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Hyperhomocysteinaemia induced by dietary folate restriction causes kidney oxidative stress in rats

Published online by Cambridge University Press:  08 March 2007

Nieves Díez ,
Raquel Pérez ,
Verónica Hurtado  and
Santiago Santidrián
Nieves Díez
Affiliation:
Department of Human Physiology, School of Medicine, University of Navarra, 31080 Pamplona, Spain
Raquel Pérez
Affiliation:
Department of Human Physiology, School of Medicine, University of Navarra, 31080 Pamplona, Spain
Verónica Hurtado
Affiliation:
Laboratory of Thrombosis and Hemostasia, School of Medicine, University of Navarra, 31080 Pamplona, Spain
Santiago Santidrián*
Affiliation:
Department of Human Physiology, School of Medicine, University of Navarra, 31080 Pamplona, Spain
*
*Corresponding author: Dr S. Santidrián, fax +34 48 425649, email santidrian@unav.es
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Abstract

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Diet is the most common cause of mild hyperhomocysteinaemia (HHcy), which occurs in approximately 5–7 % of the general population. Since HHcy causes endothelial damage by oxidative stress in different organs, the present study was designed to examine whether HHcy might be involved in renal oxidative stress. Twenty-five male Wistar rats were randomly divided into two groups: one (n 13) was fed ad libitum a folate-free diet (FF) and the other (n 12) was fed the same diet supplemented with folic acid (control, CO). After 8 weeks the animals were killed and kidneys removed. Malondialdehyde (MDA), superoxide dismutase (SOD) and glutathione peroxidase (GPx) activities were measured in plasma and kidney homogenates. Renal tissue sections were analysed by indirect immunostaining with the primary antibody against oxidatively modified LDL receptor (LOX-1). A marked HHcy was confirmed in the FF group. As compared with CO animals, MDA levels in plasma and kidney homogenate were significantly higher in FF rats (P<0·05). Similarly, renal GPx and SOD activities were significantly higher in the FF group (P<0·001). No differences were found in LOX-1 immunohistochemical expression, which in the two groups was displayed in tubular cells. The present study provides evidence that HHcy does produce renal oxidative stress mediated by lipid peroxidation, and that the increased kidney MDA displayed by FF animals may enhance kidney antioxidant activity and thereby attenuate both kidney damage and expression of LOX-1.

Keywords

HomocysteineFolic acidOxidative stressKidney
Type
Research Article
Information
British Journal of Nutrition , Volume 94 , Issue 2 , August 2005 , pp. 204 - 210
Copyright
Copyright © The Nutrition Society 2005

