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Cyclosporin A Induces Hypertension via a Cholesterol‐ and ENaC‐Dependent Mechanism
Author(s) -
Linck Valerie,
Zou Li,
Zhai YuJia,
Eaton Douglas C.,
Ma HePing
Publication year - 2018
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.2018.32.1_supplement.750.22
Subject(s) - epithelial sodium channel , amiloride , lovastatin , endocrinology , blood pressure , intracellular , medicine , chemistry , chinese hamster ovary cell , apical membrane , pharmacology , cholesterol , sodium , epithelium , receptor , biochemistry , pathology , organic chemistry
Hypertension related to the use of immunosuppressive drugs, particularly cyclosporin A (CsA), presents one of the major problems in the management of transplant recipients. Our recent studies suggest a hypothesis that CsA may cause hypertension by stimulating the renal epithelial sodium channel (ENaC) via a pathway associated with elevated intracellular cholesterol (Cho). To further determine the mechanism, we performed confocal microscopy and patch‐clamp experiments using cultured cortical collecting duct (CCD) principal cells and measured the blood pressure in mice. Confocal data show that CsA and Cho increased both the length of microvilli of CCD cells where ENaC is located and the levels of phosphatidylinositol‐4,5‐bisphosphate (PIP 2 ) in microvilli. Conversely, inhibition of Cho synthesis with lovastatin decreased the levels of PIP 2 , a well‐known ENaC activator. Patch‐clamp data shows that Cho increased ENaC activity in a PIP 2 ‐dependent manner. Interestingly, CsA elevated the blood pressure in mice and the elevation was abolished by either inhibition of Cho synthesis with lovastatin or blockade of ENaC with amiloride. These results suggest that CsA increases the blood pressure of mice by stimulating ENaC via a pathway associated with the elevation of intracellular Cho and PIP 2 in the principal cells of CCD. However, it remains to be determined whether statins or amiloride can be used for the treatment of CsA‐induced hypertension. Support or Funding Information (Supported by NIH R01DK100582 to H.M.) This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .