A New Perspective for the Treatment of Renal Diseases?
Jan T. Kielstein*, and
Carmine Zoccali
* Department of Internal Medicine, Division of Nephrology, Medical School Hannover, Germany; Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, California; and Istituto di Biomedicina-Epidemiologia Clinica e Fisiopatologia delle Malattie Renali e dell'Ipertensione Arteriosa e Unita Operativa di Nefrologia, Dialisi e Trapianto Renale, Ospedali Riuniti, Reggio Calabria, Italy
Address correspondence to: Dr. Jan T. Kielstein, Division of Nephrology, Department of Internal Medicine, Medical School Hannover, Carl-Neuberg-Strasse 1, 30625 Hannover, Germany. Phone: +49-511-532-6319; Fax: +49-511-532-4005; E-mail: kielstein{at}yahoo.com or Dr. Carmine Zoccali, Istituto di Biomedicina-Epidemiologia Clinica e Fisiopatologia delle malattie Renali e dell'Ipertensione Arteriosae Unita Operativa di Nefrologia, Dialisi e Trapianto Renale, Ospedali Riuniti, Reggio Calabria, Italy. Phone: +39-09653-97010; Fax: +39-09653-97000; E-mail: carmine.zoccali{at}tin.it
Asymmetric dimethylarginine (ADMA) is the most important endogenousinhibitor of nitric oxide synthase (NOS). It is an establisheduremic toxin (1,2) and one of the most intriguing risk markersfor both cardiovascular (CV) complications (3) and renal diseaseprogression (4). Accumulating evidence suggests that ADMA notonly signals the risk of disease but that it is also causallyimplicated in the generation and/or progression of CV and kidneydamage. Causal inference is a complex process (5) and suitableanimal models as well as observational and experimental studiesare needed for establishing causality. Importantly, the decisiveproof of causality for risk factors related to human healthis the healing or the improvement of the disease when the riskfactor is eliminated or effectively countered, a proof stillsorely lacking for ADMA in renal disease. In the last two years,a series of groundbreaking studies determined that methylarginineis a key determinant in animal models of CV and renal diseases,and as a result the interest in ADMA in the renal communityis on the rise. The last paper of this series, by Matsumotoet al. (6), appears in this issue of JASN and provides perhapsdecisive evidence on the causal role of ADMA in the progressionof renal disease in the remnant kidney model (i.e., the modelthat is currently considered as the most representative of chronickidney disease in humans) (4). Highlighting the key componentsinfluenced by the experimental maneuver adopted in this study—namelyADMA and dimethylarginine dimethylaminohydrolase (DDAH)—iscrucial for framing the novel information provided by this groundbreakingstudy (6).
ADMA: An Endogenous Inhibitor of NOS at the Crossroad of Cardiorenal Risk
ADMA and its enantiomer, symmetric dimethylarginine, were isolatedin human urine by Kakimoto and Akazawa almost four decades ago(7). They speculated that both substances "may be importantfor the study of various pathologic states" (7). Twenty-twoyears later Vallance et al. provided initial evidence that thehypothesis of Kakimoto and Akazawa might be correct (8). Onthe basis of these seminal observations it was postulated thatADMA, by impairing NO synthesis, might contribute to the excessCV morbidity and mortality in CKD. ADMA levels are higher indialysis patients with CV complications than in those withoutsuch complications (9). It correlates well with establishedclinical markers of CV burden such as intima-media thicknessof the carotid artery (10) and left ventricular mass (11). Thereis also evidence that high ADMA concentration goes along withdecreased number of circulating endothelial progenitor cells,thus impinging upon repair mechanisms (12). Furthermore, cohortstudies both in the general population and in patients withCKD demonstrated a strong and independent link between ADMA,all-cause mortality, and CV events (13,14). Infusion of exogenousADMA increases systemic vascular resistance (15,16), elevatesmean arterial pressure (15,16), decreases heart rate (15,16),reduces cardiac output (15,16), and augments pulmonary vascularresistance (17) in men. In addition, ADMA administration impairsrenal blood flow and sodium reabsorption in a dose-dependentmanner (16). Exogenous ADMA also decreases cerebral perfusionand increases vascular stiffness (18). On the basis of the coherentevidence emerging in experimental and clinical studies, it ispostulated that ADMA is not only a marker but also a potentmediator of endothelial dysfunction and atherosclerosis.