References

Aamir, M, Sattar, A, Dawood, MM, Dilawar, M, Ijaz, A & Anwar, M (2004) Hyperhomocysteinemia as a risk factor for ischemic heart disease. J Coll Physicians Surg Pak 14, 518–521.Google ScholarPubMed
Akesson, B, Fehling, C, Jagerstad, M & Stenram, U (1982) Effect of experimental folate deficiency on lipid metabolism in liver and brain. Br J Nutr 47, 505–520.CrossRefGoogle ScholarPubMed
Balaghi, M, Horne, DW & Wagner, C (1993) Hepatic one-carbon metabolism in early folate deficiency in rats. Biochem J 291, 145–149.Google Scholar
Bostom, AG, Brosnan, JT, Hall, B, Nadeau, MR & Selhub, J (1995) Net uptake of plasma homocysteine by the rat kidney in vivo. Atherosclerosis 116, 59–62.Google Scholar
Brattström, L & Wilcken, DE (2000) Homocysteine and cardiovascular disease: cause or effect? Am J Clin Nutr 72, 315–323.Google Scholar
Chen, Y-F, Li, P-L & Zou, A-P (2002) Effect of hyperhomocysteinemia on plasma or tissue adenosine levels and renal function. Circulation 106, 1275–1281.CrossRefGoogle ScholarPubMed
Clifford, AJ, Heid, MK, Muller, HG & Bills, ND (1990) Tissue distribution and prediction of total body folate of rats. J Nutr 120, 1633–1639.CrossRefGoogle ScholarPubMed
Clifford, AJ, Wilson, DS & Bills, ND (1989) Repletion of folate-depleted rats with amino acid based diet supplemented with folic acid. J Nutr 119, 1956–1961.CrossRefGoogle ScholarPubMed
Durand, P, Prost, M & Blache, D (1996) Pro-thrombotic effects of a folic acid deficient diet in rat platelets and macrophages related to elevated homocysteine and decreased n-3 polyunsaturated fatty acids. Atherosclerosis 121, 231–243.CrossRefGoogle ScholarPubMed
Durand, P, Prost, M & Blache, D (1997) Folic acid deficiency enhances oral contraceptive-induced platelet hyperactivity. Arterioscler Thromb Vasc Biol 17, 1939–1946.CrossRefGoogle ScholarPubMed
Esterbauer, H & Cheeseman, KH (1990) Determination of aldehydic lipid peroxidation products: malonaldehyde and 4-hydroxynonenal. Methods Enzymol 186, 407–421.Google Scholar
Fischer, PA, Dominguez, GN, Cuniberti, LA, Martinez, V, Werba, JP, Ramirez, AJ & Masnatta, LD (2003) Hyperhomocysteinemia induces renal hemodynamic dysfunction: is nitric oxide involved? J Am Soc Nephrol 14, 653–660.Google Scholar
Friedman, AN, Bostom, AG, Selhub, J, Levey, AS & Rosenberg, IH (2001) The kidney and homocysteine metabolism. J Am Soc Nephrol 12, 2181–2189.Google Scholar
Fruchart, JC, Nierman, MC, Stroes, ES, Kastelein, JJ & Duriez, P (2004) New risk factors for atherosclerosis and patient risk assessment. Circulation 109, Suppl. 1, III15–III19.Google Scholar
Heydrick, SJ, Weiss, N, Thomas, SR, Cap, AP, Pimentel, DR, Loscalzo, J & Keaney, JF Jr (2004) l -Homocysteine and l -homocystine stereospecifically induce endothelial nitric oxide synthase-dependent lipid peroxidation in endothelial cells. Free Radic Biol Med 36, 632–640.Google Scholar
Huang, RF, Hsu, YC, Lin, HL & Yang, F (2001) Folate depletion and elevated plasma homocysteine promote oxidative stress in rats livers. J Nutr 131, 33–38.Google Scholar
Institute of Laboratory Animal Resources Commission on Life Sciences (1996) Guide for the Care and Use of Laboratory Animals, Washington, DC: National Academy Press.Google Scholar
Janero, DR (1990) Malondialdehyde and thiobarbituric acid-reactivity as diagnostic indices of lipid peroxidation and peroxidative tissue injury. Free Radic Biol Med 9, 515–540.Google Scholar
Konukoglu, D, Serin, O, Ercan, M & Turhan, MS (2003) Plasma homocysteine levels in obese and non-obese subjects with or without hypertension; its relationship with oxidative stress and copper. Clin Biochem 36, 405–408.CrossRefGoogle ScholarPubMed
