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      Endothelial Nitric Oxide Synthase Intron 4 Polymorphism Influences the Progression of Renal Disease

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          Background/Aim: Nitric oxide is a potent regulator of intrarenal hemodynamics and may influence the renal function. We investigated whether polymorphism of intron 4 of the endothelial constitutive nitric oxide synthase (ecNOS) gene is related to the progression of chronic renal failure. Methods: Polymorphism of ecNOS intron 4 was studied in 1,005 hemodialysis patients (710 with nondiabetic nephropathy and 295 with diabetic nephropathy) and was compared with the findings in 189 healthy subjects. ecNOS genotypes were determined by the polymerase chain reaction, followed by agarose gel electrophoresis. Results: The frequencies of ecNOS4a/a, ecNOS4a/b, and ecNOS4b/b genotypes were, respectively, 0% (0/189), 13.8% (26/189), and 86.2% (163/189) in the control group; 1.7% (12/710), 22.1% (157/710), and 76.2% (541/710) in the nondiabetic nephropathy group, and 1.0% (3/295), 22.7% (67/295), and 76.3% (225/295) in the diabetic nephropathy group. The frequency of ecNOS4a (ecNOSa/a and ecNOSa/b) was significantly higher in both the nondiabetic group and in the diabetic group than in the controls (p = 0.0025 and p = 0.0438, respectively). Conclusion: There was a significantly higher frequency of the a allele of intron 4 in both nondiabetic and diabetic hemodialysis patients, so the polymorphism of intron 4 of the ecNOS gene may have a wide influence on the progression of renal disease.

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          Most cited references 7

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          Hypertension in mice lacking the gene for endothelial nitric oxide synthase.

          Nitric oxide (NO), a potent vasodilator produced by endothelial cells, is thought to be the endothelium-dependent relaxing factor (EDRF) which mediates vascular relaxation in response to acetylcholine, bradykinin and substance P in many vascular beds. NO has been implicated in the regulation of blood pressure and regional blood flow, and also affects vascular smooth-muscle proliferation and inhibits platelet aggregation and leukocyte adhesion. Abnormalities in endothelial production of NO occur in atherosclerosis, diabetes and hypertension. Pharmacological blockade of NO production with arginine analogues such as L-nitroarginine (L-NA) or L-N-arginine methyl ester affects multiple isoforms of nitric oxide synthase (NOS), and so cannot distinguish their physiological roles. To study the role of endothelial NOS (eNOS) in vascular function, we disrupted the gene encoding eNOS in mice. Endothelium-derived relaxing factor activity, as assayed by acetylcholine-induced relaxation, is absent, and the eNOS mutant mice are hypertensive. Thus eNOS mediates basal vasodilation. Responses to NOS blockade in the mutant mice suggest that non-endothelial isoforms of NOS may be involved in maintaining blood pressure.
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            NO at work

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              Gene structure, polymorphism and mapping of the human endothelial nitric oxide synthase gene.

              Endothelium-derived relaxing factor (EDRF)/nitric oxide (NO) is synthesized from L-Arginine by the endothelial, constitutive, NO synthase. No facilitate genetic studies, we have cloned the human endothelial NO synthase gene and determined its structure. The gene is composed of 26 exons, ranging from 68 to 579 bp and spans 22 kb. We determined the transcription start point using human lung mRNA. No TATA-box was found at the expected distance from the transcription start point and several consensus sequences for transcription factors, including a shear-stress responsive element were identified in the 5'-flanking region. A highly polymorphic (CA) repeat within intron 13 was studied, allowing the precise genetic mapping of the gene to chromosome 7, within a 4 cM interval delimited by genethon markers AFM199Zd4 and AFM074Xg5.

                Author and article information

                S. Karger AG
                05 September 2001
                : 89
                : 2
                : 219-223
                2nd Department of Internal Medicine, Hiroshima University School of Medicine, Hiroshima, Japan
                46071 Nephron 2001;89:219–223
                © 2001 S. Karger AG, Basel

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