in the pathophysiology of CKD, not a consequence of ESRD [14,15]. Activation of the sympathetic nervous system contributes substantially to cardiovascular events in persons with CKD, resulting in the poor prognosis for that population [13]. Increased concentrations of catecholamines and enhanced sensitivity to norepinephrine are the first indicators of overactivity of the sympathetic nervous system in CKD [16,17]. The elevated level of catecholamines in patients with ESRD is the result of not only reduced catecholamine clearance but also overspill involving the mechanisms that inhibit nitric oxide (NO) and that are associated with increased angiotensin II and increased sympathetic afferent outflow from diseased kidneys [18]. Norepinephrine clearance is reduced by 20% in mild renal failure and by up to 40% in patients receiving hemodialysis [19]. Norepinephrine affects cardiomyocytes and could be responsible for left ventricular hypertrophy [20]. Activation of the sympathetic nervous system and vagal withdrawal are closely linked to rhythm disturbances [21], which may lead to sudden cardiac death, a common cause of mortality in CKD [22]. Another concept regarding the pathogenesis of hypertension in ESRD is abnormal endothelial release of hemodynamically active compounds, that is, vasoconstrictors and vasodilators [21,22]. NO is produced in endothelial cells from L-arginine. In uremic plasma, there is a high concentration of an endogenous compound, asymmetrical dimethylarginine, which inhibits NO synthesis [23]. In addition, in an animal model of CKD, NO synthase activity progressively declines in the kidney [24]. This consequently leads to oxidative stress due to enhanced production of superoxide, which can stimulate sympathetic nerve activity [25]. Thus, NO deficiency may contribute to the development of hypertension in ESRD. RENALASE AND THE KIDNEY Discovery and properties of renalase The kidney, among its various functions, is also an endocrine organ [26]. In 2005, Xu et al. [27] described the history of the discovery of renalase and its possible role. Identifying and characterizing renalase represents an impressive illustration of the effective use of postgenomic technologies. The renalase gene, according to information available in the GenBank, is located on chromosome 10 at q23.33, contains seven exons (NC_000010), and has two transcription variants (1 and 2). It encodes four alternatively spliced isoforms (hRenalase 1–4) [28], which can be tissue-specific and reflect the particular function of renalase in these tissues. Only hRenalase1 is detected in human blood samples, which suggests that hRenalase 2–4 probably differ in function from hRenalase 1 [28]. The calculated molecular mass is approximately 38 kDa. The mouse renalase gene, residing on chromosome 19 C1, was also characterized [29]. Mouse renalase (mRenalase) is closely related to human renalase 1 with 72% amino acid identity [29]. Xu et al. [27] reported that renalase had a flavin adenine dinucleotide (FAD)-binding domain and that FAD was an essential 458 www.jhypertension.com cofactor for its stability and monoamine oxidase (MAO) activity. However, the amino acid sequence of renalase markedly differs from MAOs A and B, the main FADdependent enzymes catalyzing oxidative deamination of catecholamine in the body [27]. Renalase only shares 13.2% of its identity with MAO-A [27]. Renalase is preferentially expressed in proximal tubules, but it is also present in glomeruli and distant tubules, as well as in cardiomyocytes, liver, and skeletal muscles [27]. Recently, others have also identified renalase expression in peripheral nerves, adrenals, endothelium, and the central nervous system, as well as in adipose tissues in 12.5-day-old rat embryos and humans [28,30]. Renalase function: experimental data Xu et al. [27] indicated that the new hormone, renalase, secreted by the kidney and circulating in blood, degrades catecholamines and may play a role in the regulation of sympathetic tone and BP [27]. Renalase administered intravenously to Sprague–Dawley rats caused a fall in BP by 25%, as well as a decrease in heart rate and cardiac contractility [27]. These effects lasted only minutes and were dose-dependent. They resembled massive a-receptor and b-receptor blockade; however, no positive control was studied. A renalase knock-out mouse was generated to better understand the role of this peptide [27]. Wu et al. [31] reported no difference between the wildtype mouse and renalase knock out mouse in regard to renal function, but the knock-out mouse was hypertensive, having tachycardia, and had higher catecholamines levels than the wild-type animal. Then, the researchers tested the hypothesis that the