Abstract 12293: RNAi Knockdown of Klotho Gene Causes Hypertension and Kidney Damage
Background & Hypothesis: Klotho is a recently-discovered anti-aging gene. Genetic mutation of klotho results in multiple premature aging phenotypes and significantly shortens lifespan. In contrast, overexpression of klotho extends lifespan. Thus, klotho may be an aging-suppressor gene that can delay aging when overexpressed and accelerate aging when disrupted. In humans, the level of the circulating klotho declines with age while the prevalence of hypertension increases with age. The objective of this study was to assess our hypothesis that knockdown of klotho leads to hypertension and kidney damage in rats.
Methods and Results: The in vivo RNAi knockdown of klotho was achieved by AAV delivery of klotho shRNA (KLshRNA). In vivo expression of anti-inflammatory cytokine IL-10 was achieved by AAV delivery of human IL-10 full-length cDNA (IL10). RNAi knockdown of klotho significantly increased systolic and diastolic blood pressure. The KLshRNA-induced hypertension may be mediated by inflammation because it can be abolished by simultaneous delivery of IL−10. Indeed, knockdown of klotho caused inflammation as evidenced by increased IL-6 expression and macrophage infiltration in kidneys. Notably, knockdown of klotho increased oxidative stress levels in kidneys as determined by significant increases in superoxide production (DHE) and 4-NHE levels (marker of lipid peroxidation). The KLshRNA-induced oxidative stress may be due to the down-regulation of superoxide dismutase (SOD). Knockdown of klotho caused glomerular collapses, a sign of severe kidney damage. IL-10 gene delivery abolished the KLshRNA-induced oxidative stress and kidney damage. Both renal and circulating klotho levels were decreased in the KLshRNA group (≈35%), indicating effective knockdown of klotho.
Conclusion: A moderate reduction in klotho (similar to aged humans) leads to hypertension and kidney damage probably due to increased inflammation.
- © 2010 by American Heart Association, Inc.