Clinica Chimica Acta 440 (2015) 36–39
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Clinica Chimica Acta journal homepage: www.elsevier.com/locate/clinchim
Invited critical review
Asymmetric Dimethylarginine (ADMA) in cardiovascular and renal disease Patrícia Nessralla Alpoim a, Letícia Parreiras Nunes Sousa a, Ana Paula Lucas Mota a, Danyelle Romana Alves Rios b, Luci Maria SantAna Dusse a,⁎ a b
Departamento de Análises Clínicas e Toxicológicas, Faculdade de Farmácia, Universidade Federal de Minas Gerais, Brazil Faculdade de Farmácia — Campus Centro Oeste Dona Lindu, Universidade Federal de São João Del-Rei, Brazil
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a b s t r a c t Background: Asymmetric Dimethylarginine (ADMA) is a modified amino acid formed when intracellular arginine is methylated by methyltransferases that are widely distributed throughout the body. Nitric oxide (NO) is produced from L-arginine in a reaction catalyzed by three distinct isoforms of NO synthase (NOS). NO has emerged as a mediator involved in maintenance of vascular tonus, blood pressure regulation, inhibition of platelet aggregation, leukocyte and endothelial cell interaction and vascular permeability. ADMA is an important inhibitor that competes with NOS and compromises NO synthesis. Objective: This review aims to compile articles involving renal and cardiovascular diseases in which plasma ADMA was assessed in order to clarify its role in these diseases. Conclusion: Although current knowledge suggests that ADMA has a role in the onset of cardiovascular and renal diseases, its actions are poorly understood. Clarifying its biochemical mechanisms is essential for improving disease management and promoting better quality of life for these patients. © 2014 Elsevier B.V. All rights reserved.
Article history: Received 25 March 2014 Received in revised form 22 October 2014 Accepted 2 November 2014 Available online 7 November 2014 Keywords: L-Arginine Asymmetric Dimethyl Nitric oxide Renal disease Cardiovascular disease
Contents 1. 2. 3.
Introduction . . . . . . . . . . . . . ADMA and cardiovascular diseases . . . ADMA and renal disease . . . . . . . . 3.1. ADMA and proteinuria . . . . . 3.2. ADMA and renal transplantation . 4. Conclusion . . . . . . . . . . . . . . Acknowledgment . . . . . . . . . . . . . References. . . . . . . . . . . . . . . . .
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1. Introduction Asymmetric Dimethylarginine (ADMA) is an intracellular amino acid formed during post-translational methylation of arginine by methyltransferases. Under physiologic conditions, ADMA is present in plasma, urine, tissues and many cells. Methyltransferases enzymes are predominantly found in the cell nucleus and act in RNA processing an- ⁎ Corresponding author at: Prof. Luci Dusse. Departamento de Análises Clínicas e Toxicológicas, Faculdade de Farmácia, Universidade Federal de Federal Minas Gerais, d Av. Antônio Carlos, 6627, Pampulha CEP: 31270-901 Belo Horizonte, Minas Gerais, t- Brazil. Tel.: +55 31 3409 6880/6900. E-mail address: [email protected] (L.M.S. Dusse).
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36 37 38 38 38 38 38 38
ranscriptional control. There are two types of protein arginine methyltransferases (PRMT), I and II [1,2]. The role of arginine methylation remains unclear. However, several hypotheses have been suggested including regulation of RNA synthesis or translation, DNA repair, protein interaction in translational signaling, as well as others. PRMT type I is expressed in the heart, smooth muscle and endothelial cells [3]. The exact mechanisms involved with PRMT expression have not as yet been fully determined. However, all type I isomers are expressed on the vascular wall. It should be noted that PRMT type I is up-regulated in endothelial cells in response to shear stress [3,4], i.e., vascular perforation or increased low density lipoprotein (LDL) [4].
http://dx.doi.org/10.1016/j.cca.2014.11.002 0009-8981/© 2014 Elsevier B.V. All rights reserved.