knock-out mouse was more susceptible to myocardial ischemia [31]. They found that renalase deficiency worsened myocardial damage during acute ischemia and that treatment with recombinant renalase could ameliorate cardiac injury. These authors concluded that cardiac renalase deficiency may contribute to the increased susceptibility to myocardial injury due to ischemia and rhythm disturbances frequently found in CKD. In addition, they also reported [32] that circulating renalase lacked sufficient amine oxidase activity under basal conditions (prorenalase), but after a brief surge of epinephrine for less than 2 min, they observed a significant rise in renalase activity in normotensive rats. Simultaneously, prorenalase became maximally activated with a rise in BP more than 5 mmHg. In five of six nephrectomized rats (5/6 Nx) (a model of CKD), the authors found severe blood renalase deficiency 2–3 weeks after the surgery [32]. In addition, kidney renalase migrated as a dimer with a molecular weight of approximately 70 kDa, whereas heart renalase ran as a monomer (35 kDa) in SDS-PAGE gels [32]. Epinephrine infusion in these rats resulted in a shorter and less pronounced activation of renalase. The authors concluded that renalase deficiency might contribute to the elevated catecholamine levels in 5/6 Nx rats [32]. In another study on nephrectomized pups, Ghosh et al. [30] found that norepinephrine transporter protein and renalase protein expression in cardiac tissue were significantly lower than sham-operated and pair-fed controls, but norepinephrine levels were two times higher in nephrectomized pups. Those authors suggested that animals Volume 30
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March 2012 Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. Hypertension and kidney disease nephrectomized at an early age had increased circulating catecholamines due to decreased norepinephrine metabolism [30]. Desir et al. [33] reported that subcutaneous renalase significantly decreased SBP and DBP for up to 12 h in Dahl salt-sensitive rats. Renalase and hypertension: clinical data A link between renalase and hypertension was also demonstrated by Zhao et al. [34], who pioneered the finding that the renalase-coding gene in the Han Chinese population is a novel susceptibility gene for essential hypertension and its genetic variations may influence BP. This is probably connected with sex differences in autonomic nervous system activity, which is higher in males [35]. Polymorphisms of the renalase gene in hemodialysed patients were described, as well as their associations with hypertension in this population [36]. Hypertension was defined in this study as SBP of at least 140 mmHg, DBP of at least 90 mmHg, or taking hypotensive medication. rs2576178 polymorphism was genotyped in 369 hemodialysed patients, including 200 who were hypertensive and 169 who were normotensive, but rs10887800 polymorphism was genotyped in 421 hemodialysed patients, including 278 with hypertension and 143 controls [36]. The authors found that not only the G-allele frequencies of rs2576178 showed a significantly higher incidence, but those of rs10887800 also showed a significantly higher incidence in hypertensive, hemodialysed patients. The carrier state of the G-allele of rs2576178 polymorphism was associated with a 1.55 times greater risk of hypertension, whereas the carrier state of the G-allele of rs10887800 polymorphism was associated with 1.76 times greater risk of hypertension [36]. Because the number of patients is only slightly different for each group, it seems that the studies may have been performed on overlapping populations. It would be more interesting to know the prevalence of both polymorphisms in the same population, as the prevalence of hypertension was 54% and 66% in these two hemodialysed populations, respectively [36]. This is the first molecular analysis of renalase variants in hemodialysed patients, which we believe is paving the way to gaining a deeper insight into the origin of hypertension and its complications. Farzaneh-Far et al. [37] reported that a functional missense polymorphism (C-allele) in renalase (Glu37Asp) was associated with left ventricular hypertrophy, both systolic and diastolic dysfunction, and poor exercise capacity and inducible ischemia in whites included in the Heart and Soul Study; however, no association between this CC genotype and BP was found in the population with stable coronary artery disease [37]. Renalase in kidney and heart diseases In a study by Gu et al. [38], a model of unilateral renal artery stenosis was demonstrated in an experimental animal model. The study showed that renalase expression in the ischemic kidney was lower than in the