Objective. Klotho is a newly-discovered anti-aging gene. Klotho (KL) gene delivery prevented progression of spontaneous hypertension and attenuated kidney damage. 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. 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 FGF23 was increased significantly in the KL(+/-) mice. We then inhibited FGF23 by 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. Following the 2-week treatment, the mice were euthanized and blood, kidney, heart were collected. Distal convoluted tubules (DCT) were isolated from 1 kidney of each animal. PD significantly attenuated hypertension and 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.
Conclusions. Klotho deficiency causes hypertension and cardiac hypertrophy probably via upregulation of FGF23 which further activates the SNS.