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

Asakimori, Yukiteru; Yorioka, Noriaki; Yamamoto, Ichiro; Okumoto, Satoru; Doi, Shigehiro; Hirai, Takayuki; Taniguchi, Yoshihiko

doi:10.1159/000046071

Cited by 39 publications

(30 citation statements)

References 16 publications

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“…Recent studies have reported an association between eNOS polymorphisms that lead to decreased eNOS expression and development of advanced nephropathy in patients with type 1 (199 -201) and type 2 diabetes (202,203). Other studies have found an association of these polymorphisms with ESRD (204,205). However, not all studies have detected any potential association of these eNOS polymorphisms with DN (206 -210).…”

Section: Endothelial Nitric Oxide Synthasementioning

confidence: 99%

Mouse Models of Diabetic Nephropathy

Breyer¹,

Böttinger²,

Brosius³

et al. 2005

Journal of the American Society of Nephrology

483

516

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Mice provide an experimental model of unparalleled flexibility for studying mammalian diseases. Inbred strains of mice exhibit substantial differences in their susceptibility to the renal complications of diabetes. Much remains to be established regarding the course of diabetic nephropathy (DN) in mice as well as defining those strains and/or mutants that are most susceptible to renal injury from diabetes. Through the use of the unique genetic reagents available in mice (including knockouts and transgenics), the validation of a mouse model reproducing human DN should significantly facilitate the understanding of the underlying genetic mechanisms that contribute to the development of DN. Establishment of an authentic mouse model of DN will undoubtedly facilitate testing of translational diagnostic and therapeutic interventions in mice before testing in humans.J (1), with costs for care of these patients projected to be $12 billion/yr by 2010 (1). Despite the high prevalence of DN, only 20 to 40% of all diabetic patients are prone to developing kidney failure, and family-based studies suggest that a significant genetic component confers risk for DN (2-4). Studies of diabetic mice suggest that, like people, mice exhibit differential susceptibility to diabetes and renal and cardiovascular diseases (5-7). In mice, identification of a strain that is prone to disease provides the relevant discriminator rather than identification of an individual who is at risk for diabetic complications. However, in contrast to people, each inbred mouse strain represents a genetically homogeneous and readily replenished resource that is amenable to repeated experimental study.Biomedical experimentation in mice affords significant advantages over experimentation in other species. These advantages include the development of diverse and unique genetic resources, including completion of a detailed map of murine genomic sequence that is freely available through the internet, as well as Ͼ450 inbred strains of mice that have been generated over the past century, with each strain genetically being homogeneous and offering a unique array of phenotypes (8,9). The availability of murine embryonic stem cells has also provided the ability to disrupt the expression and function of specific preselected genes (10 -12). Finally, repositories of mice that bear multiple mutations that alter function in each known gene are gradually being assembled (13-15). These unique resources have the potential to significantly facilitate studies into the pathogenesis of disease in mice. Through the use of the unique genetic reagents that are available in mice (including knockouts and transgenics), the identification of a robust mouse model of DN should significantly facilitate understanding of the underlying genetic mechanisms that contribute to the development of DN in people as well as in mice. Establishment of a valid mouse model of DN should also facilitate testing of translational diagnostic and therapeutic interventions in mice before testing in humans. Workin...

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Section: Endothelial Nitric Oxide Synthasementioning

confidence: 99%

Mouse Models of Diabetic Nephropathy

Breyer¹,

Böttinger²,

Brosius³

et al. 2005

Journal of the American Society of Nephrology

483

516

View full text Add to dashboard Cite

show abstract

“…Such an association was observed earlier by others. Asakimori et al, in 2001, found a significantly higher frequency of the ecNOS 4a allele in haemodialysis patients, both non-diabetic and diabetic, and therefore suggested that the polymorphism in intron 4 of the ecNOS gene may have influence on the progression of renal disease. Wang et al, in 1999, in their study of 302 subjects with endstage renal disease and 248 healthy controls found a significantly higher frequency of the ecNOS 4a allele in patients with ESRD caused by non-diabetic primary renal diseases.…”

Section: Discussionmentioning

confidence: 95%

“…Freedman et al2000 evaluated the role of four NOS gene polymorphisms in ESRD patients and found that the a allele of the ecNOS 4 polymorphism in the NOS gene was associated with all-cause ESRD in probands and their siblings compared with healthy subjects. One study showed that the basal concentration of NO metabolites (nitrate plus nitrite) in the plasma was reduced in individuals with essential hypertension [Asakimori et al, 2001 andYilmaz et al, 2009]. Tsukada et al,1998 reported a strong association between the a allele of the ecNOS gene and the plasma NOx (nitrate and nitrite) levels.…”

Section: Discussionmentioning

confidence: 99%

“…Several eNOS gene polymorphisms have been reported as "susceptibility genes" in various cardiovascular (CVD) and pulmonary diseases. GT substitution in exon7 in codon 298, T786 mutation in the 5´ flanking region and high numbers of CVD , which have been repeated in intron 13 of eNOS gene are also known to be associated with an excess of risk of coronary artery disease (CAD) [Asakimori et al, 2001]. Among the reported polymorphisms of the eNOS gene, a significant association of the 4a/b polymorphism in intron 4 of the eNOS gene with CAD and arterial hypertension has also been reported (Yoon et al2000).…”

Section: Introductionmentioning

confidence: 99%

“…As both coronary lesions and chronic renal failure are basically vascular disorders, we speculate that the gene polymorphism in ecNOS intron 4 might have some relevance to progression in chronic renal failure. An association of the 4a allele of the ecNOS gene with renal disease was reported [Asakimori et al, 2001, Miyamotoet al, 1998and Thaha et al, 2008. Chronic renal failure is basically a vascular disorder and investigating ecNOS gene polymorphism might shed some light on the pathophysiology of renal disease and progression to end-stage renal disease (ESRD).…”

Section: Introductionmentioning

confidence: 99%

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