nonischemic one, indicating that renal blood flow might influence renalase synthesis [38]. Moreover, when Gu et al. studied the model of heart failure in rats [ligation of the left anterior descending coronary artery (LAD)], they found that renal renalase expression increased and reached a peak at 1 week postJournal of Hypertension LAD ligation, gradually decreasing in weeks 3 and 4; they provided no data on the serum creatinine [38]. Renalase activity was measured with the Amplex Red Monoamine Oxidase Assay Kit from Invitrogen (Carlsbad, California, USA); this measurement was based on the detection of H2O2 in a horseradish peroxidase-coupled reaction and was the same assay used by the Desir group (Xu et al. [27]). The authors found that plasma renalase activity was the highest in the operated group [38], and when they measured the renalase concentration in control, shamoperated, and operated rats, the highest concentration of this protein was found in the operated rats. The same applied to the concentration of norepinephrine. To determine the renalase concentration, the researchers used an ELISA with antirenalase antibody [1 : 32000, Abcam (Cambridge, Massachusetts, USA)]. Both the activity and concentration of renalase were higher in association with heart failure, suggesting that more highly activated renalase degraded the increased norepinephrine levels [38]. The authors proposed that the kidney synthesized and secreted more renalase to compensate for the increased catecholamine levels in the early phase of acute myocardial infarction in the animal model [38]. When renal blood flow falls to a critical level, renalase expression in the kidney fails to keep up with the elevated catecholamine concentration. This could be a decompensation phase; however, the activity and concentration of renalase measured in the plasma 4 weeks after ligation were elevated [38]. Thus, the problem of kidney function and renalase activity and levels needs further study. There is virtually no data on renalase concentration and/ or activity in humans. Xu et al. [27] found that in hemodialyzed patients (n ¼ 8) renalase expression was decreased compared with healthy volunteers (n ¼ 4). Similar findings were presented by Wang et al. [39]. They reported a decreased renalase expression in one CKD patient and one hemodialysis patient compared with two healthy controls. In a recent study [40], serum renalase was significantly higher in kidney transplant recipients relative to healthy volunteers. In this study, predictors of serum renalase were kidney function, age, time after transplantation, and DBP. Przybylowski et al. [41] showed similar findings in heart transplant recipients; however, only kidney function (serum creatinine level) was a predictor of serum renalase. Serum renalase was not affected by sex, diabetic status, and presence of hypertension. In addition, a recent study [42] reported highly elevated serum renalase in patients on peritoneal dialysis compared with healthy volunteers. In addition, renalase was positively related to the duration of peritoneal dialysis and negatively to residual renal function. No correlation between serum renalase concentration and BP, age, sex, or adequacy of dialysis was found. In only a clinical study presented as an abstract, Schlaich et al. [43] found that in patients with resistant hypertension (n ¼ 22), arterial renalase (measured by western blot analysis using a monoclonal antibodies and quantified using a gel documentation system) was significantly higher in four normotensive control participants relative to 22 hypertensive patients (P < 0.05), whereas, whole body noradrenaline spillover tended to be higher in hypertensive patients, but without reaching statistical significance www.jhypertension.com 459 Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. Malyszko et al. (P ¼ 0.12). Arterial renalase correlated negatively in univariate analysis with SBP in the entire cohort. UNRESOLVED ISSUES The plasma-specific enzyme semicarbazide-sensitive amine oxidase (SSAO) catalyzes the oxidative deamination of primary amines (methylamine, aminoacetone, benzylamine, and 2-phenylamine are preferential and physiological substrates) to form the corresponding aldehydes with H2O2 and ammonia [44]. Dopamine and, to a lesser extent, norepinephrine are oxidized by SSAO, but epinephrine is not. Vascular adhesion protein-1 is a copper-containing SSAO secreted by vascular smooth muscle cells, adipocytes, and endothelial cells with functional MAO activity [45]. It may function as a scavenger enzyme to assist MAO, but it is insensitive to MAO inhibitors. The oxidation process generates harmful products that may be involved in causing atherosclerosis and