Abstract 061: Kidney-specific Klotho Gene Deficiency Impairs Sodium Excretion and Causes Hypertension

Background & Purpose: Klotho was originally discovered as an anti-senescence gene. Mutation of klotho gene accelerates aging and shortens lifespan while overexpression of klotho gene extends lifespan in mice. We recently demonstrated that global mutation of klotho gene (+/-) increased blood pressure (BP). However, the underlying mechanism is not fully understood. The purpose of this experiment is to investigate if renal klotho plays a role in hypertension. Specifically, we assessed if kidney-specific deletion of klotho gene affects BP and renal function in male mice. Methods & Results: Briefly, kidney-specific Cre mice and klotho floxed mice were bred for generating kidney-specific klotho heterozygous (KspKL+/-) mice. Daily food and water intakes and urine output were monitored in wild type and KspKL+/- mice (16 weeks) using metabolic cages. BP was by direct cannulation of the carotid artery. Deletion of renal klotho significantly increased BP by 25 mmHg in mice without affecting the heart rate. Food and water intakes were not different between KspKL+/- and WT mice. Interestingly, 24-hr urine flow (UF) was significantly decreased in KspKL+/- mice (WT: 5.140± 0.3, KspKL+/-: 4.052±0.2,μL/min/100 gm body wt). The decrease in UF was also associated with a decrease in urinary sodium excretion (UNaV) in KspKL+/- mice compared to wild type (WT: 0.18± 0.01, KspKL+/-: 0.13±0.01, μmol/μL) without altering urinary potassium excretion. The cumulative sodium balance remained positive during the observation period with no significant difference between KspKL+/- and WT mice WT. Kidney-specific klotho deficiency did not affect the glomerular filtration rate (GFR). Conclusions: This study demonstrates for the first time that kidney klotho deficiency is sufficient to cause hypertension. Klotho deficiency-induced hypertension may be due to impaired Na excretion. Klotho may be a therapeutic target for kidney dysfunction and hypertension. An additional study is warranted to investigate if klotho regulates tubular ENaC and Na, K-ATP synthase.