Modulation of renal epithelial barrier function by mitogen-activated protein kinases (MAPKs): Mechanism of cyclosporine A–induced increase in transepithelial resistance

Kiely, Breda; Feldman, Gemma; Ryan, Michael P.

doi:10.1046/j.1523-1755.2003.00804.x

Cited by 42 publications

(37 citation statements)

References 28 publications

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“…This is in agreement with data from Horvath et al (2002) showing impaired cell-cell contact after noncytotoxic doses of OTA. Additionally, recent data indicate opposite influence of ERK1/2 and p38 on renal paracellular permeability (Kiely et al, 2003), which is in agreement with the above-described activation of MAPKs by OTA. Inhibition of ERK1/2 together with 100 nM OTA did not further increase epithelial leakage, whereas it dramatically decreased total cell number.…”

Section: Discussionsupporting

confidence: 89%

Proximal Tubular Toxicity of Ochratoxin A Is Amplified by Simultaneous Inhibition of the Extracellular Signal-Regulated Kinases 1/2

Sauvant

Holzinger²,

Gekle³

2004

J Pharmacol Exp Ther

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Ochratoxin A (OTA) is a mycotoxin involved in the development of chronic nephropathies and a known carcinogen. As we have shown previously, OTA activates mitogen-activated protein kinases [extracellular signal-regulated kinase 1 and 2 (ERK1/2), c-jun amino-terminal kinase (JNK), and extracellular-regulated protein kinase 38 (p38)] in proximal tubular cells (opossum kidney and normal rat kidney epithelial). ERK1/2, JNK, or p38 are thought to mediate opposite action on apoptosis, fibrosis, and inflammation. As we have already shown, OTA activates the latter processes. Here, we investigated the effect of OTA in the absence or presence of the ERK1/2 inhibitor U0126 [1,4-diamino-2,3-dicyano-1,4bis(2-aminophenylthio)-butadiene] to test whether OTA then will exert increased toxicity. In the presence of ERK1/2 inhibition, OTA decreased cell number and protein to a significantly larger extent compared with OTA alone. The same was true for epithelial tightness, apoptosis (caspase-3 activity), and necrosis (lactate dehydrogenase release). Furthermore, simultaneous inhibition of ERK1/2 amplified the effect of OTA on markers of inflammation (nuclear factor of the -enhancer in B cells activity), fibrosis (collagen secretion), and epithelial mesenchymal transition (␣ smooth muscle actin). OTA induces phenomena typical for chronic interstitial nephropathy and activates ERK1/2, JNK, and p38 in proximal tubular cells. Inhibition of ERK1/2 aggravates the effects of OTA or even induces toxicity at normally nontoxic concentrations. This is highly likely due to activation of JNK and p38. Our data indicate a new mechanistic explanation for the toxic actions induced by OTA, and they are notable with respect to a possible coexposition of the kidney to OTA and naturally occurring ERK1/2 inhibitors. Finally, our data give rise to an attractive hypothesis on the coincidence of increased OTA exposition and urinary tract tumors in humans.

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Section: Discussionsupporting

confidence: 89%

Proximal Tubular Toxicity of Ochratoxin A Is Amplified by Simultaneous Inhibition of the Extracellular Signal-Regulated Kinases 1/2

Sauvant

Holzinger²,

Gekle³

2004

J Pharmacol Exp Ther

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“…Inhibition of this pathway significantly attenuated the TGF-␤1-induced increase in TER after 48 and 72 h of treatment. However, we observed no significant change in the CsA-induced effect when we inhibited the p38 MAPK pathway (6), which signifies that TGF-␤1 may also be mediating its effect on barrier function via the p38 MAPK pathway, but this particular signaling route is not triggered by exposure to CsA.…”

Section: Discussioncontrasting

confidence: 55%

“…MDCK II cells (22) that were obtained from the American Type Culture Collection (Middlesex, UK) were cultured as before (6). CsA was prepared as a stock solution (4.2 mM) in 100% EtOH.…”

Section: Cell Culture and Treatmentmentioning

confidence: 99%

“…Whole-cell extracts were prepared as before (6). Briefly, after appropriate treatment, cells were scraped into radioimmunoprecipitation assay buffer (20 mM Tris [pH 7.4], 50 mM NaCl, 5 mM EDTA, 50 mM NaF, 20 mM sodium pyrophosphate, 1 mM orthovanadate, 1% [vol/vol] Triton X-100, 0.1% [wt/vol] SDS, 1 mM PMSF, 1 g/ml pepstatin, 0.5 g/ml leupeptin, and 0.5 g/ml aprotinin).…”

Section: Preparation Of Whole Extracts For Sds-pagementioning

confidence: 99%

“…Tight junctions are subject to physiologic and pharmacologic regulation/modulation. We previously showed that CsA alters the barrier function of renal epithelial cells, and the mechanism may involve activation of the extracellular signal-regulated kinase 1/2 (ERK1/2) mitogen-activated protein kinase (MAPK) pathway (6).…”

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confidence: 99%

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Role for TGF-β in Cyclosporine-Induced Modulation of Renal Epithelial Barrier Function

Feldman

Kiely²,

Martín³

et al. 2007

Journal of the American Society of Nephrology

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Down-regulation of TRPM6-mediated magnesium influx by cyclosporin A

Ikari

Okude

Sawada

et al. 2007

Naunyn-Schmied Arch Pharmacol

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Transient receptor potential melastatin 6 (TRPM6) is distributed along the apical membrane of the renal tubular cells and is involved in the reabsorption of magnesium. In this study, we show that TRPM6 expression is suppressed by cyclosporin A (CsA) via a down-regulation of c-Fos expression. TRPM6 was expressed in NRK-52E, but not in Madin-Darby canine kidney cells. In contrast, its homolog, TRPM7, was equally expressed in both cells. In NRK-52E cells, CsA dose-dependently decreased TRPM6 expression without affecting TRPM7 expression. Magnesium load measurements revealed the rise in the intracellular free magnesium concentration ([Mg2+]i) to be inhibited by CsA. The transfection of TRPM6 siRNA decreased TRPM6 expression without affecting TRPM7 expression and inhibited the elevation of [Mg2+]i. CsA did not affect the intracellular distribution of nuclear factor of activated T cells (NFATc). Furthermore, TRPM6 expression was not changed by a NFATc inhibitor. Next, we examined the effect of CsA on the transcription factors c-Fos and c-Jun. CsA decreased c-Fos expression without affecting c-Jun expression. The transfection of c-Fos siRNA suppressed TRPM6 expression without affecting TRPM7 expression. We suggest that CsA decreases TRPM6 expression mediated by inhibition of c-Fos transcription, resulting in a decrease of renal Mg2+ reabsorption.

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Modulation of renal epithelial barrier function by mitogen-activated protein kinases (MAPKs): Mechanism of cyclosporine A–induced increase in transepithelial resistance

Abstract: 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.

Cited by 42 publications

References 28 publications

Proximal Tubular Toxicity of Ochratoxin A Is Amplified by Simultaneous Inhibition of the Extracellular Signal-Regulated Kinases 1/2

Proximal Tubular Toxicity of Ochratoxin A Is Amplified by Simultaneous Inhibition of the Extracellular Signal-Regulated Kinases 1/2

Role for TGF-β in Cyclosporine-Induced Modulation of Renal Epithelial Barrier Function

Down-regulation of TRPM6-mediated magnesium influx by cyclosporin A

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