期刊
BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE
卷 1865, 期 7, 页码 1915-1924出版社
ELSEVIER SCIENCE BV
DOI: 10.1016/j.bbadis.2018.08.027
关键词
Cyclosporine A; ABCA1; Aging; PIP2; ENaC
资金
- Department of Health and Human Services (National Institutes of Health) [R01-DK100582]
- Key Project of Chinese National Program for Fundamental Research and Development (973 Program) [2014CB542401]
- National Natural Science Foundation of China [81670381, 81320108002, 91639202, 81600224]
- Nn10 program of Harbin Medical University Cancer Hospital
We have previously shown that blockade of ATP-binding cassette transporter A1 (ABCA1) with cyclosporine A (CsA) stimulates the epithelial sodium channel (ENaC) in cultured distal nephron cells. Here we show that CsA elevated systolic blood pressure in both wild-type and apolipoprotein E (ApoE) knockout (KO) mice to a similar level. The elevated systolic blood pressure was completely reversed by inhibition of cholesterol (Cho) synthesis with lovastatin. Inside-out patch-clamp data show that intracellular Cho stimulated ENaC in cultured distal nephron cells by interacting with phosphatidylinositol-4,5-bisphosphate (PIP2), an ENaC activator. Confocal microscopy data show that both alpha-ENaC and PIP2 were localized in microvilli via a Cho-dependent mechanism. Deletion of membrane Cho reduced the levels of gamma-ENaC in the apical membrane. Reduced ABCA1 expression and elevated intracellular Cho were observed in old mice, compared to young mice. In parallel, cell-attached patch-clamp data from the split-open cortical collecting ducts (CCD) show that ENaC activity was significantly increased in old mice. These data suggest that elevation of intracellular Cho due to blockade of ABCA1 stimulates ENaC, which may contribute to CsA-induced hypertension. This study also implies that reduced ABCA1 expression may mediate age-related hypertension by increasing ENaC activity via elevation of intracellular Cho.
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