Background/Aims: Polymorphism of the endothelial nitric oxide synthase (ecNOS) gene may be involved in renal disease. Recently, T-786→C polymorphism affecting ecNOS gene transcription has been reported. To clarify the role of T-786→C polymorphism in renal disease, we investigated hemodialysis patients and healthy controls for this polymorphism and we compared its frequency with that of intron 4 polymorphism in the hemodialysis patients. Methods: The subjects were 252 patients who had been on hemodialysis for less than 2 years (168 with nondiabetic nephropathy and 84 with diabetic nephropathy) and 187 healthy controls. T-786→C polymorphism was detected using polymerase chain reaction-restriction fragment length polymorphism analysis. Results: The frequencies of the T/C and C/C genotypes were significantly higher in the nondiabetic hemodialysis patients than in the controls (odds ratio 1.41; 95% Cl 1.03–2.00), and were also significantly higher in the diabetic hemodialysis patients than in the controls (odds ratio 1.56; 95% Cl 1.02–2.41). In addition, T-786→C polymorphism and intron 4 polymorphism showed strong linkage disequilibrium. Conclusion: T-786→C polymorphism may be involved in the progression of both nondiabetic and diabetic nephropathy, along with intron 4 polymorphism.

Keywords:
Endothelial nitric oxide synthase, Gene polymorphism, End-stage renal disease, Diabetic nephropathy, Nondiabetic nephropathy
1.
Zatz R, De Nucci G: Effects of acute nitric oxide inhibition on rat glomerular microcirculation. Am J Physiol 1991;261:F360–F363.
2.
Tolins JP, Palmer RMJ, Moncada S, Raij L: Role of endothelium-derived relaxing factor in regulation of renal hemodynamic responses. Am J Physiol 1990;258:H655–H662.
3.
Baylis C, Mitruka B, Deng A: Chronic blockade of nitric oxide synthesis in the rat produces systemic hypertension and glomerular damage. J Clin Invest 1992;90:278–281.
4.
Schmidt HHHW, Walter U: NO at work. Cell 1994;78:919–925.
5.
Nadaud S, Bonnardeaux A, Lathrop M, Soubrier F: Gene structure, polymorphism and mapping of the human endothelial nitric oxide synthase gene. Biochem Biophys Res Commun 1994;198:1027–1033.
6.
Marsden PA, Heng HHQ, Scherer SW, Stewart RJ, Hall AV, Shi X-M, Tsui L-C, Schappert KT: Structure and chromosomal localization of the human constitutive endothelial nitric oxide synthase gene. J Biol Chem 1993;268:17478–17488.
7.
Bredt DS, Snyder SH: Isolation of nitric oxide synthase, a calmodulin-requiring enzyme. Proc Natl Acad Sci USA 1990;87:682–685.
8.
Wang XL, Sim AS, Badenhop RF, McCredie RM, Wilcken DEL: A smoking-dependent risk of coronary artery disease associated with a polymorphism of endothelial nitric oxide synthase gene. Nat Med 1996;2:41–45.
9.
Tsukada T, Yokoyama K, Arai T, Takemoto F, Hara S, Yamada A, Kawaguchi Y, Hosoya T, Igari J: Evidence of association of the ecNOS gene polymorphism with plasma NO metabolite levels in humans. Biochem Biophys Res Commun 1998;245:190–193.
10.
Yokoyama K, Tsukada T, Matsuoka H, Hara S, Yamada A, Kawaguchi Y: High accumulation of endothelial nitric oxide synthase (ecNOS): A gene polymorphism in patients with end-stage renal disease. Nephron 1998;79:360–361.
11.
Wang Y, Kikuchi S, Suzuki H, Nagase S, Koyama A: Endothelial nitric oxide synthase gene polymorphism in intron 4 affects the progression of renal failure in non-diabetic renal diseases. Nephrol Dial Transplant 1999;14:2898–2902.
12.
Asakimori Y, Yorioka N, Yamamoto I, Okumoto S, Doi S, Hirai T, Taniguchi Y: Endothelial nitric oxide synthase intron 4 polymorphism influences the progression of renal disease. Nephron 2001;89:219–223.
13.
Nakayama M, Yasue H, Yoshimura M, Shimasaki Y, Kugiyama K, Ogawa H, Motoyama T, Saito Y, Ogawa Y, Miyamoto Y, Nakano K: T-786→C mutation in the 5′-flanking region of the endothelial nitric oxide synthase gene is associated with coronary spasm. Circulation 1999;99:2864–2870.
14.
Zanchi A, Moczulski DK, Hanna LS, Wantman M, Warram JH, Krolewski AS: Risk of advanced diabetic nephropathy in type 1 diabetes is associated with endothelial nitric oxide synthase gene polymorphism. Kidney Int 2000;57:405–413.
15.
Trachtman H, Futterweit S, Singhal P: Nitric oxide modulates the synthesis of extracellular matrix proteins in cultured rat mesangial cells. Biochem Biophys Res Commun 1995;207:120–125.
16.
Trachtman H, Futterweit S, Grag P, Reddy K, Singhal PC: Nitric oxide stimulates the activity of a 72-kDa neutral matrix metalloproteinase in cultured rat mesangial cells. Biochem Biophys Res Commun 1996;218:704–708.
17.
Trachtman H, Futterweit S, Crimmins DL: High glucose inhibits nitric oxide production in cultured rat mesangial cells. J Am Soc Nephrol 1997;8:1276–1282.
18.
Wang YX, Brooks DP, Edwards RM: Attenuated glomerular cGMP production and renal vasodilatation in streptozocin-induced diabetic rats. Am J Physiol 1993;264:R952–R956.
19.
Yoshimura M, Yasue H, Nakayama M, Shimasaki Y, Ogawa H, Kugiyama K, Saito Y, Miyamoto Y, Ogawa Y, Kaneshige T, Hiramatsu H, Yoshioka T, Kamitani S, Teraoka H, Nakao K: Genetic risk factors for coronary artery spasm: Significance of endothelial nitric oxide synthase gene T-786→C and missense Glu298Asp variants. J Invest Med 2000;48:367–374.
© 2002 S. Karger AG, Basel
2002
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