Format

Send to

Choose Destination
See comment in PubMed Commons below
Am J Physiol Renal Physiol. 2009 Dec;297(6):F1622-31. doi: 10.1152/ajprenal.00078.2009. Epub 2009 Sep 23.

Oxidative stress-induced JNK activation contributes to proinflammatory phenotype of aging diabetic mesangial cells.

Author information

1
Divison of Experimental Diabetes and Aging, Department of Geriatrics, Mount Sinai School of Medicine, New York, NY 10029, USA.

Abstract

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.

PMID:
19776174
PMCID:
PMC2801342
DOI:
10.1152/ajprenal.00078.2009
[Indexed for MEDLINE]
Free PMC Article
PubMed Commons home

PubMed Commons

0 comments
How to join PubMed Commons

    Supplemental Content

    Full text links

    Icon for HighWire Icon for PubMed Central
    Loading ...
    Support Center