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P.N. Alpoim et al. / Clinica Chimica Acta 440 (2015) 36–39
ADMA is released into cytosol when proteins undergo hydrolysis thus becoming an obligatory product of normal protein turnover. Therefore, the amount of ADMA generated depends on the extent of arginine methylation in protein and rate of its turnover [5]. In addition to ADMA, two other methylarginine compounds have been described, symmetric dimethylarginine (SDMA), an ADMA inert isomer, and N-monomethylL-arginine (L-NMMA) [6–8]. Type I PRMT produces ADMA, type II generates SDMA and L-NMMA can be produced by both [2]. Hibbs et al. [9], were first to show methylarginine biologic action by demonstrating that L-NMMA inhibits macrophage activation in vivo. It is well known that macrophage activation is related to nitric oxide (NO) production. NO, a gaseous free radical, was historically considered an air pollutant and toxic agent. Currently, NO has been identified as an important endogenous cellular signaling molecule essential to many physiologic processes [10,11]. NO is generated from L-arginine and other co-factors in a reaction catalyzed by a family of enzymes called NO synthases (NOS) in many cell types. In endothelial cells, NO is produced by endothelial NOsynthase (eNOS). Following its release, NO is transported to muscle cells where it activates soluble guanylate cyclase (sGC). This enzyme converts guanosine triphosphate (GTP) to cyclic guanosine-3′,5′monophosphate (cGMP). cGMP is involved in many aspects of cellular function via interaction with specific kinases, ion channels, and phosphodiesterases [10]. High intracellular cGMP results in decreased Ca2+ leading to vasodilatation and inhibition of platelet activation. NO produced by endothelial cells has emerged as a versatile mediator involved in maintenance of vascular tonus, blood pressure regulation, prevention of platelet aggregation, leukocyte–endothelial cell interaction and vascular permeability [10,12]. In the kidney, synthesis of arginine occurs primarily in the proximal tubules. Constitutive NO synthase (cNOS) is present in the glomerulus, vessels and tubular segments including the macula dense and inner medullary segments of the collecting duct system [13]. The inducible isoform (iNOS) has been found in the smooth muscle cells of blood vessels, the distal end of the efferent arteriole and medullary area of the ascending limb of the Henle loop. Cytokines that stimulate this form (iNOS) have been found in cell cultures generated from proximal tubules, inner medullary segments of the collecting duct system and the mesangium [14]. ADMA is a key NO inhibitor. It competes with NOS isoforms thus impairing NO synthesis [6,7]. NOS inhibitory effect can be reversed by excessive L-arginine supplementation [7,15]. In vitro studies have shown that increased ADMA significantly inhibits NOS and reduces NO production in endothelial cell cultures and isolated human blood vessels [16–18]. Furthermore, it was demonstrated that ADMA administration to healthy rats resulted in increased renal vascular resistance and increased blood pressure [19]. All three methylarginine isoforms interfere with NOS transport which is mediated by the membrane transport system y + thus explaining SDMA inhibitory effect over NO bioavailability [20]. The kidney plays an important role in ADMA removal [8]. Of the 300 μmol of ADMA generated per day, only 20% is excreted in the urine. The majority is removed by metabolic conversion to citrulline and dimethylamin by dimethylarginine dimethylaminohydrolase (DDAH) [21]. DDAH has two isoforms (I and II) with similar activity, but different tissue distribution [22]. Unfortunately, molecular mechanisms responsible for regulating its expression remain mostly unknown. It has been demonstrated that incubation of endothelial cells with tumor necrosis factor alpha (TNF-α) or oxidized low-density lipoprotein reduced DDAH activity [23]. Other factors such as oxidative stress, high glucose and homocysteine levels may also contribute to reduced enzyme activity resulting in increased ADMA [24,25]. Some studies have suggested that the liver is involved in methylarginine metabolism due to its intrinsic DDAH activity [26,27]. Vallance and Leone were the first to describe ADMA as an endogenous inhibitor of the arginine-NO pathway [28]. The role of ADMA
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in regulating NO production is currently attracting increased interest. Because increased ADMA has been reported in cardiovascular and renal disease, this molecular may serve as a potential biomarker [29,30]. 