vascular damage in diabetes. Elevation of SSAO activity is observed in atherosclerosis, diabetes mellitus, and obesity [46–48]. The SSAO level in human plasma is very low and exerts a minor influence on catecholamines in in-vitro incubation [44]. In addition, SSAO overexpression in transgenic mice has had no influence on BP after adrenaline administration in contrast to the wild-type animals [49]. On the contrary, the administration of geraniin (hydrolysable tannin from Phyllantus urinaria), which possesses SSAO inhibitory and antioxidant properties, resulted in a fall in BP [50]. Taking all these data together, Medvedev et al. [51] concluded that SSAO was not involved in the degradation of catecholamines in the circulation. Boomsma and Tipton [44] questioned the method used by Xu et al. [27] to measure renalase activity. Xu et al. [27] measured MAO activity and extrapolated the results to renalase. In addition, Boomsma and Tipton [44] considered that the pathophysiological concentrations of catecholamines are lower than the concentrations used in the experiments. They further concluded that it was unlikely that renalase is a catecholamine-metabolizing enzyme. They suggested that it may have important cardiovascular functions, but through another mechanism [44]. In another study, Pandini et al. [52] reported expression of human renalase in Escherichia coli cells and its purification to homogeneity. Moreover, this renalase contained noncovalently bound FAD, which dissociated easily in the presence of SDS (0.2% concentration). However, using two different methods, the authors were unable to prove that renalase exhibited MAO activity. Nevertheless, when administered to rats, it exerted its hypotensive properties, despite being catalytically inactive [52]. Therefore, is the question whether renalase is really a MAO still valid? Luft [53] noted that dopamine is associated with lower BP and decreased cardiovascular risk, and that is why diminishing dopaminergic tone (by renalase, for example) would increase BP and cardiovascular risk. Eikelis et al. [54] also questioned the hypothesis that renalase could degrade catecholamines because of the lack of definitive evidence in the literature to directly support this hypothesis. In addition, authors’ own sequencing of renalase transcripts from various mouse strains demonstrated that renalase in these animals was shorter than rat and human renalase and 460 www.jhypertension.com did not contain the N-terminal flavin adenosine dinucleotide-binding site characterized by a GxGxxG motif, as described by Wu et al. [31]. Therefore, it is difficult to comprehend how renalase normally functions in mice if the protein does not possess this supposedly essential active site. In addition, Milani et al. [55] pointed out that renalase is not a MAO and most probably is not an oxidase. The absence of a recognizable NADP-binding site in the protein structure and its poor affinity for, or poor reactivity toward, NADH and NADPH suggest that these are not physiological ligands of renalase. Xu et al. [27], using western blot technique with polyclonal antibodies, found that renalase expression in eight hemodialysed patients was diminished when compared with four healthy controls. In another study by Wang et al. [39], recombinant renalase and monoclonal antibody were obtained. The human renalase gene was amplified from nephrectomized human kidney (no cause for nephrectomy was given) by specific primer, and DNA fragments into pET22b, the gene was transformed to E. coli BL21. Upon induction by IPTG, BL-21 transformed bacteria produced 38 kDa protein as shown on SDS-PAGE electrophoresis, whereas, according to Li et al. [32], renal renalase was run as a dimer with a mass of 70 kDa on SDS-PAGE. The Balb/c mouse was immunized with purified protein to prepare the monoclonal antibody by hybridoma technique. The monoclonal antibody could react with the both recombinant and human serum renalase. Wang et al. [39] also showed renalase expression in patient with CKD, patient with hemodialysis, and healthy controls. However, in the methods section, the information on the patients was as follows: ‘the serum of both healthy persons and chronic renal failure patients was incubated with the recombinant renalase monoclonal antibody, followed by soaking in the HRP-IgG (Sigma) and visualized by ECL kits (GE Co. Ltd)’ [39]. However, no further data were given. Western blot is only a semiqualitative method, whereas an ELISA assay with a monoclonal antibody specific to renalase is commercially available from at least two companies. The assays measure the total level of renalase 1, independent of whether this peptide is active or inactive. Moreover, it is possible that the