Klotho gene delivery suppresses oxidative stress in vivo

Department of General Medicine, Osaka University Hospital, Osaka, Japan
Geriatrics & Gerontology International (Impact Factor: 2.19). 09/2007; 7(3):293 - 299. DOI: 10.1111/j.1447-0594.2007.00406.x


Objective: Mice deficient in the klotho gene exhibit a syndrome resembling premature human aging. A recent report also suggested that klotho transgenic mice exhibited a long lifespan, which shows that klotho is an antisenescence gene. Previously, klotho has been reported to improve endothelial dysfunction, and also to have a preventive effect against oxidative stress. In the present study, we investigated the effect of klotho gene delivery on blood pressure and oxidative stress in vivo.Methods: Klotho plasmid was injected into the tail vein of mice and spontaneous hypertensive rats over 5 s.Results: Klotho gene delivery upregulated manganese superoxide dismutase protein expression and total superoxide dismutase activity in the aorta of mice compared with the control. It upregulated nitric oxide production, and downregulated lipid peroxide concentration in the serum of mice. When klotho plasmid was administered to spontaneously hypertensive rats, superoxide dismutase activity in the kidney and liver was significantly increased, and lipid peroxide concentration in the kidney and liver was significantly decreased, compared with the control. Klotho gene delivery in spontaneously hypertensive rats did not alter systolic blood pressure.Conclusion: These results suggest that klotho gene infusion into the tail vein of mice and rats has a suppressive effect against oxidative stress. These findings may provide a new insight into the therapeutic potential of klotho gene delivery in vivo to regulate oxidative stress.

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    • "Ohta et al.47 investigated the effect of Klotho gene delivery on blood pressure and oxidative stress in vivo. They found that Klotho gene upregulated MnSOD expression and total SOD activity in the aorta of mice, enhanced nitric oxide production, and downregulated lipid peroxide concentration in serum of mice. "
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    ABSTRACT: Reactive oxygen species (ROS) superoxide and hydrogen peroxide perform important signaling functions in many physiological and pathophysiological processes. Cell senescence and organismal age are not exemptions.Aging-regulating genes p66shc, Sirtuin, FOXO3a and Klotho are new important factors which are stimulated by ROS signaling. It has been shown that ROS participate in initiation and prolongation of gene-dependent aging development.ROS also participate in the activation of protein kinases Akt/PKB and extracellular signal-regulated kinase ERK, which by themselves or through gene activation stimulates or retards cell senescence.Different retarding/stimulating effects of ROS might depend on the nature of signaling species-superoxide or hydrogen peroxide. Importance of radical anion superoxide as a signaling molecule with"super-nucleophilic" properties points to the possibility of the use of superoxide scavengers (SOD mimetics, ubiquinones and flavonoids) for retarding the development of aging.
    Oxidative Medicine and Cellular Longevity 04/2010; 3(2):77-85. DOI:10.4161/oxim.3.2.11050 · 3.36 Impact Factor
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    ABSTRACT: Fibroblast growth factor (FGF) 23 and Klotho are two factors associated with several metabolic disorders. Similar to humans, accelerated aging processes characterized by chronic vascular disease, bone demineralization, skin atrophy and emphysema have been recognized in FGF23-null mice and Klotho-deficient mice. The role of these factors in the control of mineral metabolism homeostasis have been shown recently, particularly at the level of parathyroid cells and also in modulating active vitamin D production, two phenomena which are relevant in the presence of chronic kidney disease. In addition, the hormonal affect of circulating FGF23 and Klotho proteins on vascular reactivity, either directly on endothelial cell functions or indirectly by modulating the brain endothelin-1-dependent sympathetic nervous system activity, has contributed to understanding their role in the pathophysiology of hypertension and atherosclerotic vasculopathies. Consequently, very recent clinical investigations seem to confirm the involvement of Klotho in modulating the severity and prognosis of human cardiovascular (CV) disorders and longevity. The present review reports data related to the possible interactive effects of Klotho and FGF23 on the prognosis of renal and CV diseases.
    Nephrology Dialysis Transplantation 05/2011; 26(8):2433-8. DOI:10.1093/ndt/gfr208 · 3.58 Impact Factor
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    ABSTRACT: Background/aims: The incidence of urolithiasis has considerably increased throughout the world in the last two decades. Clinical researches have showed an association between oxidative stress and stone formation. Emerging evidence indicated a novel function for klotho protein in anti-oxidative stress. In this study, we aimed at investigating a possible relationship between klotho gene polymorphisms and the risk of calcium oxalate urolithiasis in the population of Han nationality in Eastern China. Methods: Klotho gene polymorphisms rs3752472 in exon3, rs650439 in intron 4 and rs577912 in intron 1 were investigated in 426 patients with calcium oxalate stones compared with 282 age-matched healthy volunteers with no history of stone formation, using TaqMan SNP Genotyping Assays. Results: Significant differences were found between rs3752472 and the risk of nephrolithiasis as CC genotype of rs3752472 klotho polymorphism had almost 2-fold increased stone risk compared with the heterozygote genotype CT and homozygous genotype TT(95% CI=1.013-2.255, OR=1.512,p=0.043). Conclusion: Our results showed that the rs3752472 polymorphism of klotho gene is associated with the risk of calcium oxalate urolithiasis and may act as a risk factor during stone formation in our study population.
    Gene 06/2013; 526(2). DOI:10.1016/j.gene.2013.06.001 · 2.14 Impact Factor
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