2. ADMA and cardiovascular diseases Hypertension is a well-known predictor for cardiovascular disease and NO is essential for blood pressure control. Therefore, a role of ADMA in cardiovascular disease is reasonable. It should be noted that ADMA is actively absorbed by endothelial cells resulting in extracellular levels that are 5–10 fold lower. As such, slight changes in plasma ADMA could potentially result in significant intracellular changes thus modifying NO production and contributing to the development of cardiovascular disease. Under pathologic conditions, ADMA may increase 3–9 fold resulting in significant inhibition (30–70%) of NO production [31]. Two mechanisms have been suggested to explain the involvement of ADMA in hypertension pathogenesis. The first involves ADMA inhibition of eNOS whereas the second involves inhibition of renal sodium excretion [32,33]. Matsuguma et al. [34], described increased DDAH expression and a consequent reduction of ADMA in chronic kidney disease. It is well established that homocysteine plays an important role in cardiovascular pathophysiology. Increased homocysteine can increase atherosclerotic risk by direct inhibition of DDAH activity [35]. DDAH contains four cysteine residues critical for its activity. Agents that block sulfhydryl residues such as p-chloromercuribenzoic acid and mercury chloride are potent DDAH inhibitors. Homocysteine also possesses very reactive sulfhydryl groups which participate in the formation of covalent bonds with protein. It is quite reasonable that homocysteine also forms disulfide bonds with DDAH thereby blocking ADMA binding to the active site thus slowing degradation. Stühlinger et al. [24], suggested that homocysteine bonding would modify the spatial configuration of the enzyme potentially inhibiting its activity. Furthermore, the high reactivity of homocysteine may cause protein degradation via structural destabilization thus increasing oxidative stress. As such, methylated arginine residues are released generating ADMA. S-adenosylmethionine, the methyl group donor in the arginine methylation cycle, is a homocysteine precursor. Thus, excess homocysteine may increase ADMA thereby contributing to cardiovascular risk. ADMA has two methyl groups and its synthesis produces two homocysteine molecules [24]. Holven et al. [35], reported that plasma ADMA was positively correlated with homocysteine in subjects with hyperhomocysteinemia. Teerlink et al. [36], confirmed a strong correlation between ADMA and plasma homocysteine in a large cohort study. Rabbits and monkeys, in which atherosclerosis was induced by consumption of a hypercholesterolemic diet, showed an association between increased ADMA and endothelial dysfunction [37]. Accordingly, a positive correlation between cholesterol and ADMA was also verified in hypercholesterolemic subjects [38]. Studies have shown that endothelial cell incubation with oxidized low density lipoprotein (LDL) results in increased ADMA in the culture medium due to reduced DDAH activity [23]. LOX-1 receptor is the main oxidized LDL receptor in endothelial cells. It is known that oxidized LDL binds to LOX-1 receptor enhancing the intracellular generation of reactive oxygen species. Interestingly, it was demonstrated that incubation of endothelial cells with ADMA up-regulated LOX-1 [39]. Thus, it has been assumed that ADMA and oxidized LDL are part of a vicious cycle in which oxidative stress, induced by high oxidized LDL, leads to DDAH inhibition and increased ADMA. Consequently, ADMA boosts LOX-1 expression, enhancing oxidative stress and production of oxidized LDL [5]. Osanai et al. [4], have shown that ADMA released by endothelial cells was increased and DDAH activity did not change after shear stress. Since eNOS activity is also stimulated by shear stress, it appears that ADMA and eNOS activity antagonistically regulate the NO production in the circulation.
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P.N. Alpoim et al. / Clinica Chimica Acta 440 (2015) 36–39
Kielstein et al. [40], demonstrated that systemic ADMA infusion in healthy volunteers resulted in an immediate increase in blood pressure and decreased heart rate. Cardiac output at rest, as well as cardiac output during exercise, were strongly attenuated after ADMA infusion, suggesting a key role of ADMA in heart failure and in reduced exercise tolerance [32]. The Cardiac Multicenter Study investigated risk of coronary heart disease and ADMA [41]. It was shown that coronary heart disease manifestations in the presence of other risk factors (hypertension, hypercholesterolemia, diabetes mellitus and smoking) were associated with increased ADMA suggesting a role for this amino acid as a novel marker for cardiovascular disease. 3. ADMA and renal disease Kidneys have a dual function in ADMA metabolism, i.e., they excrete ADMA and possess high levels of DDAH. The first clinical study that suggested a role for ADMA in atherosclerosis was conducted in end-stage renal disease (ESRD) patients [42]. Amino acid metabolism tends to be impaired in chronic renal failure due to abnormal synthesis or excretion. In fact, hyperhomocysteinemia occurs in more than 85% of patients after kidney transplantation and those with ESRD [43]. It is often considered an independent risk factor for cardiovascular disease. Increased ADMA in early and ESRD is considered a uremic toxin [44–47]. Although attributed to impaired renal function, it is not yet clear whether ADMA is a marker or a risk factor for renal disease progression [44,45]. Because it acts as a nontraditional cardiovascular risk factor, increased ADMA could explain the high cardiovascular risk that typically accompanies renal disease. Increased ADMA has been associated with more rapid renal disease progression and mortality [44]. Some of the rationale to explain increased ADMA in renal disease include increased protein turnover, increased PRMT, i.e., the enzyme that catalyzes its synthesis, decreased DDAH, i.e., responsible for its elimination, and decreased renal excretion [45,46]. It is believed that the kidneys and the liver are the main organs involved in ADMA elimination via DDAH [45,46]. The pro-oxidative environment frequently observed