ADMA (asymmetric dimethylarginine): an atherosclerotic disease mediating agent in patients with renal disease?

Jan T. Kielstein1,, Jürgen C. Frölich2, Hermann Haller1 and Danilo Fliser1

1 Department of Nephrology and 2 Institute of Clinical Pharmacology, Hannover Medical School, D-30625 Hannover, Germany

Keywords: ADMA; nitric oxide; atherosclerosis; renal disease

Introduction

Nitric oxide (NO) is a potent endogenous vasodilator that is released by endothelial cells in response to different stimuli such as shear stress. It plays a critical role in the regulation of vascular resistance and tissue blood flow. There is abundant experimental data that NO inhibits key processes of atherosclerosis, for example, monocyte adhesion, platelet aggregation, and vascular smooth muscle cell proliferation. Hence, endothelial dysfunction as a result of reduced NO activity is an early step in the course of atherosclerotic vascular disease, and evidence has accumulated that inhibition of NO synthesis by endogenous substances may be causally involved in this process [1].

Interference with NO synthesis by asymmetric dimethylarginine

NO is synthesized by stereospecific oxidation of the terminal guanidino nitrogen of the amino acid L-arginine by the action of a family of NO synthases (NOS) with endothelial, neuronal, and macrophage isoforms [2]. NO synthesis can be selectively inhibited by competitive blockade of the NOS active site with guanidino-substituted analogues of L-arginine such as N-monomethyl-L-arginine (NMA) and asymmetric dimethylarginine (ADMA) (Figure 1Go) [3]. As the blood concentration of the latter is about 10-fold higher than that of NMA, it is considered to be the predominant endogenous NOS inhibitor. ADMA is released from proteins that have been post-translationally methylated and subsequently hydrolysed [3]. These proteins are largely found in the nucleolus and appear to be involved in RNA processing and transcriptional control [4]. There are two types of enzymes that methylate arginine residues: protein arginine methyltransferase type I (PRMT I) forms ADMA and NMA, whereas PRMT II forms symmetric dimethylarginine (SDMA), that is a stereoisomer of ADMA, which has no (direct) inhibitory effect on NOS [5]. A number of cell types including human endothelial cells elaborate ADMA [3,6,7]. ADMA is renally excreted to some extent, but the major metabolic pathway is degradation by the enzyme dimethylarginine dimethylaminohydrolase (DDAH), which hydrolyses ADMA to dimethylamine and L-citrulline (Figure 1Go) [8,9]. So far, two isoforms of DDAH have been characterized and cloned: DDAH I is predominately found in tissues that express neuronal NOS, whereas DDAH II is predominately found in tissues expressing endothelial NOS [10]. Co-localization of DDAH and NOS supports the hypothesis that the methylarginine concentration is actively and cell specifically regulated in NO-generating cells.



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Fig. 1. Biochemical pathways for generation and degradation of asymmetric dimethylarginine (ADMA) (for explanation see text). The methionine/homocysteine pathway is linked to the generation of ADMA.

 

ADMA–an innocent bystander or culprit of the atherosclerotic process?

Data from experimental studies document that pathophysiologically relevant ADMA blood concentrations, that is between 2 and 10 µmol/l, significantly inhibit NOS in isolated human blood vessels, in cultured macrophages and in endothelial cells, thereby reducing the generation of NO [11,12]. Administration of equipotent doses of ADMA and the exogenous NOS inhibitor L-NNMA to animals resulted in a similar increase of mean arterial blood pressure and renal, mesenteric and hindquarters vascular resistance [13]. In non-renal patients increased ADMA levels correlate strongly with the severity of the atherosclerotic disease [1417]. For example, in patients with manifest peripheral atherosclerosis 2- to 3-fold increased plasma ADMA levels were accompanied by reduced urinary excretion of nitrate, the stable oxidation product of NO [14]. Moreover, even in asymptomatic young hypercholesterolemic subjects with normal renal function, a 2-fold increase of plasma ADMA concentrations was found [15]. Results from a cross-sectional study in 116 subjects revealed that plasma ADMA levels were positively correlated with age, mean arterial blood pressure, and glucose intolerance [16]. Most strikingly, stepwise regression analysis documented that plasma ADMA levels were significantly correlated with the intima-media thickness of the carotid arteries as measured by high-resolution sonography. Thus, increased plasma ADMA concentrations not only indicate cardiovascular morbidity as a result of atherosclerotic complications, but may be causally involved in the genesis of atherosclerosis [1].

