Correlation between Pentosidine and Endothelin-1 in Subjects Undergoing Chronic Hemodialysis

Abstract

Advanced glycation end-products (AGEs), which accumulate in the blood and tissues of patients with chronic renal failure (CRF) undergoing chronic hemodialysis, play an important role in the pathogenesis of uremic complications. Endothelin 1 (ET1), a 21-amino acid peptide with vasoconstricting and mitogenic properties, is an important factor in the endothelial dysfunction occurring in uremia. The circulating levels of both AGEs and ET1 have been reported to be increased in chronic renal failure. In the present study we evaluated the possible relationship between pentosidine and ET1 plasma levels in CRF patients undergoing chronic hemodialysis treatment. The plasma concentrations of “free” and bound pentosidine (HPLC methods) and endothelin-1 (RIA method) were measured before the hemodialysis session in 40 nondiabetic CRF patients (22 males and 18 females; 54±3 years) on chronic hemodialysis for at least 1 year. Forty age- and sex-matched normal subjects served as a control group. In hemodialyzed patients, the overall pentosidine residues and pentosidine-free adduct plus pentosidine-free adduct bound reversibly to protein levels (24.9±2.04 pmol/mg protein and 110.5±5.9 pmol/ml, respectively) were significantly higher than those recorded in normal subjects (2.0±0.2 pmol/mg protein and 0.7±0.2 pmol/ml, respectively ). Endothelin-1 was also significantly (p<0.01) increased in CRF patients (10.6±0.4 pmol/ml in CRF patients and 2.7±0.3 pmol/ml in normal subjects). A significant positive correlation (p<0.01) was seen between “total” pentosidine (pentosidine residues and pentosidine-free adduct plus pentosidine-free adduct bound reversibly to protein) levels and endothelin-1 plasma values. The correlation between pentosidine and endothelin-1 provides further evidence that some AGEs exert a detrimental effect on the vascular endothelium, thereby contributing to the hypertension and other cardiovascular damage seen in CRF patients.

