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Conditional knock‐down of Kidney‐specific Klotho Gene Impairs Sodium Reabsorption by Downregulating Epithelial Sodium Channel Expression
Author(s) -
Ali Quaisar,
Lin Yi,
Wang Xiuqing,
Sun Zhongjie
Publication year - 2016
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.30.1_supplement.967.31
Subject(s) - klotho , epithelial sodium channel , endocrinology , medicine , reabsorption , kidney , sodium , chemistry , excretion , conditional gene knockout , renal sodium reabsorption , natriuresis , renal physiology , biology , biochemistry , gene , organic chemistry , phenotype
Background & Purpose Aging is associated with an increased risk of abnormal sodium metabolism. The levels of Klotho, an anti‐senescence gene recedes with age. The Na‐transporters in the distal tubules finely regulate sodium re‐absorption. Klotho is primarily expressed in the renal distal tubules. However it is not known if klotho directly regulates sodium excretion. The purpose of this experiment is to investigate if conditional knockout of renal klotho affects tubular function. Methods & Results Briefly, kidney specific cre and klotho floxed mice were bred to generate kidney‐specific Cre‐loxP mice. Daily food and water intakes and urine output were monitored in Klotho floxed (control) and KspKL−/− mice for 12 days using metabolic cages. Food and water intakes, urine flow (UF), urinary sodium (U Na V), sodium balance (Na‐balance) and potassium excretion (U k V) were not different between KspKL−/− and control mice either during the baseline or five days of tamoxifen injection. Daily Injection of tamoxifen for 5 days efficiently knocked down kidney klotho (KspKL−/−). Interestingly, conditional deletion of renal klotho caused significant increases in UF, U Na V, and U k V within 3 days. Hematocrit, plasma and blood volume also significantly decreased during this period, suggesting volume depletion. Western blotting analysis showed a significant decrease in the expression of epithelial Na channel alpha (ENaCα) in kidney cortex while expression of ENaC β or ENaC γ remains unchanged. Conclusions This study demonstrates that depletion of klotho causes impairment in Na reabsorption, probably via suppressing ENaCα expression. Support or Funding Information NIH R01 HL118558, DK093403 HL105302 and HL102074