DDAH: The Key Step in the Regulation of ADMA Levels
DDAH is a key regulator of ADMA levels. Humans generate approximately300 µmol ADMA (approximately 60 mg) per day (15). Only20% of ADMA is excreted in the urine. The majority of ADMA,about 80%, is cleared by DDAH, which was first isolated fromrat kidney. DDAH converts ADMA to citrulline and dimethylamine.Two isoforms of DDAH have been characterized and cloned: DDAHI is predominately found in tissues that express neuronal NOS,whereas DDAH II is predominately found in tissues expressingendothelial NOS (19). Colocalization of DDAH and NOS in variouscell types including renal tubular cells supports the hypothesisthat the intracellular concentration of ADMA is actively andcell-specifically regulated in NO-generating cells (20). Byregulating ADMA levels, DDAH protects NOS activity. Such regulationis fundamental because NO, the final effector molecule of thesystem, is a most potent biologic vasodilator that inhibitsmonocyte adhesion, platelet aggregation, and vascular smoothmuscle cell proliferation, which are all fundamental steps inthe atherosclerosis process. Endothelial dysfunction as a resultof reduced NO activity is an early step in the course of atheroscleroticvascular disease and evidence has accumulated that inhibitionof NO synthesis by endogenous substances may be causally involvedin this process.
CKD is now recognized as a major public health problem, as recentlyre-emphasized in a report by the Center for Diseases Control(21). Research on CKD is perceived as a priority because availabletreatments are still insufficient to effectively counter thisepidemic. The hypothesis that lowering ADMA by enhancing DDAHactivity ameliorates the progression of CKD was tested by Matsumotoet al. (6) using a rat model of 5/6 subtotal nephrectomy. Fourweeks after subtotal nephrectomy the animals received eitheran adenoviral transfer of DDAH I or a control transfection.DDAH I gene transfer prevented further deterioration of renalfunction during the 2-wk follow-up. Moreover, increasing DDAHI activity alleviated tubulointerstitial fibrosis, which couldat least in part be explained by a downregulation of TGF- geneand protein expression. The positive effect of DDAH I gene transferon morphologic changes was also reflected by the fact that DDAHI gene transfer prevented the increase in proteinuria. Thereare still many open questions. Why does overexpression of onlyone DDAH isoform have such profound biologic effects? Are thereactions of DDAH beyond lowering ADMA? Are there adverse effectsof a long-term increase in DDAH expression and/or activity?What is the importance of ADMA production/liberation in chronicrenal disease? However, it is more important to point out thatthe experimental study goes along with observations in CKD andESRD patients, as recently summarized (4). Furthermore, databy Matsumoto et al. (6) are in line with findings in DDAH transgenicmice, which exhibit low ADMA levels as a result of high DDAHI activity (22). These animals are less susceptible to vascularlesions (23), which is in part attributable to enhanced angiogenicpotential (24), and they have a higher ability to regenerateendothelium (24). In contrast, knocking out this enzyme compromisesADMA degradation, which eventually results in inhibition ofNO synthesis, increased vascular resistance and hypertension(25).
ADMA is increased early in the course of CKD, well before areduction in GFR is measurable (26). Two recent studies havecoherently shown that high ADMA predicts a faster rate of renalfunction loss (27,28). Therefore, lowering ADMA by increasingDDAH expression/activity might prevent progression in renaldamage. Thus the study by Matsumoto et al. represents an importantproof of concept that lowering ADMA may retard renal diseaseprogression (6). Preclinical studies with drugs that lower ADMAby increasing DDAH transcription have already been published(29), which may open an entirely new opportunity for the treatmentof CV and renal disease. Advancing risk factors research intothe translational and clinical phases needs solid basic science,coherent experimental data, and epidemiologic and clinical observations.This is a multidimensional process that requires well-concertedefforts by a large number of research groups with differentknowledge bases and expertise. Knowledge on ADMA has increasedtremendously in recent years. Matsumoto et al. now provide anew and decisive piece of information for deciphering the roleof ADMA in renal disease progression, and their study will certainlyattract investigators and resources into this very promisingresearch area (6).
This work was supported by a grant of the Deutsche Forschungsgemeinschaft(Ki 8591/-1) and by annual grants (1999 to 2003) provided bythe Regione Calabria–Consiglio Nazionale delle Ricercheagreement.
Footnotes
Published online ahead of print. Publication date availableat www.jasn.org.
See the related article, "Dimethylarginine DimethylaminohydrolasePrevents Progression of Renal Dysfunction by Inhibiting Lossof Peritubular Capillaries and Tubulointerstitial Fibrosis ina Rat Model of Chronic Kidney Disease," on pages 1525–1533.
Kielstein JT, Zoccali C: Asymmetric dimethylarginine: A cardiovascular risk factor and a uremic toxin coming of age?
Am J Kidney Dis 46
: 186
–202, 2005[CrossRef][Medline]
Vanholder R, De SR, Glorieux G, Argiles A, Baurmeister U, Brunet P, Clark W, Cohen G, De Deyn PP, Deppisch R, Scamps-Latscha B, Henle T, Jorres A, Lemke HD, Massy ZA, Passlick-Deetjen J, Rodriguez M, Stegmayr B, Stenvinkel P, Tetta C, Wanner C, Zidek W: Review on uremic toxins: Classification, concentration, and interindividual variability.
