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- Title
Modulation of renal epithelial barrier function by mitogen-activated protein kinases (MAPKs): mechanism of cyclosporine A-induced increase in transepithelial resistance.
- Authors
Kiely, Breda; Feldman, Gemma; Ryan, Michael P.
- Abstract
<bold>Background: </bold>Cyclosporine A (CsA) has been shown to increase transepithelial resistance in Madin-Darby canine kidney (MDCK) cells, and the mechanism may involve altered phosphorylation of junctional proteins. In this study, we examine the effect of the extracellular signal-regulated protein kinase (ERK) 1/2 and p38 mitogen-activated protein kinase (MAPK) pathways on the basal transepithelial resistance (TER) and on the CsA-induced increase in TER across MDCK monolayers. Here we present evidence that CsA may be mediating some of its effects through activation of the ERK 1/2 MAPK pathway.<bold>Methods: </bold>MDCK cells were treated with CsA (4.2 micromol/L) and paracellular permeability was assessed by measuring TER. The role of the ERK 1/2 and the p38 MAPK pathways in modulating TER was investigated using the inhibitors PD98059 and U0126 for ERK 1/2 and SB203580 for p38. ERK 1/2 and p38 phosphorylation/activation was also examined by Western blot analysis.<bold>Results: </bold>CsA (4.2 micromol/L) increased the TER of MDCK monolayers. The ERK 1/2 inhibitor PD98059 decreased basal TER and also ameliorated the CsA-induced increase in TER. Similar results were found with the U0126 inhibitor of ERK 1/2. The p38 inhibitor SB203580 had no effect on the basal TER of the monolayers, however, SB203580 significantly augmented the CsA-induced increase in TER. CsA was shown to significantly activate ERK 1/2 and this activation by CsA was prevented by PD98059. Inhibition of the p38 pathway by SB203580 also resulted in activation of ERK 1/2 and this activation of ERK 1/2 was further enhanced by CsA. No effect of CsA or the inhibitors PD98059 or SB203580 on p38 phosphorylation was detected.<bold>Conclusion: </bold>The results presented here suggest that activation of the ERK 1/2 MAPK cascade is important in the regulation of the paracellular permeability in MDCK cells. Activation of this pathway appears to be pivotal to the CsA-induced increase in TER.
- Subjects
PROTEIN kinases; KIDNEYS; EPITHELIAL cells; ANIMAL experimentation; BIOLOGICAL transport; CELL lines; CELLULAR signal transduction; COMPARATIVE studies; CYCLOSPORINE; ENZYME inhibitors; FLAVONOIDS; IMIDAZOLES; IMMUNOSUPPRESSIVE agents; BIOELECTRIC impedance; RESEARCH methodology; MEDICAL cooperation; PHOSPHORYLATION; PYRIDINE; RESEARCH; TRANSFERASES; EVALUATION research; PHARMACODYNAMICS
- Publication
Kidney International, 2003, Vol 63, Issue 3, p908
- ISSN
0085-2538
- Publication type
journal article
- DOI
10.1046/j.1523-1755.2003.00804.x