Cyclosporin A and tacrolimus induce renal Erk1/2 pathway via ROS-induced and metalloproteinase-dependent EGF-receptor signaling

被引：35

作者：

Akool, El-Sayed ^{[1
]}

Gauer, Stefan ^{[2
]}

Osman, Bashier ^{[1
]}

Doller, Anke ^{[1
]}

Schulz, Sebastian ^{[1
]}

Geiger, Helmut ^{[2
]}

Pfeilschifter, Josef ^{[1
]}

Eberhardt, Wolfgang ^{[1
]}

机构：

[1] Klinikum Johann Wolfgang Goethe Univ, Pharmazentrum Frankfurt ZAFES, D-60590 Frankfurt, Germany

[2] Klinikum Johann Wolfgang Goethe Univ, Zentrum Inneren Med, Funkt Bereich Nephrol, D-60590 Frankfurt, Germany

来源：

BIOCHEMICAL PHARMACOLOGY | 2012年 / 83卷 / 02期

关键词：

Calcineurin inhibitor; Heparin binding-epidermal growth factor; Metalloproteinases; Reactive oxygen species; Extracellular-regulated kinase; EPIDERMAL-GROWTH-FACTOR; MESANGIAL CELL-PROLIFERATION; PROTEIN-COUPLED RECEPTORS; TGF-BETA; HB-EGF; CALCINEURIN INHIBITORS; MOLECULAR-MECHANISMS; MATRIX EXPANSION; OXIDATIVE STRESS; CROSS-TALK;

D O I：

10.1016/j.bcp.2011.11.001

中图分类号：

R9 [药学];

学科分类号：

100702 [药剂学];

摘要：

We previously demonstrated that the widely used immunosuppressive drugs cyclosporin A (CsA) and tacrolimus (FK506), independent of immunophilin binding, can activate profibrogenic transforming growth factor beta (TGF beta)/Smad signaling cascades in rat renal mesangial cells (MC). Here we report that both peptidyl-prolyl cis/trans isomerase (PPlase) inhibitors activate the extracellular-signaling regulated kinase (ERK) a member of the mitogen activated protein kinase (MAPK) and induce a rapid and transient increase in ERR phosphorylation. The MEK inhibitor U0126, the reactive oxygen species (ROS) scavenger N-acetyl-cysteine (NAC), a cell-permeant superoxide dismutase (SOD) and stigmatellin, an inhibitor of mitochondrial cytochrome bc1 complex strongly attenuated the increase in ERK1/2 phosphorylation triggered by PPlase inhibitors. Moreover, neutralizing antibodies against heparin binding-epidermal growth factor (HB-EGF), and inhibition of the EGF receptor by either small interfering (si)RNA or AG1478, demonstrate that ERR activation by both PPlase inhibitors is mediated via HB-EGF-induced EGF receptor (EGFR) tyrosine kinase activation. The strong inhibitory effects achieved by GM6001 and TAPI-2 furthermore implicate the involvement of a desintegrin and metalloproteinase 17 (ADAM17). Concomitantly, the PPIase inhibitor-induced ADAM17 secretase activity was significantly reduced by SOD and stigmatellin thus suggesting that mitochondrial ROS play a primary role in PPlase inhibitor-induced and ADAM17-mediated HB-EGF shedding. Functionally, both immunosuppressants caused a strong increase in MC proliferation which was similarly impeded when cells were treated in the presence of NAC. TAPI-2 or AG1478, respectively. Our data suggest that CsA and FK506, via ROS-dependent and ADAM17-catalyzed HB-EGF shedding induce the mitogenic ERK1/2 signaling cascade in renal MC. (C) 2011 Elsevier Inc. All rights reserved.

引用

页码：286 / 295

页数：10

共 52 条

[1]

Molecular mechanisms of TGFβ receptor-triggered signaling cascades rapidly induced by the calcineurin inhibitors cyclosporin A and FK506 [J].