Kidney Int 63
: 1934
–1943, 2003[CrossRef][Medline]
Zoccali C: Asymmetric dimethylarginine (ADMA): A cardiovascular and renal risk factor on the move.
J Hypertens 24
: 611
–619, 2006[Medline]
Zoccali C, Kielstein JT: Asymmetric dimethylarginine: A new player in the pathogenesis of renal disease?
Curr Opin Nephrol Hypertens 15
: 314
–320, 2006[Medline]
Rothman KJ, Greenland S:
Modern Epidemiology, 2nd ed., Philadelphia, Lippincott Williams & Wilkins, 1998
Matsumoto Y, Ueda S, Yamagishi S, Matsumoto K, Fukami K, Matsuoka H, Imaizumi T, Okuda S: Dimethylarginine dimethylaminohydrolase prevents progression of renal dysfunction by inhibiting loss of peritubular capillaries and tubulointerstitial fibrosis in a rat model of chronic kidney disease.
J Am Soc Nephrol 18
: 1525
–1533, 2007[Abstract/Free Full Text]
Kakimoto Y, Akazawa S: Isolation and identification of N-G,N-G- and N-G,N'-G-dimethyl- arginine, N-epsilon-mono-, di-, and trimethyllysine, and glucosylgalactosyl- and galactosyl-delta-hydroxylysine from human urine.
J Biol Chem 245
: 5751
–5758, 1970[Abstract/Free Full Text]
Vallance P, Leone A, Calver A, Collier J, Moncada S: Accumulation of an endogenous inhibitor of nitric oxide synthesis in chronic renal failure.
Lancet 339
: 572
–575, 1992[CrossRef][Medline]
Kielstein JT, Boger RH, Bode-Boger SM, Schaffer J, Barbey M, Koch KM, Frolich JC: Asymmetric dimethylarginine plasma concentrations differ in patients with end-stage renal disease: Relationship to treatment method and atherosclerotic disease.
J Am Soc Nephrol 10
: 594
–600, 1999[Abstract/Free Full Text]
Zoccali C, Benedetto FA, Maas R, Mallamaci F, Tripepi G, Salvatore ML, Boger R: Asymmetric dimethylarginine, C-reactive protein, and carotid intima-media thickness in end-stage renal disease.
J Am Soc Nephrol 13
: 490
–496, 2002[Abstract/Free Full Text]
Zoccali C, Mallamaci F, Maas R, Benedetto FA, Tripepi G, Malatino LS, Cataliotti A, Bellanuova I, Boger R: Left ventricular hypertrophy, cardiac remodeling and asymmetric dimethylarginine (ADMA) in hemodialysis patients.
Kidney Int 62
: 339
–345, 2002[CrossRef][Medline]
Thum T, Tsikas D, Stein S, Schultheiss M, Eigenthaler M, Anker SD, Poole-Wilson PA, Ertl G, Bauersachs J: Suppression of endothelial progenitor cells in human coronary artery disease by the endogenous nitric oxide synthase inhibitor asymmetric dimethylarginine.
J Am Coll Cardiol 46
: 1693
–1701, 2005[Abstract/Free Full Text]
Meinitzer A, Seelhorst U, Wellnitz B, Halwachs-Baumann G, Boehm BO, Winkelmann BR, Marz W: Asymmetrical dimethylarginine independently predicts total and cardiovascular mortality in individuals with angiographic coronary artery disease (the Ludwigshafen Risk and Cardiovascular Health study).
Clin Chem 53
: 273
–283, 2007[Abstract/Free Full Text]
Zoccali C, Bode-Boger S, Mallamaci F, Benedetto F, Tripepi G, Malatino L, Cataliotti A, Bellanuova I, Fermo I, Frolich J, Boger R: Plasma concentration of asymmetrical dimethylarginine and mortality in patients with end-stage renal disease: A prospective study.
Lancet 358
: 2113
–2117, 2001[CrossRef][Medline]
Achan V, Broadhead M, Malaki M, Whitley G, Leiper J, MacAllister R, Vallance P: Asymmetric dimethylarginine causes hypertension and cardiac dysfunction in humans and is actively metabolized by dimethylarginine dimethylaminohydrolase.
Arterioscler Thromb Vasc Biol 23
: 1455
–1459, 2003[Abstract/Free Full Text]
Kielstein JT, Impraim B, Simmel S, Bode-Boger SM, Tsikas D, Frolich JC, Hoeper MM, Haller H, Fliser D: Cardiovascular effects of systemic nitric oxide synthase inhibition with asymmetrical dimethylarginine in humans.
