The monocyte chemoattractant protein-1/CCR2 loop, inducible by TGF-β, increases podocyte motility and albumin permeability

Young Lee Eun, Hee Chung Choon, Charbel C. Khoury, Kin Yeo Tet, Petr E. Pyagay, Amy Wang, Sheldon Chen

Research output: Contribution to journalArticlepeer-review

92 Scopus citations

Abstract

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 noninflammatory 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-β (TGF-β) significantly increased MCP-1 production, which was prevented by SB431542 and LY294002, indicating that signaling proceeded through the TGF-β type I receptor kinase and the phosphatidylinositol 3-kinase pathway. The TGF-β-induced MCP-1 was found to activate the podocyte's cysteine-cysteine chemokine receptor 2 (CCR2) and, as a result, enhance the cellular motility, cause rearrangement of the actin cytoskeleton, and increase podocyte permeability to albumin in a Transwell assay. The preceding effects of TGF-βwere 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-β 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.

Original languageEnglish
Pages (from-to)F85-F94
JournalAmerican Journal of Physiology - Renal Physiology
Volume297
Issue number1
DOIs
StatePublished - Jul 2009

Keywords

  • Albuminuria
  • Cytoskeleton
  • Diabetes
  • Nephropathy

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