PMID- 19776174
OWN - NLM
STAT- MEDLINE
DCOM- 20091228
LR  - 20211020
IS  - 1522-1466 (Electronic)
IS  - 0363-6127 (Print)
IS  - 1522-1466 (Linking)
VI  - 297
IP  - 6
DP  - 2009 Dec
TI  - Oxidative stress-induced JNK activation contributes to proinflammatory phenotype 
      of aging diabetic mesangial cells.
PG  - F1622-31
LID - 10.1152/ajprenal.00078.2009 [doi]
AB  - Chronic inflammation and increased oxidative stress (OS) play an important role 
      in diabetic nephropathy progression. Herein, we show that mesangial cells from 
      streptozotocin-induced aging diabetic mice, a model of progressive diabetic 
      nephropathy, exhibited increased OS and a proinflammatory phenotype characterized 
      by elevated chemokines and ICAM-1 expression. This phenotypic change was 
      consistent with the extensive inflammatory lesions present in aging diabetic 
      kidneys and was not found in mesangial cells from old and young controls or young 
      diabetic mice. Activation of the c-Jun NH(2)-terminal kinase (JNK) pathway was a 
      likely contributor to the proinflammatory phenotype of aging diabetic mesangial 
      cells since 1) phosphorylated JNK levels and JNK kinase activity were increased 
      in these cells, 2) suppression of JNK significantly decreased monocyte 
      chemoattractant protein-1 (MCP-1) production in these cells, and 3) activation of 
      JNK in normal mesangial cells induced inflammation. Elevated OS in aging diabetic 
      mesangial cells may be a cause of JNK activation and inflammation, because 
      antioxidant treatment decreased JNK phosphorylation and MCP-1 production. 
      Additionally, decreased expression of mitogen-activated protein kinase 
      phosphatase 5 (MKP5) may also contribute to increased JNK and inflammation in 
      aging diabetic mesangial cells since overexpression of MKP5 in these cells 
      normalized phosphorylated JNK levels and reversed the proinflammatory phenotype. 
      Moreover, knocking down of MKP5 expression in old control mesangial cells 
      resulted in JNK activation and MCP-1 production, a phenotype seen in aging 
      diabetic mesangial cells. Interestingly, MKP5 phosphatase activity was diminished 
      by free radicals in vitro. Thus, OS may induce inflammation in mesangial cells by 
      activating JNK through either a direct activation of JNK or indirectly by 
      suppression of MKP5 activity. Proinflammatory phenotype of mesangial cells may 
      contribute to chronic inflammatory lesions and disease progression of aging 
      diabetic mice.
FAU - Wu, Jin
AU  - Wu J
AD  - Divison of Experimental Diabetes and Aging, Department of Geriatrics, Mount Sinai 
      School of Medicine, New York, NY 10029, USA.
FAU - Mei, Changlin
AU  - Mei C
FAU - Vlassara, Helen
AU  - Vlassara H
FAU - Striker, Gary E
AU  - Striker GE
FAU - Zheng, Feng
AU  - Zheng F
LA  - eng
GR  - 5R01AG027628-03/AG/NIA NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20090923
PL  - United States
TA  - Am J Physiol Renal Physiol
JT  - American journal of physiology. Renal physiology
JID - 100901990
RN  - 0 (Ccl2 protein, mouse)
RN  - 0 (Chemokine CCL2)
RN  - 0 (Chemokine CXCL1)
RN  - 0 (Chemokine CXCL2)
RN  - 0 (Cxcl1 protein, mouse)
RN  - 0 (Cxcl2 protein, mouse)
RN  - 0 (RNA, Messenger)
RN  - EC 2.7.11.24 (JNK Mitogen-Activated Protein Kinases)
RN  - EC 3.1.3.16 (Dusp10 protein, mouse)
RN  - EC 3.1.3.48 (Dual-Specificity Phosphatases)
SB  - IM
MH  - Aging/metabolism
MH  - Animals
MH  - Cells, Cultured
MH  - *Cellular Senescence
MH  - Chemokine CCL2/biosynthesis/genetics
MH  - Chemokine CXCL1/genetics
MH  - Chemokine CXCL2/genetics
MH  - Diabetes Mellitus, Experimental/pathology/*physiopathology
MH  - Down-Regulation
MH  - Dual-Specificity Phosphatases/genetics/metabolism
MH  - Enzyme Activation
MH  - Female
MH  - Gene Expression
MH  - Glomerular Mesangium/metabolism/pathology/*physiopathology
MH  - In Vitro Techniques
MH  - Inflammation/*etiology/genetics
MH  - JNK Mitogen-Activated Protein Kinases/*metabolism
MH  - Kidney Glomerulus/metabolism
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - *Oxidative Stress
MH  - Phenotype
MH  - Phosphorylation
MH  - RNA, Messenger/metabolism
PMC - PMC2801342
EDAT- 2009/09/25 06:00
MHDA- 2009/12/29 06:00
PMCR- 2010/12/01
CRDT- 2009/09/25 06:00
PHST- 2009/09/25 06:00 [entrez]
PHST- 2009/09/25 06:00 [pubmed]
PHST- 2009/12/29 06:00 [medline]
PHST- 2010/12/01 00:00 [pmc-release]
AID - 00078.2009 [pii]
AID - F-00078-2009 [pii]
AID - 10.1152/ajprenal.00078.2009 [doi]
PST - ppublish
SO  - Am J Physiol Renal Physiol. 2009 Dec;297(6):F1622-31. doi: 
      10.1152/ajprenal.00078.2009. Epub 2009 Sep 23.