Submitted on October 27, 2008
Revised on April 10, 2009
Accepted on April 28, 2009
Monocyte chemoattractant protein-1/CCR2 loop, inducible by TGF-
, increases podocyte motility and albumin permeability
Eun Young Lee1, Choon Hee Chung2, Charbel C. Khoury3, Tet Kin Yeo3, Petr E. Pyagay3, Amy Wang3, and Sheldon Chen3*
1 Soon Chun Hyang University
2 Yonsei University
3 Northwestern University
* To whom correspondence should be addressed. E-mail: sheldon-chen{at}northwestern.edu.
The role of monocyte chemoattractant protein-1 (MCP-1) in diabetic nephropathy is typically viewed through the lens of inflammation, but MCP-1 might exert non-inflammatory effects on the kidney cells directly. Glomerular podocytes in culture, verified to express the marker nephrin, were exposed to diabetic mediators such as high glucose or angiotensin II and assayed for MCP-1. Only transforming growth factor-beta (TGF-
) significantly increased MCP-1 production, which was prevented by SB431542 and LY294002, indicating that signaling proceeded through the TGF- type I receptor kinase and the phosphatidylinositol 3-kinase pathway. The TGF--induced MCP-1 was found to activate the podocyte's CCR2 receptor and, as a result, enhance the cellular motility, cause rearrangement of the actin cytoskeleton, and increase the podocyte permeability to albumin in a Transwell assay. The preceding effects of TGF- were replicated by treatment with recombinant MCP-1 and blocked by a neutralizing anti-MCP-1 antibody or a specific CCR2 inhibitor, RS102895. In conclusion, this is the first description that TGF- signaling through PI3K induces the podocyte expression of MCP-1 that can then operate via CCR2 to increase cellular migration and alter albumin permeability characteristics. The pleiotropic effects of MCP-1 on the resident kidney cells such as the podocyte may exacerbate the disease process of diabetic albuminuria.