Kumagai, H, Katoh, S, Hirosawa, K, Kimura, M, Hishida, A & Ikegaya, N (2002) Renal tubulointerstial injury in weanling rats with hyperhomocysteinemia. Kidney Int 62, 1219–1228.Google Scholar
Lawrence de Koning, AB, Werstuck, GH, Zhou, J & Austin, C (2003) Hyperhomocysteinemia and its role in the development of atherosclerosis. Clin Biochem 36, 411–498.Google Scholar
Lentz, SR (1997) Homocysteine and vascular dysfunction. Life Sci 61, 1205–1215.CrossRefGoogle ScholarPubMed
Li, N, Chen, Y-F & Zou, A-P (2002) Implications of hyperhomocysteinemia in glomerular sclerosis in hypertension. Hypertension 39, 443–448.CrossRefGoogle ScholarPubMed
McCord, JM & Fridovich, J (1987) Superoxide dismutase. J Biol Chem 244, 6049–6055.Google Scholar
McCully, KS (1996) Homocysteine and vascular disease. Nat Med 2, 386–389.Google Scholar
Malinow, MR (1990) Hyperhomocysteinemia: a common and easily reversible risk factor for occlusive disease. Circulation 81, 2004–2006.CrossRefGoogle Scholar
Miller, A, Mujumdar, V, Shek, E, Guillot, J, Angelo, M, Palmer, L & Tyagi, SC (2000) Hyperhomocyst(e)inemia induces multiorgan damage. Heart Vessels 15, 135–143.Google Scholar
Miller, JW, Nadeau, MR, Smith, J, Smith, D & Selhub, J (1994) Folate-deficiency-induced homocysteinaemia in rats: disruption of S -adenosylmethionine's co-ordinate regulation of homocysteine metabolism. Biochem J 298, 415–419.Google Scholar
Misra, HP (1974) Generation of superoxide free radicals during the autooxidation of thiols. J Biol Chem 249, 2151–2155.CrossRefGoogle Scholar
Moat, SJ, Bonham, JR, Cragg, RA & Powers, HJ (2000) Elevated plasma homocysteine elicits an increase in antioxidant enzyme activity. Free Radic Res 32, 171–179.Google Scholar
Moat, SJ, Lang, D, McDowell, IF, Clarke, ZL, Madhavan, AK, Lewis, MJ & Goodfellow, J (2004) Folate, homocysteine, endothelial function and cardiovascular disease. J Nutr Biochem 15, 64–79.Google Scholar
Morita, H, Kurihara, H, Yoshida, S, Saito, Y, Shindo, T, Oh-Hashi, Y, Kurihara, Y, Yazaki, Y & Nagai, R (2001) Diet-induced hyperhomocysteinemia exacerbates neointima formation in rat carotid arteries after balloon injury. Circulation 103, 133–139.CrossRefGoogle ScholarPubMed
Nagase, M, Kaname, S, Nagase, T, Wang, G, Ando, K, Sawamura, T & Fujita, T (2001) Expression of LOX-1, an oxidized low-density lipoprotein receptor, in experimental hypertensive glomerulosclerosis. J Am Soc Nephrol 11, 1826–1836.Google Scholar
O'Leary, K & Sheehy, PJA (2001) Influence of folic acid-fortified foods on folate status in a folate depletion–repletion rat model. Br J Nutr 85, 441–446.Google Scholar
Paglia, DE & Valentine, WN (1967) Studies on the quantitative and qualitative characterization of erythrocyte glutathione peroxidase. J Lab Clin Med 70, 158–169.Google Scholar
Perna, AF, Ingrosso, D, Satta, E, Romano, M, Cimmino, A, Galletti, P, Zappia, V, De Santo, NG (2001) Metabolic consequences of hyperhomocysteinemia in uremia. Am J Kidney Dis 38, Suppl. 1, S85–S90.Google Scholar
Pfeiffer, CM, Huff, DL & Gunter, EW (1999) Rapid and accurate HPLC assay for plasma total homocysteine and cysteine in a clinical laboratory setting. Clin Chem 45, 290–292.Google Scholar
Raijmakers, MT, Schilders, GW, Roes, EM, Van Tits, LJ, Hak-Lemmers, HL, Steegers, EA & Peters, WH (2003) N -Acetylcysteine improves the disturbed thiol redox balance after methionine loading. Clin Sci (Lond) 105, 173–180.Google Scholar