in renal disease and reduced tubular mass may also contribute to increased ADMA by enhancing PMRT1 and reducing DDAH [46]. Increased ADMA reduces NO bioavailability resulting in inflammation and oxidative stress, which are typical features of renal disease progression. It is also possible that ADMA contributes to progressive renal dysfunction, since it can functionally impair the glomerular filtration barrier, promoting proteinuria, interstitial and glomerular fibrosis and oxidative stress. On the other hand, progression of chronic renal disease and changes in other biochemical variables may affect plasma ADMA [44,46,48]. Recently, Raptis et al. [49], observed that increased plasma ADMA was associated with oxidative stress in early stages of polycystic kidney disease. Reduced NO synthesis resulted in increased mRNA expression of oxidative stress markers. Eiselt et al. [50], also observed increased ADMA, markers of oxidative stress and homocysteine in chronic kidney disease (CKD) stages 3–5, comparing to healthy controls. These researchers showed that disease progression was dependent on increased ADMA and baseline estimated glomerular filtration rate (eGFR). Increased ADMA was predictive of rapid progression even with higher baseline eGFR values (initial eGFR N 36 mL/min/1.73 m2). The association between ADMA and eGFR decline has been previously reported [59]. More rapid eGFR decline was associated with increased advanced glycation end products (AGE), hypertension and proteinuria. 3.1. ADMA and proteinuria Proteinuria, even microalbuminuria, is a traditional progression marker of kidney damage with or without diabetes or hypertension [51]. There is an increasing body of evidence that endothelial dysfunction is also linked to proteinuria [52]. Impaired NO production is a characteristic feature of endothelial dysfunction and ADMA appears related
to proteinuria [53]. It has been proposed that glomerular permeability to protein is regulated by NO bioavailability which is related to ADMA [54]. There are several possible mechanisms by which ADMA and other inhibitors of NO are involved in the pathogenesis of proteinuria. The first mechanism involves impairment to glomerular size and charge selectivity. This phenomenon is likely to reflect functional rather than structural disruption of the glomerular wall [52]. The second mechanism involves ADMA-mediated compromise of filtration barrier integrity by altering the NO bioavailability and oxygen superoxide (O− 2 ) production [53]. The third mechanism involves altered protein turnover, PRMT [55] or other mechanisms involving the renin–angiotensin system-RAS (RAS blockade using Ramipril results in decreased ADMA, proteinuria and cell death mediators) [56]. On the other hand, tubular DDAH activity might be inactivated by proteinuria-elicited oxidative stress, leading to ADMA accumulation in patients with CKD and proteinuria [57]. 3.2. ADMA and renal transplantation Although there is a great interest in clarifying the role of ADMA in renal transplant, especially in cardiovascular risk, only a few studies have been performed until now. Yilmaz et al. [58], reported that renal transplant greatly decreased ADMA for up to four weeks vs prior to transplant. Other studies also found decreased ADMA during the first month after renal transplant, but they remained increased relative to control subjects [59]. The initial ADMA decrease resulted in increased NO synthesis and improved endothelial function. This finding appears independent of immunosuppressive therapy [60]. Two studies showed that there is more rapid deterioration of renal function in CKD patients with increased ADMA [61,62]. As such, ADMA may act as an independent prognostic marker for the renal disease progression. In a prospective observational follow-up study involving patients with type 1 diabetic nephropathy, increased ADMA was associated with a decline in glomerular filtration rate [63]. Increased ADMA was a significant risk factor for increased plasma creatinine and graft failure in renal transplantation [64]. Mihout et al. [63], admitted that ADMA might induce exaggerated synthesis of extracellular matrix protein, leading to kidney fibrosis and CKD thereby contributing to cardiovascular morbidity and mortality in transplant patients. 4. Conclusion The ubiquitous distribution of arginine and methyltransferases in the human body can potentially contribute to large amounts of ADMA production. Because ADMA competitively inhibits eNOS, increased ADMA reduces NO production thereby contributing to endothelial dysfunction, cardiovascular risk and progressive renal damage. Although its actions are not completely understood, current data suggests that ADMA has a role in the onset of cardiovascular and renal diseases; clarifying this issue is essential for improving the disease management and promoting a better life quality for these patients. Acknowledgment The authors thank FAPEMIG (CDS APQ-3535-4.04) and CNPq/Brazil (480637/2013-0). LMD is grateful to CNPq Research Fellowship (302794/2012-3). References [1] Vallance P, Leone A, Calver A, Collier J, Moncada S. Accumulation of an endogenous inhibitor of nitric oxide synthesis in chronic renal failure. Lancet 1992;339:572–5. [2] Wada K, Inoue K, Hagiwara M. Identification of methylated proteins by protein arginine N-methyltransferase 1, PRMT1, with a new expression cloning strategy. Biochim Biophys Acta 2002;1591:1–10.
