Abstract 17552: Anti-aging Gene Klotho, A New Etiological Factor for Hypertension
Background and Objective. The prevalence of hypertension increases with age while the level of klotho (KL) declines with age. KL is a recently discovered anti-aging gene. Genetic mutation of KL expedites the aging process and shortens the lifespan while overexpression of KL slows down the aging process and extends the lifespan in mice. The purpose of this study is to investigate if KL deficiency causes hypertension and vascular dysfunction and if in vivo expression of KL attenuates hypertension and organ damage in spontaneous hypertensive rats (SHR).
Methods and Results. Blood pressure (BP) was elevated spontaneously in KL heterozygeous (+/-) mice around the age of 4.5 months. Vasodilatory responses to acetylcholine and sodium nitroprusside were decreased in KL (+/-) mice. Therefore, KL deficiency causes hypertension and vascular endothelial dysfunction. In another experiment, we silenced KL gene in rats using the in vivo RNAi approach. KL-shRNA effectively silenced KL gene which leads to macrophage infiltration, upregulation of superoxide production, downregulation of Mn-SOD expression, and oxidative stress damage in kidneys. Glomerular atrophy and collapse were found in rats treated with KL-shRNA, indicating kidney damage. Silencing of KL significantly increased BP. Interestingly, simultaneous overexpression of anti-inflammatory cytokine IL-10 gene abolished inflammation and oxidative stress and prevented the development of hypertension and kidney damage in rats treated with KL-shRNA. These results suggest that KL deficiency-induced hypertension may be mediated by increased inflammation. On the other hand, plasma levels of KL and IL-10 were decreased significantly in SHRs. Notably, in vivo KL gene delivery increased the IL-10 level, suppressed superoxide levels, abolished kidney damages (glomerular collapse, tubule atrophy, protein deposition), and improved kidney function in SHRs.
Conclusion. KL is essential in the maintenance of normal blood pressure. KL deficiency may be a new etiological factor for hypertension. In vivo expression of KL may be a novel therapeutic approach for hypertension.
- © 2012 by American Heart Association, Inc.