Circulation 109
: 172
–177, 2004[Abstract/Free Full Text]
Kielstein JT, Donnerstag F, Gasper S, Menne J, Kielstein A, Martens-Lobenhoffer J, Scalera F, Cooke JP, Fliser D, Bode-Boger SM: ADMA increases arterial stiffness and decreases cerebral blood flow in humans.
Stroke 37
: 2024
–2029, 2006[Abstract/Free Full Text]
Leiper JM, Santa Maria J, Chubb A, MacAllister RJ, Charles IG, Whitley GS, Vallance P: Identification of two human dimethylarginine dimethylaminohydrolases with distinct tissue distributions and homology with microbial arginine deiminases.
Biochem J 343
: 209
–214, 1999[CrossRef][Medline]
Tojo A, Welch WJ, Bremer V, Kimoto M, Kimura K, Omata M, Ogawa T, Vallance P, Wilcox CS: Colocalization of demethylating enzymes and NOS and functional effects of methylarginines in rat kidney.
Kidney Int 52
: 1593
–1601, 1997[Medline]
Center for Disease Control: Prevalence of chronic kidney disease and associated risk factors—United States, 1999–2004.
MMWR Morb Mortal Wkly Rep 56
: 161
–165, 2007[Medline]
Dayoub H, Achan V, Adimoolam S, Jacobi J, Stuehlinger MC, Wang BY, Tsao PS, Kimoto M, Vallance P, Patterson AJ, Cooke JP: Dimethylarginine dimethylaminohydrolase regulates nitric oxide synthesis: Genetic and physiological evidence.
Circulation 108
: 3042
–3047, 2003[Abstract/Free Full Text]
Jacobi J, Sydow K, von DG, Zhang Y, Dayoub H, Wang B, Patterson AJ, Kimoto M, Blau HM, Cooke JP: Overexpression of dimethylarginine dimethylaminohydrolase reduces tissue asymmetric dimethylarginine levels and enhances angiogenesis.
Circulation 111
: 1431
–1438, 2005[Abstract/Free Full Text]
Leiper J, Nandi M, Torondel B, Murray-Rust J, Malaki M, O'Hara B, Rossiter S, Anthony S, Madhani M, Selwood D, Smith C, Wojciak-Stothard B, Rudiger A, Stidwill R, McDonald NQ, Vallance P: Disruption of methylarginine metabolism impairs vascular homeostasis.
Nat Med 13
: 198
–203, 2007[CrossRef][Medline]
Kielstein JT, Boger RH, Bode-Boger SM, Frolich JC, Haller H, Ritz E, Fliser D: Marked increase of asymmetric dimethylarginine in patients with incipient primary chronic renal disease.
J Am Soc Nephrol 13
: 170
–176, 2002[Abstract/Free Full Text]
Fliser D, Kronenberg F, Kielstein JT, Morath C, Bode-Boger SM, Haller H, Ritz E: Asymmetric dimethylarginine and progression of chronic kidney disease: The Mild to Moderate Kidney Disease Study.
J Am Soc Nephrol 16
: 2456
–2461, 2005[Abstract/Free Full Text]
Ravani P, Tripepi G, Malberti F, Testa S, Mallamaci F, Zoccali C: Asymmetrical dimethylarginine predicts progression to dialysis and death in patients with chronic kidney disease: A competing risks modeling approach.
J Am Soc Nephrol 16
: 2449
–2455, 2005[Abstract/Free Full Text]
Hu T, Chouinard M, Cox AL, Sipes P, Marcelo M, Ficorilli J, Li S, Gao H, Ryan TP, Michael MD, Michael LF: Farnesoid X receptor agonist reduces serum asymmetric dimethylarginine levels through hepatic dimethylarginine dimethylaminohydrolase-1 gene regulation.
J Biol Chem 281
: 39831
–39838, 2006[Abstract/Free Full Text]
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[Abstract][PDF]
Top
Introduction
ADMA: An Endogenous Inhibitor...
gene and protein expression. The positive effect of DDAH I gene transfer on morphologic changes was also reflected by the fact that DDAH I gene transfer prevented the increase in proteinuria. There are still many open questions. Why does overexpression of only one DDAH isoform have such profound biologic effects? Are there actions of DDAH beyond lowering ADMA? Are there adverse effects of a long-term increase in DDAH expression and/or activity? What is the importance of ADMA production/liberation in chronic renal disease? However, it is more important to point out that the experimental study goes along with observations in CKD and ESRD patients, as recently summarized (4). Furthermore, data by Matsumoto et al. (6) are in line with findings in DDAH transgenic mice, which exhibit low ADMA levels as a result of high DDAH I activity (22). These animals are less susceptible to vascular lesions (23), which is in part attributable to enhanced angiogenic potential (24), and they have a higher ability to regenerate endothelium (24). In contrast, knocking out this enzyme compromises ADMA degradation, which eventually results in inhibition of NO synthesis, increased vascular resistance and hypertension (25). 