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Contents lists available at ScienceDirect
Clinica Chimica Acta journal homepage: www.elsevier.com/locate/clinchim
Invited critical review
Asymmetric Dimethylarginine (ADMA) in cardiovascular and renal disease Patrícia Nessralla Alpoim a, Letícia Parreiras Nunes Sousa a, Ana Paula Lucas Mota a, Danyelle Romana Alves Rios b, Luci Maria SantAna Dusse a,⁎ a b
Departamento de Análises Clínicas e Toxicológicas, Faculdade de Farmácia, Universidade Federal de Minas Gerais, Brazil Faculdade de Farmácia — Campus Centro Oeste Dona Lindu, Universidade Federal de São João Del-Rei, Brazil
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a b s t r a c t Background: Asymmetric Dimethylarginine (ADMA) is a modified amino acid formed when intracellular arginine is methylated by methyltransferases that are widely distributed throughout the body. Nitric oxide (NO) is produced from L-arginine in a reaction catalyzed by three distinct isoforms of NO synthase (NOS). NO has emerged as a mediator involved in maintenance of vascular tonus, blood pressure regulation, inhibition of platelet aggregation, leukocyte and endothelial cell interaction and vascular permeability. ADMA is an important inhibitor that competes with NOS and compromises NO synthesis. Objective: This review aims to compile articles involving renal and cardiovascular diseases in which plasma ADMA was assessed in order to clarify its role in these diseases. Conclusion: Although current knowledge suggests that ADMA has a role in the onset of cardiovascular and renal diseases, its actions are poorly understood. Clarifying its biochemical mechanisms is essential for improving disease management and promoting better quality of life for these patients. © 2014 Elsevier B.V. All rights reserved.
Article history: Received 25 March 2014 Received in revised form 22 October 2014 Accepted 2 November 2014 Available online 7 November 2014 Keywords: L-Arginine Asymmetric Dimethyl Nitric oxide Renal disease Cardiovascular disease
Contents 1. 2. 3.
Introduction . . . . . . . . . . . . . ADMA and cardiovascular diseases . . . ADMA and renal disease . . . . . . . . 3.1. ADMA and proteinuria . . . . . 3.2. ADMA and renal transplantation . 4. Conclusion . . . . . . . . . . . . . . Acknowledgment . . . . . . . . . . . . . References. . . . . . . . . . . . . . . . .
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1. Introduction Asymmetric Dimethylarginine (ADMA) is an intracellular amino acid formed during post-translational methylation of arginine by methyltransferases. Under physiologic conditions, ADMA is present in plasma, urine, tissues and many cells. Methyltransferases enzymes are predominantly found in the cell nucleus and act in RNA processing an- ⁎ Corresponding author at: Prof. Luci Dusse. Departamento de Análises Clínicas e Toxicológicas, Faculdade de Farmácia, Universidade Federal de Federal Minas Gerais, d Av. Antônio Carlos, 6627, Pampulha CEP: 31270-901 Belo Horizonte, Minas Gerais, t- Brazil. Tel.: +55 31 3409 6880/6900. E-mail address: [email protected] (L.M.S. Dusse).
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ranscriptional control. There are two types of protein arginine methyltransferases (PRMT), I and II [1,2]. The role of arginine methylation remains unclear. However, several hypotheses have been suggested including regulation of RNA synthesis or translation, DNA repair, protein interaction in translational signaling, as well as others. PRMT type I is expressed in the heart, smooth muscle and endothelial cells [3]. The exact mechanisms involved with PRMT expression have not as yet been fully determined. However, all type I isomers are expressed on the vascular wall. It should be noted that PRMT type I is up-regulated in endothelial cells in response to shear stress [3,4], i.e., vascular perforation or increased low density lipoprotein (LDL) [4].
http://dx.doi.org/10.1016/j.cca.2014.11.002 0009-8981/© 2014 Elsevier B.V. All rights reserved.
