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.
    Full-text · Article · Apr 2010 · Oxidative Medicine and Cellular Longevity
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    ABSTRACT: Harman's Free Radical Theory of Aging has been considered as a major theory of aging for more than 50 years. In 1956 Dr. Harman proposed that the accumulation of free radicals with the age causes the damage of biomolecules by these reactive species and the development of pathological disorders resulting in cell senescence and organismal aging. His hypothesis was supported by numerous experimental studies demonstrated an increase in free radical levels in cells and living organisms with aging. In subsequent years important discoveries of new physiological free radicals superoxide and nitric oxide have been made that led to understanding of other important functions of free radicals. It has been shown that superoxide and nitric oxide together with their diamagnetic reaction products hydrogen peroxide and peroxynitrite (all are now named reactive oxygen and nitrogen species, ROS and RNS) function as signaling species in many physiological enzymatic/gene processes. Furthermore, the disturbance of ROS and RNS physiological signaling can be an origin of various pathologies and aging. These discoveries demanded to widen original free radical theory of aging and to consider the damaging ROS signaling as an important, maybe major route to cell senescence and organismal aging. However, some experimental findings such as the extension of lifespan by calorie restriction of yeast, flies, worms, and mice, and favorable effects of physical exercises stimulated criticism of free radical theory because the expansion of lifespan accompanied in some cases by increasing oxidative stress. On these grounds such theories as Hormesis and Target of rapamycin (mTOR) theories refute the role of ROS and oxidative stress in aging. Accordingly, a major purpose of this review to show that ROS signaling is probably the most important enzyme/gene pathway responsible for the development of cell senescence and organismal aging and that ROS signaling might be considered as further development of free radical theory of aging. In spite of apparent contradictions the Hormesis or TOR theories are also describing processes of aging development regulated by ROS signaling.
    Full-text · Article · Oct 2010 · Aging and Disease
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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.
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