Klotho gene delivery suppresses oxidative stress in vivo

Department of General Medicine, Osaka University Hospital, Osaka, Japan
Geriatrics & Gerontology International (Impact Factor: 1.58). 09/2007; 7(3):293 - 299. DOI: 10.1111/j.1447-0594.2007.00406.x

ABSTRACT 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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    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.
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