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P.N. Alpoim et al. / Clinica Chimica Acta 440 (2015) 36–39
ADMA is released into cytosol when proteins undergo hydrolysis thus becoming an obligatory product of normal protein turnover. Therefore, the amount of ADMA generated depends on the extent of arginine methylation in protein and rate of its turnover [5]. In addition to ADMA, two other methylarginine compounds have been described, symmetric dimethylarginine (SDMA), an ADMA inert isomer, and N-monomethylL-arginine (L-NMMA) [6–8]. Type I PRMT produces ADMA, type II generates SDMA and L-NMMA can be produced by both [2]. Hibbs et al. [9], were first to show methylarginine biologic action by demonstrating that L-NMMA inhibits macrophage activation in vivo. It is well known that macrophage activation is related to nitric oxide (NO) production. NO, a gaseous free radical, was historically considered an air pollutant and toxic agent. Currently, NO has been identified as an important endogenous cellular signaling molecule essential to many physiologic processes [10,11]. NO is generated from L-arginine and other co-factors in a reaction catalyzed by a family of enzymes called NO synthases (NOS) in many cell types. In endothelial cells, NO is produced by endothelial NOsynthase (eNOS). Following its release, NO is transported to muscle cells where it activates soluble guanylate cyclase (sGC). This enzyme converts guanosine triphosphate (GTP) to cyclic guanosine-3′,5′monophosphate (cGMP). cGMP is involved in many aspects of cellular function via interaction with specific kinases, ion channels, and phosphodiesterases [10]. High intracellular cGMP results in decreased Ca2+ leading to vasodilatation and inhibition of platelet activation. NO produced by endothelial cells has emerged as a versatile mediator involved in maintenance of vascular tonus, blood pressure regulation, prevention of platelet aggregation, leukocyte–endothelial cell interaction and vascular permeability [10,12]. In the kidney, synthesis of arginine occurs primarily in the proximal tubules. Constitutive NO synthase (cNOS) is present in the glomerulus, vessels and tubular segments including the macula dense and inner medullary segments of the collecting duct system [13]. The inducible isoform (iNOS) has been found in the smooth muscle cells of blood vessels, the distal end of the efferent arteriole and medullary area of the ascending limb of the Henle loop. Cytokines that stimulate this form (iNOS) have been found in cell cultures generated from proximal tubules, inner medullary segments of the collecting duct system and the mesangium [14]. ADMA is a key NO inhibitor. It competes with NOS isoforms thus impairing NO synthesis [6,7]. NOS inhibitory effect can be reversed by excessive L-arginine supplementation [7,15]. In vitro studies have shown that increased ADMA significantly inhibits NOS and reduces NO production in endothelial cell cultures and isolated human blood vessels [16–18]. Furthermore, it was demonstrated that ADMA administration to healthy rats resulted in increased renal vascular resistance and increased blood pressure [19]. All three methylarginine isoforms interfere with NOS transport which is mediated by the membrane transport system y + thus explaining SDMA inhibitory effect over NO bioavailability [20]. The kidney plays an important role in ADMA removal [8]. Of the 300 μmol of ADMA generated per day, only 20% is excreted in the urine. The majority is removed by metabolic conversion to citrulline and dimethylamin by dimethylarginine dimethylaminohydrolase (DDAH) [21]. DDAH has two isoforms (I and II) with similar activity, but different tissue distribution [22]. Unfortunately, molecular mechanisms responsible for regulating its expression remain mostly unknown. It has been demonstrated that incubation of endothelial cells with tumor necrosis factor alpha (TNF-α) or oxidized low-density lipoprotein reduced DDAH activity [23]. Other factors such as oxidative stress, high glucose and homocysteine levels may also contribute to reduced enzyme activity resulting in increased ADMA [24,25]. Some studies have suggested that the liver is involved in methylarginine metabolism due to its intrinsic DDAH activity [26,27]. Vallance and Leone were the first to describe ADMA as an endogenous inhibitor of the arginine-NO pathway [28]. The role of ADMA
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in regulating NO production is currently attracting increased interest. Because increased ADMA has been reported in cardiovascular and renal disease, this molecular may serve as a potential biomarker [29,30]. 