antibody in the assay binds to common fragments of different isoforms; therefore, the measured level could be very high and not related to activity. As Xu et al. [27] assessed the activity of the enzyme using a commercially available assay, it is not possible to compare the activity with the antigen due to the fact that renalase has isoforms. The manufacturers of the assay claimed that only renalase 1 levels were measured, and there are no data on the possible cross-reactivity. As renalase is secreted not only by the kidney but also by cardiomyocytes, liver, and adipose tissue, in the case of ESR failure, other organs and tissues may oversecrete renalase and, therefore, the levels could be very high as was found in clinical studies [40–42]. When expression of the renalase is assessed, we cannot be sure that the protein is active. In addition, as Xu et al. [27] suggested, there is an inhibitor of renalase in plasma. Therefore, the level of the enzyme can be high, but its activity can be low or negligible. Li et al. [32] have shown that the infusion of catecholamines causes an increase in blood renalase activity in Volume 30
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March 2012 Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. Hypertension and kidney disease experimental animals. They also found that renalase circulates as a proenzyme that lacks enzymatic activity, but is rapidly activated by elevated plasma catecholamines. For more than 30 years, it has been known that plasma levels of norepinephrine are elevated in chronic renal failure, leading to increased sympathetic nerve activity. The kidneys make a 15–24% contribution to the clearance of circulating catecholamines [19]. Most circulating catecholamines are actively removed from the circulation by nonneuronal monoamine transporters in other tissues and organs in which the amines are subsequently metabolized before excretion [18]. Although decreases in circulatory clearance resulting from impaired renal function may contribute to increased plasma concentration of catecholamines, these increases in patients with renal failure probably result mainly from activation of the sympathetic nervous system [18]. Therefore, we may speculate that in the state of catecholamine excess, that is, in ESRD, the activation of proenzyme renalase into active renalase is more rapid and efficient in several tissues. Much progress has been achieved in the study of the expression of renalase, but, with the wide tissue distribution, the function may be tissue-specific. There are few data on the possible activators and/or inhibitors of renalase. It seems that urinary and serum renalase are not identical, as the experimentally determined molecular mass of the urinary enzyme (35 kDa) [32] is lower than the calculated molecular mass (37.8 kDa) [27,29,55]. CONCLUSION Further studies are needed to prove or disprove the possible role of renalase in the pathogenesis of hypertension in patients with kidney diseases. Regulation of BP and development of cardiovascular complications are complex processes [56–58], and the contribution of renalase is far from clear. It should also be stressed that there is a lack of information on renalase concentration and activity in specific conditions in humans, and publications are scarce and often only in abstract form [33,43,59–61]. Whether renalase will become a novel therapeutic target for hypertension, as suggested by Paulis and Unger [62], remains an open question. Recombinant renalase or renalase antibodies could be attractive therapeutic option, providing that renalase does really participate in the regulation of BP. Therefore, ‘proof of concept’ studies are urgently needed. In addition, a basic question whether renalase is a MAO should also be addressed and how this may be related to catecholamines. Renalase is ‘an interesting protein’ with, so far, poorly defined biochemical functions. We are at the very beginning of solving the problem of whether renalase is a causative factor of hypertension in kidney disease or just an innocent bystander. We know for sure that it is an intriguing protein with, so far, poorly defined biochemical functions. Whether renalase will be a novel therapeutic target for hypertension, as suggested by Paulis and Unger [62], remains an open question. ACKNOWLEDGEMENT The authors have not received any payments in connection with the preparation of this review. No medical or Journal of Hypertension pharmaceutical company was involved with the preparation of this article. Conflicts of interest There are no conflicts of interests. REFERENCES 1. Agarwal R, Nissenson AR, Batlle D, Coyne DW, Trout JR, Warnock DG. 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