Intracellular cholesterol stimulates ENaC by interacting with phosphatidylinositol‑4,5‑bisphosphate and mediates cyclosporine A-induced hypertension
| Autor: | Yu-Jia Zhai, Qiang Yue, Valerie Linck, Shipeng Wei, Clintoria R. Williams, Bin-Lin Song, Chang Song, Li Zou, Shuai Zhang, Zhi-Ren Zhang, Ming-Ming Wu, He-Ping Ma |
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| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Apolipoprotein E Epithelial sodium channel medicine.medical_specialty Xenopus Blood Pressure Cell Line Mice 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Phosphatidylinositol Phosphates Internal medicine medicine Animals Enzyme Inhibitors Epithelial Sodium Channels Molecular Biology biology urogenital system Activator (genetics) Chemistry respiratory system Apical membrane Mice Inbred C57BL Cholesterol 030104 developmental biology Endocrinology Phosphatidylinositol 4 5-bisphosphate 030220 oncology & carcinogenesis ABCA1 Hypertension Cyclosporine biology.protein Molecular Medicine lipids (amino acids peptides and proteins) Lovastatin Intracellular ATP Binding Cassette Transporter 1 medicine.drug |
| Zdroj: | Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease. 1865:1915-1924 |
| ISSN: | 0925-4439 |
| DOI: | 10.1016/j.bbadis.2018.08.027 |
| Popis: | 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 α‑ENaC and PIP2 were localized in microvilli via a Cho-dependent mechanism. Deletion of membrane Cho reduced the levels of γ‑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. |
| Databáze: | OpenAIRE |
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