2. ADMA and cardiovascular diseases Hypertension is a well-known predictor for cardiovascular disease and NO is essential for blood pressure control. Therefore, a role of ADMA in cardiovascular disease is reasonable. It should be noted that ADMA is actively absorbed by endothelial cells resulting in extracellular levels that are 5–10 fold lower. As such, slight changes in plasma ADMA could potentially result in significant intracellular changes thus modifying NO production and contributing to the development of cardiovascular disease. Under pathologic conditions, ADMA may increase 3–9 fold resulting in significant inhibition (30–70%) of NO production [31]. Two mechanisms have been suggested to explain the involvement of ADMA in hypertension pathogenesis. The first involves ADMA inhibition of eNOS whereas the second involves inhibition of renal sodium excretion [32,33]. Matsuguma et al. [34], described increased DDAH expression and a consequent reduction of ADMA in chronic kidney disease. It is well established that homocysteine plays an important role in cardiovascular pathophysiology. Increased homocysteine can increase atherosclerotic risk by direct inhibition of DDAH activity [35]. DDAH contains four cysteine residues critical for its activity. Agents that block sulfhydryl residues such as p-chloromercuribenzoic acid and mercury chloride are potent DDAH inhibitors. Homocysteine also possesses very reactive sulfhydryl groups which participate in the formation of covalent bonds with protein. It is quite reasonable that homocysteine also forms disulfide bonds with DDAH thereby blocking ADMA binding to the active site thus slowing degradation. Stühlinger et al. [24], suggested that homocysteine bonding would modify the spatial configuration of the enzyme potentially inhibiting its activity. Furthermore, the high reactivity of homocysteine may cause protein degradation via structural destabilization thus increasing oxidative stress. As such, methylated arginine residues are released generating ADMA. S-adenosylmethionine, the methyl group donor in the arginine methylation cycle, is a homocysteine precursor. Thus, excess homocysteine may increase ADMA thereby contributing to cardiovascular risk. ADMA has two methyl groups and its synthesis produces two homocysteine molecules [24]. Holven et al. [35], reported that plasma ADMA was positively correlated with homocysteine in subjects with hyperhomocysteinemia. Teerlink et al. [36], confirmed a strong correlation between ADMA and plasma homocysteine in a large cohort study. Rabbits and monkeys, in which atherosclerosis was induced by consumption of a hypercholesterolemic diet, showed an association between increased ADMA and endothelial dysfunction [37]. Accordingly, a positive correlation between cholesterol and ADMA was also verified in hypercholesterolemic subjects [38]. Studies have shown that endothelial cell incubation with oxidized low density lipoprotein (LDL) results in increased ADMA in the culture medium due to reduced DDAH activity [23]. LOX-1 receptor is the main oxidized LDL receptor in endothelial cells. It is known that oxidized LDL binds to LOX-1 receptor enhancing the intracellular generation of reactive oxygen species. Interestingly, it was demonstrated that incubation of endothelial cells with ADMA up-regulated LOX-1 [39]. Thus, it has been assumed that ADMA and oxidized LDL are part of a vicious cycle in which oxidative stress, induced by high oxidized LDL, leads to DDAH inhibition and increased ADMA. Consequently, ADMA boosts LOX-1 expression, enhancing oxidative stress and production of oxidized LDL [5]. Osanai et al. [4], have shown that ADMA released by endothelial cells was increased and DDAH activity did not change after shear stress. Since eNOS activity is also stimulated by shear stress, it appears that ADMA and eNOS activity antagonistically regulate the NO production in the circulation.
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Kielstein et al. [40], demonstrated that systemic ADMA infusion in healthy volunteers resulted in an immediate increase in blood pressure and decreased heart rate. Cardiac output at rest, as well as cardiac output during exercise, were strongly attenuated after ADMA infusion, suggesting a key role of ADMA in heart failure and in reduced exercise tolerance [32]. The Cardiac Multicenter Study investigated risk of coronary heart disease and ADMA [41]. It was shown that coronary heart disease manifestations in the presence of other risk factors (hypertension, hypercholesterolemia, diabetes mellitus and smoking) were associated with increased ADMA suggesting a role for this amino acid as a novel marker for cardiovascular disease. 3. ADMA and renal disease Kidneys have a dual function in ADMA metabolism, i.e., they excrete ADMA and possess high levels of DDAH. The first clinical study that suggested a role for ADMA in atherosclerosis was conducted in end-stage renal disease (ESRD) patients [42]. Amino acid metabolism tends to be impaired in chronic renal failure due to abnormal synthesis or excretion. In fact, hyperhomocysteinemia occurs in more than 85% of patients after kidney transplantation and those with ESRD [43]. It is often considered an independent risk factor for cardiovascular disease. Increased ADMA in early and ESRD is considered a uremic toxin [44–47]. Although attributed to impaired renal function, it is not yet clear whether ADMA is a marker or a risk factor for renal disease progression [44,45]. Because it acts as a nontraditional cardiovascular risk factor, increased ADMA could explain the high cardiovascular risk that typically accompanies renal disease. Increased ADMA has been associated with more rapid renal disease progression and mortality [44]. Some of the rationale to explain increased ADMA in renal disease include increased protein turnover, increased PRMT, i.e., the enzyme that catalyzes its synthesis, decreased DDAH, i.e., responsible for its elimination, and decreased renal excretion [45,46]. It is believed that the kidneys and the liver are the main organs involved in ADMA elimination via DDAH [45,46]. The pro-oxidative environment frequently observed in renal disease and reduced tubular mass may also