PMID- 20490773
OWN - NLM
STAT- MEDLINE
DCOM- 20100914
LR  - 20211020
IS  - 1867-0687 (Electronic)
VI  - 6
IP  - 2
DP  - 2010 May
TI  - SP600125, an inhibitor of c-Jun NH2-terminal kinase, blocks expression of 
      angiotensin II-induced monocyte chemoattractant protein-1 in human mesangial 
      cells.
PG  - 169-76
LID - 10.1007/s12519-010-0033-2 [doi]
AB  - BACKGROUND: We investigated the role of c-Jun NH2-terminal kinase (JNK), a member 
      of the mitogen-activated protein kinase family, in the expression of angiotensin 
      II (Ang II)-induced monocyte chemoattractant protein-1 (MCP-1) and transforming 
      growth factor-1 (TGF-1), and in the production of fibronectin (FN), by human 
      mesangial cells (HMCs). METHODS: JNK activation in cultured human mesangial cells 
      was determined by Western blotting with an antibody against the phosphorylated 
      Ser63 residue of c-Jun. Binding of the activator protein (AP-1) to the MCP-1 AP-1 
      motif was detected via the electrophoretic mobility shift assay (EMSA). The 
      transient luciferase reporter was used to examine MCP-1 promoter activity; an 
      RNase protection assay and ELISA were used respectively to detect the expression 
      of MCP-1 mRNA and production of MCP-1, TGF-beta and FN. RESULTS: Anthra (1,9-cd) 
      pyrazol-6(2H)-one (SP600125), a pharmacological inhibitor of JNK, almost 
      completely abolished Ang II-induced Ser63 phosphorylation of c-Jun at 
      concentrations of 5-20 micromol/L: JNK activity was reduced by 75% with 10 
      micromol/L SP600125, and by 90% with 20 micromol/L. Ang II increased AP-1 binding 
      to the MCP-1 AP-1 motif in a time-dependent manner, as detected by EMSA, while 
      SP600125 effectively blocked this increased AP-1 binding in a 
      concentration-dependent manner. Treatment with 100 nmol/L Ang II led to a steady 
      increase in MCP-1 mRNA expression, and to an enhanced production of MCP-1, 
      TGF-beta and FN. These effects were blocked by SP60025 in a dose-dependent 
      manner. SP600125 also reduced MCP-1 mRNA stability: the halflife of MCP-1 mRNA 
      was approximately 5 hours in cells treated with Ang II only, but was reduced to 2 
      hours when treated with a combination of Ang II and SP600125. CONCLUSIONS: These 
      results show that the JNK/AP-1 pathway is involved in the expression of MCP-1 and 
      TGF-beta, and in extracellular matrix production. JNK is an important therapeutic 
      target for glomerulonephritis and glomerulosclerosis.
FAU - Ding, Gui-Xia
AU  - Ding GX
AD  - Department of Nephrology, Nanjing Children's Hospital, Affiliated to Nanjing 
      Medical University, Nanjing, Jiangsu, China.
FAU - Zhang, Ai-Hua
AU  - Zhang AH
FAU - Huang, Song-Ming
AU  - Huang SM
FAU - Pan, Xiao-Qin
AU  - Pan XQ
FAU - Chen, Rong-Hua
AU  - Chen RH
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20100521
PL  - Switzerland
TA  - World J Pediatr
JT  - World journal of pediatrics : WJP
JID - 101278599
RN  - 0 (Anthracenes)
RN  - 0 (Chemokine CCL2)
RN  - 0 (Fibronectins)
RN  - 0 (RNA, Messenger)
RN  - 0 (Transcription Factor AP-1)
RN  - 0 (Transforming Growth Factor beta)
RN  - 11128-99-7 (Angiotensin II)
RN  - 1TW30Y2766 (pyrazolanthrone)
RN  - EC 2.7.11.24 (JNK Mitogen-Activated Protein Kinases)
SB  - IM
MH  - Angiotensin II/*pharmacology
MH  - Anthracenes/*pharmacology
MH  - Cells, Cultured
MH  - Chemokine CCL2/genetics/*metabolism
MH  - Fibronectins/metabolism
MH  - Half-Life
MH  - Humans
MH  - JNK Mitogen-Activated Protein Kinases/antagonists & inhibitors
MH  - Mesangial Cells/*metabolism
MH  - RNA, Messenger/metabolism
MH  - Signal Transduction/drug effects
MH  - Transcription Factor AP-1/metabolism
MH  - Transforming Growth Factor beta/metabolism
EDAT- 2010/05/22 06:00
MHDA- 2010/09/15 06:00
CRDT- 2010/05/22 06:00
PHST- 2009/05/15 00:00 [received]
PHST- 2009/08/25 00:00 [accepted]
PHST- 2010/05/22 06:00 [entrez]
PHST- 2010/05/22 06:00 [pubmed]
PHST- 2010/09/15 06:00 [medline]
AID - 10.1007/s12519-010-0033-2 [doi]
PST - ppublish
SO  - World J Pediatr. 2010 May;6(2):169-76. doi: 10.1007/s12519-010-0033-2. Epub 2010 
      May 21.