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1 Stimulates MCP-1 Expression in Mesangial Cells via a PDE4-Dependent Process
1 Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA
2 Nephrology, Mayo Clinic, Rochester, MN, USA
3 Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA; Nephrology, Mayo Clinic, Rochester, MN, USA
* To whom correspondence should be addressed. E-mail: grande.joseph{at}mayo.edu.
MCP-1 and TGF-
1 are critical mediators of renal injury by promoting excessive inflammation and extracellular matrix deposition, thereby contributing to progressive renal disease. In renal disease models, MCP-1 stimulates the production of TGF-1. However, a potential role of TGF-1 in regulation of MCP-1 production by mesangial cells has not been previously evaluated. The objectives of this study were to define the role of TGF-1 in regulation of MCP-1 expression in cultured mesangial cells (MC) and to define mechanisms through which rolipram, a phosphodiesterase-4 (PDE4) inhibitor with anti-inflammatory properties, alters MCP-1 expression. TGF-1 induced MCP-1 in a time- and dose-dependent manner without increasing transcription of the MCP-1 gene. TGF-1-mediated induction of MCP-1 occurred without activation of the NF-
B pathway. Rolipram blocked TGF-1-stimulated MCP-1 expression via a protein kinase A-dependent process, at least in part, by decreasing MCP-1 message stability. Rolipram exerted no effect on activation of the Smad pathway by TGF-1. TGF-1-mediated induction of MCP-1 required activation of ERK and p38, both of which were suppressed by a PDE4 inhibitor. TGF-1 stimulated ROS generation by MC, and rolipram inhibited ROS generation in TGF-1-stimulated MC; additionally, both rolipram and ROS scavengers blocked TGF-1-stimulated MCP-1 expression. We conclude that TGF-1 stimulates MCP-1 expression through pathway(s) involving activation of ERK, p38, and ROS generation. Positive crosstalk between TGF-1 and MCP-1 signaling in MC may underlie the development of progressive renal disease. Rolipram, by preventing TGF-1-stimulated MCP-1 production, may offer a therapeutic approach in retarding the progression of renal disease.
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