Abstract 12407: Anti-aging Gene Klotho Deficiency Causes Hypertension via Upregulation of Fibroblast Growth Factor 23
Background & Objective: The prevalence of hypertension increases with age. Klotho (KL) is a newly-discovered anti-aging gene. In humans, the KL levels decrease with age. In vivo KL gene delivery prevented the progression of spontaneous hypertension and attenuated kidney damage in SHRs. The purpose of this study is to determine if KL deficiency affects blood pressure and investigate the underlying mechanism.
Methods & Results: Two groups of wild-type (WT) and 2 groups of KL heterozygous (+/-) mice were used (8 mice/group). Blood pressure was elevated significantly in KL(+/-) mice vs the WT mice (mean BP 126 vs 103 mmHg), suggesting that KL gene deficiency causes hypertension. Plasma level of fibroblast growth factor-23 (FGF23) was elevated significantly in the KL(+/-) mice. We then inhibited FGF23 using a FGF receptor inhibitor (PD173074). One group of each strain received PD at 1 mg/kg/day (IP) for one week followed by 10 mg/kg for another week, while the other group received vehicle and served as a control. PD abolished KL deficiency-induced hypertension and attenuated cardiac hypertrophy. Interestingly, the level of urine norepinephrine was increased in KL(+/-) mice (KL(+/-) 490 ng/ml vs WT 350 ng/ml), suggesting that KL deficiency activates the sympathetic nervous system (SNS). PD abolished the KL deficiency-induced increase in urine norepinephrine, indicating effective inhibition of the SNS activity. In neuroblastoma cells, FGF23 increased protein expression and activity of tyrosine hydroxylase (TH) and synthesis of norepinephrine. PD prevented FGF23-induced upregulation of TH and release of norepinephrine in neuroblastoma cells.
Conclusions: This study demonstrates, for the first time, that KL deficiency causes hypertension via upregulation of FGF23. The results also reveal a previously unidentified role of FGF23 in the regulation of the SNS activity.
- © 2013 by American Heart Association, Inc.