Atherosclerosis, endothelial (dys)function and ADMA in patients with renal disease

Patients with non-diabetic renal diseases are characterized by high cardiovascular morbidity and mortality due to complications of premature atherosclerosis, such as coronary heart disease, and many of them die before they reach the stage of terminal renal failure [18,19]. Thus, the old concept of accelerated atherosclerosis in patients with end-stage renal disease (ESRD) has recently been questioned, because many dialysis patients have more or less marked vascular lesions even at the beginning of dialysis treatment, and the risk factors in the pre-dialysis phase may be of overwhelming importance for the manifestation of cardiovascular disease [19,20]. The pathophysiological background of this excessive cardiovascular risk is not completely understood, but impaired NO-mediated endothelial-dependent vasodilatation, for example, the hallmark of atherosclerosis, has been reported in children with chronic renal failure, in adult patients on maintenance haemodialysis, and even in patients with adult polycystic kidney disease and normal renal function [2123]. Furthermore, it has been demonstrated that impaired endothelium-dependent vasodilation improves after a haemodialysis session in patients with ESRD [24]. In addition, L-arginine, but not D-arginine, restores endothelial function in ESRD patients independent of haemodialysis treatment; this observation points to reduced availability of NO in these patients [24]. These findings are in line with results of recent studies, which demonstrated decreased whole body NO production in patients with chronic renal failure [25,26].

In 1992, Vallance et al. were the first to report increased plasma concentrations of ADMA and SDMA in a small group of patients with ESRD [8]. They hypothesized that the high incidence of hypertension and atherosclerosis in patients with terminal renal failure might be caused, at least in part, by dysfunction of the L-arginine/ NO pathway secondary to accumulation of ADMA as a result of declining renal excretion. Indeed, the same authors demonstrated that infusion of ADMA into the brachial artery attenuated endothelial-dependent vasodilation in healthy volunteers [8]. Several recent studies confirmed markedly increased plasma ADMA levels in patients with terminal renal failure [2629]. However, the assumption that decreased urinary excretion is the main cause of elevated plasma ADMA concentrations in ESRD patients has been questioned by the observation that SDMA, which is not degraded by DDAH, accumulates eight times more than ADMA in patients with ESRD. Furthermore, we could recently document markedly increased plasma ADMA concentrations in patients with incipient renal disease, for example, even in patients with normal renal function as documented by measurement of true glomerular filtration rate using inulin clearance (Kielstein JT, submitted for publication). Interestingly, ADMA levels were elevated independent of the type of renal disease, and this observation favours the hypothesis that impaired ADMA degradation by (renal?) DDAH rather than reduced renal excretion is the cause of markedly increased plasma ADMA concentrations in patients with primary renal disease. DDAH is present in abundance in endothelial cells within the glomerulus and renal vessels, and particularly in renal tubular cells [30]. It regulates (intra)cellular methylarginine levels, thereby, governing cell-specific L-arginine uptake and NO generation in tubular cells. Destruction of DDAH rich renal tissue may, therefore, impair renal degradation of ADMA.

Whatever the cause of increased plasma ADMA concentrations in patients with renal disease, results of recent in vitro studies suggest that ADMA concentrations in patients with ESRD are high enough to sufficiently decrease NO production [12]. Indirect evidence for a pathophysiological role of ADMA in this population is observations that in ESRD patients with manifest atherosclerosis plasma ADMA levels were significantly higher than in patients without signs of atherosclerotic disease [27]. Furthermore, in a prospective study in 225 patients with ESRD plasma ADMA concentrations were not only significantly related to the severity of carotid atherosclerosis but, in addition, were the strongest predictor of cardiovascular mortality among several risk factors assessed [31].

Conclusion

Increased plasma ADMA concentration, that is the only biologically active endogenous NOS inhibitor, is found at a very early stage of primary renal disease. This observation has several implications for further research and for the management of renal patients. Interventions such as administration of NO-donors, preferably early on, could, therefore, prove to be a feasible way of modulating the atherogenic profile of renal patients or even of retarding progression of renal failure [32].

Notes

Correspondence and offprint requests to: Jan T. Kielstein, MD, Department of Nephrology, Medical School Hannover, Carl-Neuberg-Strasse 1, D-30625 Hannover, Germany. Back

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