Cysteine-rich protein 61 plays a proinflammatory role in obstructive kidney fibrosis

PLoS One. 2013;8(2):e56481. doi: 10.1371/journal.pone.0056481. Epub 2013 Feb 15.

Abstract

Cysteine-rich protein 61 (Cyr61) is a secreted matrix-associated protein that regulates a broad spectrum of biological and cellular activities. This study aimed to investigate the role of Cyr61 in progressive kidney fibrosis induced by unilateral ureteral obstruction (UUO) surgery in mice. The expression of Cyr61 transcripts and proteins in the obstructed kidneys were increased from day 1 and remained high until day 10 after surgery. Immunohistochemistry indicated that Cyr61 was expressed mainly in renal tubular epithelial cells. The upregulated Cyr61 in UUO kidneys was reduced in mice treated with pan-transforming growth factor-β (TGF-β) antibody. The role of TGF-β in tubular Cyr61 upregulation after obstructive kidney injury was further supported by experiments showing that TGF-β1 stimulated Cyr61 expression in cultured tubular epithelial cells. Notably, the upregulation of Cyr61 in UUO kidneys was followed by a marked increase in monocyte chemoattractant protein 1 (MCP-1) transcripts and macrophage infiltration, which were attenuated in mice treated with anti-Cyr61 antibodies. This proinflammatory property of Cyr61 in inducing MCP-1 expression was further confirmed in tubular epithelial cells cultured with Cyr61 protein. The anti-Cyr61 antibody in UUO mice also reduced the levels of collagen type 1-α1 transcripts, collagen fibril accumulation evaluated by picrosirius red staining, and the levels of α-smooth muscle actin (α-SMA) transcripts and proteins on day 4 after surgery; however, the antifibrotic effect was not sustained. In conclusion, the TGF-β-mediated increase in tubular Cyr61 expression involved renal inflammatory cell infiltration through MCP-1 induction during obstructive kidney injury. The Cyr61 blockade attenuated kidney fibrosis in the early phase, but the antifibrotic effect could not be sustained.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Chemokine CCL2 / genetics
  • Cysteine-Rich Protein 61 / chemistry
  • Cysteine-Rich Protein 61 / genetics
  • Cysteine-Rich Protein 61 / immunology
  • Cysteine-Rich Protein 61 / metabolism*
  • Down-Regulation
  • Epithelial Cells / metabolism
  • Fibrosis
  • Inflammation / metabolism
  • Kidney / injuries
  • Kidney / metabolism
  • Kidney / pathology*
  • Kidney Tubules / pathology
  • Male
  • Mice
  • Mice, Inbred ICR
  • Molecular Sequence Data
  • Transforming Growth Factor beta / genetics
  • Up-Regulation
  • Ureteral Obstruction / complications

Substances

  • Ccl2 protein, mouse
  • Chemokine CCL2
  • Cysteine-Rich Protein 61
  • Transforming Growth Factor beta

Grant support

This study was supported by grants from the National Science Council (NSC 96-2628-B-002-015-MY3), Far Eastern Memorial Hospital (FEMH-95-C-024), Ta-Tung Kidney Foundation and Mrs. Hsiu-Chin Lee Kidney Research Fund for supporting this study. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.