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Kidney‐specific Conditional Knockout of Klotho Gene Impairs Natriuresis and causes hypertension by upregulating Epithelial Sodium Channel alpha
Author(s) -
Ali Quaisar,
Lin Yi,
Wang Shirley,
Chen Kai,
Chen Jianglei,
Sun Zhongjie
Publication year - 2017
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.31.1_supplement.722.3
Subject(s) - endocrinology , medicine , epithelial sodium channel , amiloride , klotho , natriuresis , kidney , blood pressure , endothelial dysfunction , renal function , chemistry , sodium , organic chemistry
Background and Purpose Excessive reabsorption of sodium by the kidney tubules contributes to renal dysfunction and high blood pressure. Deletion of Klotho leads to hypertension. The purpose of this study is to investigate if renal epithelial sodium channel (ENaC) contributes to klotho deficiency‐induced hypertension. Methods and Results We generated kidney‐specific conditional klotho null (KspKL −/− ) mice and found out that renal alpha subunit of ENaC is significantly upregulated compared to wild type (WT) mice. Blood pressure measured by telemetry demonstrated systolic hypertension and elevated pulse pressure suggesting vascular dysfunction in KspKL −/− . Pulse wave velocity, a marker of arterial stiffening was significantly increased in KspKL −/− mice. Amiloride, an ENaC inhibitor, completely prevented systolic hypertension and arterial stiffening in KspKL −/− mice. Ex vivo vascular relaxing responses to acetylcholine were diminished in mesenteric arteries in KspKL −/− group, indicating that klotho deficiency causes vascular endothelial dysfunction. Interestingly, treatment with amiloride abolished Klotho deficiency‐induced vascular endothelial dysfunction. We found that urinary sodium excretion (U Na V) was significantly impaired in KspKL −/− group. Na retention was also associated with a decrease in glomerular filtration rate (GFR), suggesting impaired renal function in KspKL −/− mice. Treatment with amiloride prevented sodium retention and improved GFR in KspKL −/− mice. Total renal nitric oxide bioavailabililty and eNOS activity were significantly decreased in KspKl −/− mice which was ameliorated by amiloride treatment. Histological and morphometric analysis showed glomerular and tubular damage in KspKL −/− , which was improved by amiloride treatment. Western blotting analysis demonstrated a significant decrease in the αγ subunits of ENaC in the kidney cortex following treatment with amiloride. Conclusion This study demonstrates for the first time that depletion of klotho causes impairment in Na‐excretion and hypertension by affecting ENaCα levels. ENaC may be a promising therapeutic target for klotho deficiency‐induced renal and vascular dysfunction and hypertension.