PMID- 22100870
OWN - NLM
STAT- MEDLINE
DCOM- 20120207
LR  - 20181201
IS  - 1873-2968 (Electronic)
IS  - 0006-2952 (Linking)
VI  - 83
IP  - 2
DP  - 2012 Jan 15
TI  - Cyclosporin A and tacrolimus induce renal Erk1/2 pathway via ROS-induced and 
      metalloproteinase-dependent EGF-receptor signaling.
PG  - 286-95
LID - 10.1016/j.bcp.2011.11.001 [doi]
AB  - 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 (TGFbeta)/Smad signaling 
      cascades in rat renal mesangial cells (MC). Here we report that both 
      peptidyl-prolyl cis/trans isomerase (PPIase) 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 ERK 
      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 PPIase 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 ERK activation by both PPIase 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 PPIase 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.
CI  - Copyright (c) 2011 Elsevier Inc. All rights reserved.
FAU - Akool, El-Sayed
AU  - Akool el-S
AD  - pharmazentrum frankfurt/ZAFES, Klinikum der Johann Wolfgang Goethe-Universitat, 
      Theodor-Stern-Kai 7, D-60590 Frankfurt am Main, Germany.
FAU - Gauer, Stefan
AU  - Gauer S
FAU - Osman, Bashier
AU  - Osman B
FAU - Doller, Anke
AU  - Doller A
FAU - Schulz, Sebastian
AU  - Schulz S
FAU - Geiger, Helmut
AU  - Geiger H
FAU - Pfeilschifter, Josef
AU  - Pfeilschifter J
FAU - Eberhardt, Wolfgang
AU  - Eberhardt W
LA  - eng
PT  - Comparative Study
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20111109
PL  - England
TA  - Biochem Pharmacol
JT  - Biochemical pharmacology
JID - 0101032
RN  - 0 (Reactive Oxygen Species)
RN  - 83HN0GTJ6D (Cyclosporine)
RN  - EC 2.7.10.1 (ErbB Receptors)
RN  - EC 3.4.- (Metalloproteases)
RN  - EC 3.4.24.- (ADAM Proteins)
RN  - EC 3.4.24.86 (ADAM17 Protein)
RN  - EC 3.4.24.86 (ADAM17 protein, human)
RN  - EC 3.4.24.86 (Adam17 protein, rat)
RN  - WM0HAQ4WNM (Tacrolimus)
SB  - IM
MH  - ADAM Proteins/metabolism
MH  - ADAM17 Protein
MH  - Animals
MH  - Cells, Cultured
MH  - Cyclosporine/*pharmacology
MH  - Enzyme Induction/drug effects/physiology
MH  - ErbB Receptors/*physiology
MH  - Humans
MH  - MAP Kinase Signaling System/drug effects/*physiology
MH  - Mesangial Cells/drug effects/enzymology/metabolism
MH  - Metalloproteases/*physiology
MH  - Rats
MH  - Reactive Oxygen Species/*metabolism
MH  - Tacrolimus/*pharmacology
EDAT- 2011/11/22 06:00
MHDA- 2012/02/09 06:00
CRDT- 2011/11/22 06:00
PHST- 2011/08/18 00:00 [received]
PHST- 2011/11/01 00:00 [revised]
PHST- 2011/11/02 00:00 [accepted]
PHST- 2011/11/22 06:00 [entrez]
PHST- 2011/11/22 06:00 [pubmed]
PHST- 2012/02/09 06:00 [medline]
AID - S0006-2952(11)00818-5 [pii]
AID - 10.1016/j.bcp.2011.11.001 [doi]
PST - ppublish
SO  - Biochem Pharmacol. 2012 Jan 15;83(2):286-95. doi: 10.1016/j.bcp.2011.11.001. Epub 
      2011 Nov 9.