Key words

Glycation - pentosidine - hemodialysis - endothelin-1

References

• 1 Wautier JL, Schmidt AM. Protein glycation: a firm link to endothelial cell dysfunction.  Circ Res. 2004;  95 233-238
• 2 Vlassara H, Palace MR. Glycoxidation: the menace of diabetes and aging.  Mt Sinai J Med. 2003;  70 232-241
• 3 Takahashi M, Oikawa M, Nagano A. Effect of age and menopause on serum concentrations of pentosidine, an advanced glycation end product.  J Gerontol A Biol Sci Med Sci. 2000;  55 M137-M140
• 4 Lapolla A, Reitano R, Baccarin L, Sartore G, Plebani M, Fedele D. Pentosidine plasma levels and relation with metabolic control in diabetic patients.  Horm Metab Res. 2005;  37 252-256
• 5 Bohlender JM, Franke S, Stein G, Wolf G. Advanced glycation end products and the kidney.  Am J Physiol Renal Physiol. 2005;  289 F645-F659
• 6 Miyata T, van Ypersele de Strihou C, Kurokawa K, Baynes JW. Alterations in nonenzymatic biochemistry in uremia: origin and significance of “carbonyl stress” in long-term uremic complications.  Kidney Int. 1999;  55 389-399
• 7 Ahmed N. Advanced glycation endproducts-role in pathology of diabetic complications.  Diabetes Res Clin Pract.. 2005;  67 3-21
• 8 Miyauchi T, Masaki T. Pathophysiology of endothelin in the cardiovascular system.  Annu Rev Physiol. 1999;  61 391-415
• 9 Sorokin A, Kohan DE. Physiology and pathology of endothelin-1 in renal mesangium.  Am J Physiol Renal Physiol. 2003;  285 F579-F589
• 10 Demuth K, Blacher J, Guerin AP, Benoit MO, Moatti N, Safar ME, London GM. Endothelin and cardiovascular remodelling in end-stage renal disease.  Nephrol Dial Transplant. 1998;  13 375-383
• 11 Rosendorff C. Endothelin, vascular hypertrophy, and hypertension.  Cardiovasc Drugs Ther. 1996;  10 795-802
• 12 Wolf SC, Amend T, Risler T, Amann K, Brehm BR. Influence of endothelin receptor antagonists on myocardial protein kinase C isoforms in uraemic cardiomyopathy.  Clin Sci (Lond). 2002;  103 ((Suppl 48)) 276S-279S
• 13 Gagliardi GM, Rossi S, Manes MT, Gerace G, Martire V, Caruso F, Vocaturo G, De Napoli N. Impact of left ventricular patterns and diastolic dysfunction on hemodialysis patients.  G Ital Nefrol. 2004;  21 45-50
• 14 Quehenberger P, Bierhaus A, Fasching P, Muellner C, Klevesath M, Hong M, Stier G, Sattler M, Schleicher E, Speiser W, Nawroth PP. Endothelin 1 transcription is controlled by nuclear factor-kappaB in AGE-stimulated cultured endothelial cells.  Diabetes. 2000;  49 1561-1570
• 15 Odetti P, Cosso L, Pronzato MA, Dapino D, Gurreri G. Plasma advanced glycosylation end-products in maintenance haemodialysis patients.  Nephrol Dial Transplant. 1995;  10 2110-2113
• 16 Odetti P, Fogarty J, Sell DR, Monnier VM. Chromatographic quantitation of plasma and erythrocyte pentosidine in diabetic and uremic subjects.  Diabetes. 1992;  41 153-159
• 17 Bierhaus A, Chevion S, Chevion M, Hofmann M, Quehenberger P, Illmer T. et al . Advanced glycation end product-induced activation of NF-kappaB is suppressed by alpha-lipoic acid in cultured endothelial cells.  Diabetes. 1997;  46 1481-1490
• 18 Michael JR, Markewitz BA, Kohan DE. Oxidant stress regulates basal endothelin-1 production by cultured rat pulmonary endothelial cells.  Am J Physiol. 1997;  273 L768-774
• 19 Yura T, Fukunaga M, Khan R, Nassar GN, Badr KF, Montero A. Free-radical-generated F2-isoprostane stimulates cell proliferation and endothelin-1 expression on endothelial cells.  Kidney Int. 1999;  56 471-478
• 20 Kahler J, Ewert A, Weckmuller J, Stobbe S, Mittman C, Koster R. et al . Oxidative stress increases endothelin-1 synthesis in human coronary artery smooth muscle cells.  J Cardiovasc Pharmacol. 2001;  38 49-57
• 21 Weiss MF, Scivittaro V, Anderson JM. Oxidative stress and increased expression of growth factors in lesions of failed hemodialysis access.  Am J Kidney Dis. 2001;  37 970-980
• 22 Kahler J, Mendel S, Weckmuller J, Orzechowski HD, Mittmann C, Koster R. et al . Oxidative stress increases synthesis of big endothelin-1 by activation of the endothelin-1 promoter.  J Mol Cell Cardiol. 2000;  32 1429-1437
• 23 Ruef J, Moser M, Kubler W, Bode C. Induction of endothelin-1 expression by oxidative stress in vascular smooth muscle cells.  Cardiovasc Pathol. 2001;  10 311-315
• 24 Sonin NV, Garcia-Pagan JC, Nakanishi K, Zhang JX, Clemens MG. Patterns of vasoregulatory gene expression in the liver response to ischemia/reperfusion and endotoxemia.  Shock. 1999;  11 175-179
• 25 Ishizuka T, Takamizawa-Matsumoto M, Suzuki K, Kurita A. Endothelin-1 enhances vascular cell adhesion molecule-1 expression in tumor necrosis factor alpha-stimulated vascular endothelial cells.  Eur J Pharmacol. 1999;  369 237-245
• 26 Schmidt AM, Hori O, Chen JX, Li JF, Crandall J, Zhang J. et al . Advanced glycation endproducts interacting with their endothelial receptor induce expression of vascular cell adhesion molecule-1 (VCAM-1) in cultured human endothelial cells and in mice. A potential mechanism for the accelerated vasculopathy of diabetes.  J Clin Invest. 1995;  96 1395-1403
• 27 Chakravarthy U, Hayes RG, Stitt AW, McAuley E, Archer DB. Constitutive nitric oxide synthase expression in retinal vascular endothelial cells is suppressed by high glucose and advanced glycation end products.  Diabetes. 1998;  47 945-952
• 28 Lander HM, Tauras JM, Ogiste JS, Hori O, Moss RA, Schmidt AM. Activation of the receptor for advanced glycation end products triggers a p21(ras)-dependent mitogen-activated protein kinase pathway regulated by oxidant stress.  J Biol Chem. 1997;  272 17810-17814
• 29 Huttunen HJ, Fages C, Rauvala H. Receptor for advanced glycation end products (RAGE)-mediated neurite outgrowth and activation of NF-kappaB require the cytoplasmic domain of the receptor but different downstream signaling pathways.  J Biol Chem. 1999;  274 19919-19924
• 30 Barton M, Kiowski W. The therapeutic potential of endothelin receptor antagonists in cardiovascular disease.  Curr Hypertens Rep. 2001;  3 322-330

Correspondence