Abstract
We examined whether endothelial function of the renal microcirculation was impaired in a model of chronic renal failure (CRF), and further assessed the role of asymmetrical dimethylarginine (ADMA) and its degrading enzyme, dimethylarginine dimethylaminohydrolase (DDAH), in mediating the deranged nitric oxide (NO) synthesis in CRF. CRF was established in male mongrel dogs by subtotal nephrectomy, and the animals were used in experiments after a period of 4 weeks. The endothelial function of the renal afferent and efferent arterioles was evaluated according to the response to acetylcholine, using an intravital needle-lens charge-coupled device camera. Intrarenal arterial infusion of acetylcholine (0.01 μg/kg/min) elicited 22±2% and 20±2% dilation of the afferent and efferent arterioles in normal dogs. In dogs with CRF, this vasodilation was attenuated (afferent, 12±2%; efferent, 11±1%), and the attenuation paralleled the diminished increments in urinary nitrite+nitrate excretion. In the animals with CRF, plasma concentrations of homocysteine (12.2 ±0.7 vs. 6.8±0.4 μmol/l) and ADMA were elevated (2.60±0.13 vs. 1.50 ±0.08 μmol/l). The inhibition of S-adenosylmethionine-dependent protein arginine N-methyltransferase by adenosine dialdehyde decreased plasma ADMA levels, and improved the acetylcholine-induced changes in urinary nitrite+nitrate excretion and arteriolar vasodilation. Acute methionine loading impaired the acetylcholine-induced renal arteriolar vasodilation in CRF, but not normal dogs, and the impairment in CRF dogs coincided with the changes in plasma ADMA levels. Real-time polymerase chain reaction revealed downregulation of the mRNA expression of DDAH-II in the dogs with CRF. Collectively, these results provide direct in vivo evidence of endothelial dysfunction in canine CRF kidneys. The endothelial dysfunction was attributed to the inhibition of the NO production by elevated ADMA, which involved the downregulation of DDAH-II. The deranged NO metabolic pathway including ADMA and DDAH is a novel mechanism for the aggravation of renal function.
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Foley RN, Parfrey PS : Cardiovascular disease and mortality in ESRD. J Nephrol 1998; 11: 239–245.
Lindner A, Charra B, Sherrard DJ, Scribner BH : Accelerated atherosclerosis in prolonged maintenance hemodialysis. N Engl J Med 1974; 290: 697–701.
Samuelsson O, Wilhelmsen L, Elmfeldt D, et al: Predictors of cardiovascular morbidity in treated hypertension: results from the primary preventive trial in Goteborg, Sweden. J Hypertens 1985; 3: 167–176.
Diercks GF, Stroes ES, van Boven AJ, et al: Urinary albumin excretion is related to cardiovascular risk indicators, not to flow-mediated vasodilation, in apparently healthy subjects. Atherosclerosis 2002; 163: 121–126.
Stefanski A, Schmidt KG, Waldherr R, Ritz E : Early increase in blood pressure and diastolic left ventricular malfunction in patients with glomerulonephritis. Kidney Int 1996; 50: 1321–1326.
Hatta T, Nakata T, Harada S, et al: Lowering of blood pressure improves endothelial dysfunction by increase of nitric oxide production in hypertensive rats. Hypertens Res 2002; 25: 455–460.
Stack AG, Saran R : Clinical correlates and mortality impact of left ventricular hypertrophy among new ESRD patients in the United States. Am J Kidney Dis 2002; 40: 1202–1210.
Kronenberg F, Kuen E, Ritz E, et al: Lipoprotein (a) serum concentrations and apolipoprotein (a) phenotypes in mild and moderate renal failure. J Am Soc Nephrol 2000; 11: 105–115.
Chauveau P, Chadefaux B, Coude M, et al: Hyperhomocysteinemia, a risk factor for atherosclerosis in chronic uremic patients. Kidney Int 1993; 43 ( Suppl 41): S72–S77.
Moustapha A, Naso A, Nahlawi M, et al: Prospective study of hyperhomocysteinemia as an adverse cardiovascular risk factor in end-stage renal disease. Circulation 1998; 97: 138–141.
Upchurch GR Jr, Welch GN, Fabian AJ, et al: Homocysteine decreases bioavailable nitric oxide by a mechanism involving glutathione peroxidase. J Biol Chem 1997; 272: 17012–17017.
Kanani PM, Sinkey CA, Browning RL, Allaman M, Knapp HR, Haynes WG : Role of oxidant stress in endothelial dysfunction produced by experimental hyperhomocyst(e)inemia in humans. Circulation 1999; 100: 1161–1168.
Okatani Y, Wakatsuki A, Reiter RJ : Protective effect of melatonin against homocysteine-induced vasoconstriction of human umbilical artery. Biochem Biophys Res Commun 2000; 277: 470–475.
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: 572–575.
Miyazaki H, Matsuoka H, Cooke JP, et al: Endogenous nitric oxide synthase inhibitor—a novel marker of atherosclerosis. Circulation 1999; 99: 1141–1146.
Zoccali C, Bode-Böger S, Mallamaci F, et al: Plasma concentration of asymmetrical dimethylarginine and mortality in patients with end-stage renal disease: a prospective study. Lancet 2001; 358: 2113–2117.
Böger RH, Sydow K, Borlak J, et al: LDL cholesterol upregulates synthesis of asymmetrical dimethylarginine in human endothelial cells: involvement of S-adenosylmethionine-dependent methyltransferases. Circ Res 2000; 87: 99–105.
Leiper JM, Santa Maria J, Chubb A, et al: Identification of two human dimethylarginine dimethylaminohydrolases with distinct tissue distributions and homology with microbial arginine deiminases. Biochem J 1999; 343: 209–214.
Arrigoni FI, Vallance P, Haworth SG, Leiper JM : Metabolism of asymmetric dimethylarginines is regulated in the lung developmentally and with pulmonary hypertension induced by hypobaric hypoxia. Circulation 2003; 107: 1195–1201.
Yamamoto T, Hayashi K, Matsuda H, et al: In vivo visualization of tubuloglomerular feedback- and angiotensin II-induced renal vasoconstriction in dogs by an intravital pencil lens-probe videomicroscope. Kidney Int 2001; 60: 364–369.
Matsuda H, Hayashi K, Arakawa K, et al: Zonal heterogeneity in action of angiotensin-converting enzyme inhibitor on renal microcirculation: role of intrarenal bradykinin. J Am Soc Nephrol 1999; 10: 2272–2282.
Matsuda H, Hayashi K, Arakawa K, et al: Distinct modulation of superficial and juxtamedullary arterioles by prostaglandin in vivo. Hypertens Res 2002; 25: 901–910.
Vester B, Rasmussen K : High performance liquid chromatography method for rapid and accurate determination of homocysteine in plasma and serum. Eur J Clin Chem Clin Biochem 1991; 29: 549–554.
Matsuoka H, Itoh S, Kimoto M, et al: Asymmetrical dimethylarginine, an endogenous nitric oxide synthase inhibitor, in experimental hypertension. Hypertension 1997; 29: 242–247.
Ohta K, Araki N, Shibata M, et al: A novel in vivo assay system for consecutive measurement of brain nitric oxide production combined with the microdialysis technique. Neurosci Lett 1994; 176: 165–168.
Wever R, Boer P, Hijmering M, et al: Nitric oxide production is reduced in patients with chronic renal failure. Arterioscler Thromb Vasc Biol 1999; 19: 1168–1172.
Annuk M, Zilmer M, Lind L, Linde T, Fellstrom B : Oxidative stress and endothelial function in chronic renal failure. J Am Soc Nephrol 2001; 12: 2747–2752.
Tsikas D, Böger RH, Sandmann J, Bode-Böger SM, Frolich JC : Endogenous nitric oxide synthase inhibitors are responsible for the L-arginine paradox. FEBS Lett 2000; 478: 1–3.
Böger RH, Bode-Böger SM, Szuba A, et al: Asymmetric dimethylarginine: a novel risk factor for endothelial dysfunction: its role in hypercholesterolemia. Circulation 1998; 98: 1842–1847.
Lundman P, Tornvall P : Acute triglyceridemia and endothelial function. Am J Cardiol 2002; 90: 447.
Jonkers IJ, van de Ree MA, Smelt AH, et al: Insulin resistance but not hypertriglyceridemia per se is associated with endothelial dysfunction in chronic hypertriglyceridemia. Cardiovasc Res 2002; 53: 496–501.
Böger RH, Lentz SR, Bode-Böger SM, Knapp HR, Haynes WG : Elevation of asymmetrical dimethylarginine may mediate endothelial dysfunction during experimental hyperhomocysteinaemia in humans. Clin Sci 2001; 100: 161–167.
Xiao S, Wagner L, Schmidt RJ : Circulating endothelial nitric oxide synthase inhibitory factor in some patients with chronic renal disease. Kidney Int 2001; 59: 1466–1472.
Tojo A, Kimoto M, Wilcox CS : Renal expression of constitutive NOS and DDAH: separate effects of salt intake and angiotensin. Kidney Int 2000; 58: 2075–2083.
Stühlinger MC, Tsao PS, Her JH, Kimoto M, Balint RF, Cooke JP : Homocysteine impairs the nitric oxide synthase pathway: role of asymmetric dimethylarginine. Circulation 2001; 104: 2569–2575.
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Okubo, K., Hayashi, K., Wakino, S. et al. Role of Asymmetrical Dimethylarginine in Renal Microvascular Endothelial Dysfunction in Chronic Renal Failure with Hypertension. Hypertens Res 28, 181–189 (2005). https://doi.org/10.1291/hypres.28.181
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DOI: https://doi.org/10.1291/hypres.28.181