Journal
JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY
Volume 26, Issue 7, Pages 1576-1587Publisher
AMER SOC NEPHROLOGY
DOI: 10.1681/ASN.2013121326
Keywords
K channels; signaling; tubule cells; statins; cyclosporin
Categories
Funding
- Department of Health and Human Services, National Institutes of Health [5R37-DK037963, 5R01-DK067110]
- National Natural Science Foundation of China [81130028, 31210103913]
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We recently showed that lovastatin attenuates cyclosporin A (CsA)-induced damage of cortical collecting duct (CCD) principal cells by reducing intracellular cholesterol. Previous studies showed that, in cell expression models or artificial membranes, exogenous cholesterol directly inhibits inward rectifier potassium channels, including Kir1.1 (Kcnj1; the gene locus for renal outer medullary K+ [ROMK1] channels). Therefore, we hypothesized that lovastatin might stimulate ROMK1 by reducing cholesterol in CCD cells. Western blots showed that mpkCCD(c14) cells express ROMK1 channels with molecular masses that approximate the molecular masses of ROMK1 in renal tubules detected before and after treatment with DTT. Confocal microscopy showed that ROMK1 channels were not in the microvilli, where cholesterol-rich lipid rafts are located, but rather, the planar regions of the apical membrane of mpkCCD(c14) cells. Furthermore, phosphatidylinositol-4,5-bisphosphate [PI(4,5)P-2], an activator of ROMK channels, was detected mainly in the microvilli under resting conditions along with the kinase responsible for PI(4,5)P-2 synthesis, phosphatidylinositol-4-phosphate 5-kinase, type I [PI(4)P5K I ], which may explain the low basal open probability and increased sensitivity to tetraethylammonium observed here for this channel. Notably, lovastatin induced PI(4)P5K I diffusion into planar regions and elevated PI(4,5)P-2 and ROMK1 open probability in these regions through a cholesterol-associated mechanism. However, exogenous cholesterol alone did not induce these effects. These results suggest that lovastatin stimulates ROMK1 channels, at least in part, by inducing PI(4,5)P-2 synthesis in planar regions of the renal CCD cell apical membrane, suggesting that lovastatin could reduce cyclosporin-induced nephropathy and associated hyperkalemia.
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