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Lovastatin attenuates cyclosporine inhibition of potassium channels in cortical collecting duct cells
Author(s) -
Ma HePing
Publication year - 2013
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.27.1_supplement.913.32
Subject(s) - lovastatin , apical membrane , potassium channel , chemistry , potassium channel blocker , tight junction , patch clamp , epithelial polarity , biophysics , microbiology and biotechnology , bk channel , membrane , biochemistry , biology , cholesterol , receptor
Statins may benefit patients receiving cyclosporine A (CsA) treatment after organ transplantation. However, there is little in vitro data to support the use of statins to reduce the harmful effects of CsA such as hyperkalemia. Our cell‐attached patch‐clamp data showed that CsA inhibited an inwardly rectifying potassium channel in the apical membrane of mouse cortical collecting duct principal cells (mpkCCD c14 line) and that lovastatin attenuated the inhibition. Phosphatidylinositol‐3,4,5‐trisphosphate (PIP 3 ) is a lipid which is known to stimulate inward rectifier potassium channels. Under normal conditions, PIP 3 is synthesized in the basolateral membrane and can pass tight junctions to diffuse to the apical membrane. It appears that this diffusion is blocked by CsA because confocal microscopy showed that CsA reduced PIP 3 in the apical membrane, but increased PIP 3 in the basolateral membrane. Lovastatin reversed the effects of CsA on PIP 3 levels. We also found that CsA increased, but lovastatin decreased, the transepithelial resistance by altering the levels of zonula occludens‐1 (ZO‐1) and cholesterol in tight junctions. Using scanning ion conductance microscopy, we showed that the apical membrane of mpkCCD c14 cells contains cellular protrusions in the area near tight junctions. CsA significantly increased the height of the protrusions. In contrast, lovastatin eliminated the protrusions and even caused a modest depression between the cells. These data suggest that lovastatin can abolish CsA inhibition of potassium channels in the apical membrane of CCD cells by altering the lateral diffusion of PIP 3 which possibly controlled by both ZO‐1 and cholesterol levels in tight junctions. The present study provides one molecular mechanism for the previous suggestion that statins benefit CsA treatment of patients with organ transplantation.