Rensma, PL, Apperloo, AJ & de Jong, PE (2003) Why does elevated plasma homocysteine result in severe microvascular injury, but not glomerular damage? Circulation 107, e77.Google Scholar
Rolland, PH, Friggi, A, Barlatier, A, Piquet, P, Latrilla, V, Faye, MM, Guillou, J, Charpiot, P, Bodard, H & Ghiringhelli, O (1995) Hyperhomocysteinemia-induced vascular damage in the minipig. Captopril–hydrochlorothiazide combination prevents elastic alterations. Circulation 91, 1161–1174.Google Scholar
Sachdev, P, Parslow, R, Salonikas, C, Lux, O, Wen, W, Kumar, R, Naidoo, D, Christensen, H & Jorm, A (2004) Homocysteine and the brain in midadult life: evidence for an increased risk of leukoaraiosis in men. Arch Neurol 61, 1369–1376.Google Scholar
Selhub, J, Jacques, PF, Wilson, PW, Rush, D & Rosenberg, IH (1993) Vitamin status and intake as primary determinants of homocysteinemia in an elderly population. JAMA 270, 2693–2698.Google Scholar
Sindhu, RK, Roberts, CK, Ehdaie, A, Zhan, CD & Vaziri, ND (2005) Effects of aortic coarctation on aortic antioxidant enzymes and NADPH oxidase protein expression. Life Sci 76, 945–953.Google Scholar
Southern, FN, Cruz, C, Fink, LM, Cooney, CA, Barone, GW, Eidt, VF & Moursi, MM (1998) Hyperhomocysteinemia increases internal hyperplasia in a rat carotid endarterectomy model. J Vasc Surg 28, 909–918.Google Scholar
Stadtman, ER & Oliver, CN (1991) Metal-catalyzed oxidation of proteins. Physiological consequences. J Biol Chem 266, 2005–2008.Google Scholar
Stanger, O, Weger, M, Renner, W & Konetschny, R (2001) Vascular dysfunction in hyperhomocyst(e)inemia. Implications for atherothrombotic disease. Clin Chem Lab Med 39, 725–733.Google Scholar
Starkebaum, G & Harlan, JM (1986) Endothelial cell injury due to copper-catalyzed hydrogen peroxide generation from homocysteine. J Clin Invest 77, 1370–1376.Google Scholar
Turrens, JF, Freeman, BA & Crapo, JD (1982) Hyperoxia increases H2O2 release by lung mitochondria and microsomes. Arch Biochem Biophys 217, 411–421.Google Scholar
Ventura, P, Panini, R, Verlato, C, Scarpetta, G & Salvioli, G (2000) Peroxidation indices and total antioxidant capacity in plasma during hyperhomocysteinemia induced by methionine oral loading. Metabolism 49, 225–228.Google Scholar
Viedt, C & Orth, SR (2002) Monocyte chemoattractant protein-1 (MCP-1) in the kidney: does it more than simply attract monocytes?. Nephrol Dial Trasplant 17, 2043–2047.CrossRefGoogle ScholarPubMed
Welch, GN, Upchurch, G & Loscalzo, J (1997) Hyperhomocysteinemia and atherothrombosis. Ann NY Acad Sci 811, 48–58.Google Scholar
Werstuck, GH, Lentz, SR, Dayal, S, et al. (2001) Homocysteine-induced endoplasmic reticulum stress causes dysregulation of the cholesterol and triglyceride biosynthetic pathways. J Clin Invest 107, 1263–1273.Google Scholar
Wilcken, DE, Wang, XL, Adachi, T, Hara, H, Duarte, N, Green, K & Wilcken, B (2000) Relationship between homocysteine and superoxide dismutase in homocystinuria: possible relevance to cardiovascular risk. Arterioscler Thromb Vasc Biol 20, 1199–1202.Google Scholar
Yang, Z-Z & Zou, A-P (2003) Homocysteine enhances TIMP-1 expression and cell proliferation associated with NADH oxidase in rat mesangial cells. Kidney Int 63, 1012–1020.Google Scholar
Young, PB, Kennedy, S, Molloy, AM, Scott, JM, Weir, DG & Kennedy, DG (1997) Lipid peroxidation induced in vivo by hyperhomocysteinemia in pigs. Atherosclerosis 129, 67–71.Google Scholar
Zhou, J, Moller, J, Ritskes-Hoitinga, M, Larsen, ML, Austin, RC & Falk, E (2003) Effects of vitamin supplementation and hyperhomocysteinemia on atherosclerosis in apoE-deficient mice. Atherosclerosis 168, 255–262.Google Scholar