contribute to increased ADMA by enhancing PMRT1 and reducing DDAH [46]. Increased ADMA reduces NO bioavailability resulting in inflammation and oxidative stress, which are typical features of renal disease progression. It is also possible that ADMA contributes to progressive renal dysfunction, since it can functionally impair the glomerular filtration barrier, promoting proteinuria, interstitial and glomerular fibrosis and oxidative stress. On the other hand, progression of chronic renal disease and changes in other biochemical variables may affect plasma ADMA [44,46,48]. Recently, Raptis et al. [49], observed that increased plasma ADMA was associated with oxidative stress in early stages of polycystic kidney disease. Reduced NO synthesis resulted in increased mRNA expression of oxidative stress markers. Eiselt et al. [50], also observed increased ADMA, markers of oxidative stress and homocysteine in chronic kidney disease (CKD) stages 3–5, comparing to healthy controls. These researchers showed that disease progression was dependent on increased ADMA and baseline estimated glomerular filtration rate (eGFR). Increased ADMA was predictive of rapid progression even with higher baseline eGFR values (initial eGFR N 36 mL/min/1.73 m2). The association between ADMA and eGFR decline has been previously reported [59]. More rapid eGFR decline was associated with increased advanced glycation end products (AGE), hypertension and proteinuria. 3.1. ADMA and proteinuria Proteinuria, even microalbuminuria, is a traditional progression marker of kidney damage with or without diabetes or hypertension [51]. There is an increasing body of evidence that endothelial dysfunction is also linked to proteinuria [52]. Impaired NO production is a characteristic feature of endothelial dysfunction and ADMA appears related
to proteinuria [53]. It has been proposed that glomerular permeability to protein is regulated by NO bioavailability which is related to ADMA [54]. There are several possible mechanisms by which ADMA and other inhibitors of NO are involved in the pathogenesis of proteinuria. The first mechanism involves impairment to glomerular size and charge selectivity. This phenomenon is likely to reflect functional rather than structural disruption of the glomerular wall [52]. The second mechanism involves ADMA-mediated compromise of filtration barrier integrity by altering the NO bioavailability and oxygen superoxide (O− 2 ) production [53]. The third mechanism involves altered protein turnover, PRMT [55] or other mechanisms involving the renin–angiotensin system-RAS (RAS blockade using Ramipril results in decreased ADMA, proteinuria and cell death mediators) [56]. On the other hand, tubular DDAH activity might be inactivated by proteinuria-elicited oxidative stress, leading to ADMA accumulation in patients with CKD and proteinuria [57]. 3.2. ADMA and renal transplantation Although there is a great interest in clarifying the role of ADMA in renal transplant, especially in cardiovascular risk, only a few studies have been performed until now. Yilmaz et al. [58], reported that renal transplant greatly decreased ADMA for up to four weeks vs prior to transplant. Other studies also found decreased ADMA during the first month after renal transplant, but they remained increased relative to control subjects [59]. The initial ADMA decrease resulted in increased NO synthesis and improved endothelial function. This finding appears independent of immunosuppressive therapy [60]. Two studies showed that there is more rapid deterioration of renal function in CKD patients with increased ADMA [61,62]. As such, ADMA may act as an independent prognostic marker for the renal disease progression. In a prospective observational follow-up study involving patients with type 1 diabetic nephropathy, increased ADMA was associated with a decline in glomerular filtration rate [63]. Increased ADMA was a significant risk factor for increased plasma creatinine and graft failure in renal transplantation [64]. Mihout et al. [63], admitted that ADMA might induce exaggerated synthesis of extracellular matrix protein, leading to kidney fibrosis and CKD thereby contributing to cardiovascular morbidity and mortality in transplant patients. 4. Conclusion The ubiquitous distribution of arginine and methyltransferases in the human body can potentially contribute to large amounts of ADMA production. Because ADMA competitively inhibits eNOS, increased ADMA reduces NO production thereby contributing to endothelial dysfunction, cardiovascular risk and progressive renal damage. Although its actions are not completely understood, current data suggests that ADMA has a role in the onset of cardiovascular and renal diseases; clarifying this issue is essential for improving the disease management and promoting a better life quality for these patients. Acknowledgment The authors thank FAPEMIG (CDS APQ-3535-4.04) and CNPq/Brazil (480637/2013-0). LMD is grateful to CNPq Research Fellowship (302794/2012-3). References [1] Vallance P, Leone A, Calver A, Collier J, Moncada S. Accumulation of an endogenous inhibitor of nitric oxide synthesis in chronic renal failure. Lancet 1992;339:572–5. [2] Wada K, Inoue K, Hagiwara M. Identification of methylated proteins by protein arginine N-methyltransferase 1, PRMT1, with a new expression cloning strategy. Biochim Biophys Acta 2002;1591:1–10.
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