Published Online
on September 3, 2002

A more recent version of this article appeared on October 1, 2002

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Submitted on January 28, 2002
Revised on February 19, 2002

Association of eNOS Glu298Asp Polymorphism With End-Stage Renal Disease

Eisei Noiri^*; Hiroaki Satoh; Jun-ichi Taguchi; Sergey V. Brodsky; Akihide Nakao; Yumiko Ogawa; Satomi Nishijima; Takehiko Yokomizo; Katsushi Tokunaga; and Toshiro Fujita

From the Departments of Nephrology and Endocrinology (E.N., A.N., T.F.), Diabetes Mellitus and Metabolism (H.S.), Human Genetics (K.T.), and Biochemistry and Molecular Biology (T.Y.), University of Tokyo, Tokyo, Japan; Department of Cardiovascular Disease, Tokai University (J.T.), Kanagawa, Japan; Department of Medicine, State University of New York at Stony Brook (S.V.B.), Stony Brook, New York; and Molecular Medicine Laboratories, Yamanouchi Pharmaceutical Co, Ltd (Y.O., S.N.), Tsukuba, Japan.

^* To whom correspondence should be addressed. E-mail: noiri-tky{at}umin.ac.jp.

Abstract—Nitric oxide (NO) derived from endothelial cells is profoundly related to the maintenance of physiological vascular tone. Impairment of endothelial NO generation brought about by gene polymorphism is considered the major deterioration factor for progressive renal disease, including diabetic nephropathy. The present study aimed to elucidate the Glu298Asp polymorphism of endothelial NO synthase (eNOS) in patients with end-stage renal disease (ESRD) and its role as a predisposing factor for cardiovascular complications. Glu298Asp in exon 7 of the eNOS gene was determined by polymerase chain reaction, followed by restriction fragment length polymorphism analysis, in ESRD patients (n=185) and compared with that of unrelated healthy individuals (n=304). The occurrence of 298Asp was significantly higher in the ESRD group (P=0.0020; odds ratio [OR] 1.65; 95% confidential interval [CI]: 1.21 to 2.25). In this group, 72 patients had type 2 diabetes mellitus (DM). Although 298Asp did not reach a significant level in the non-DM ESRD subgroup, the occurrence of 298Asp was significantly higher in DM-derived ESRD patients (P=0.0010; OR 2.02; 95% CI: 1.37 to 3.07). The functional effect of the Glu298Asp was examined using Chinese hamster ovary (CHO) cells stably overexpressing either 1917G or 1917T. NO-selective electrode measurements and fluorometric nitrite assay revealed a statistically significant difference in NO production or nitrite accumulation between CHO 1917G and 1917T (P<0.01). These data indicated that Glu298Asp is the predisposing factor in ESRD, especially DM-derived ESRD. The functional difference in NO generation depending on eNOS with either glutamate or aspartate at position 298 was also confirmed in vitro.

Key words: polymorphism • polymerase chain reaction • nitric oxide synthase • diabetes mellitus

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