Published online before print January 17, 2008

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Copyright © 2008 American Society for Investigative Pathology
American Journal of Pathology, doi:10.2353/ajpath.2008.070726

Accepted for publication October 25, 2007.

Article

Galectin-3 Expression and Secretion Links Macrophages to the Promotion of Renal Fibrosis

Neil C. Henderson^*, Alison C. Mackinnon^*, Sarah L. Farnworth^*, Tiina Kipari^*, Christopher Haslett^*, John P. Iredale^*, Fu-Tong Liu, Jeremy Hughes^*, and Tariq Sethi^*@

From the Centre for Inflammation Research,* The Queen's Medical Research Institute, University of Edinburgh, Edinburgh, United Kingdom; and the Department of Dermatology, School of Medicine, University of California, Davis, Sacramento, California

^@ To whom correspondence should be addressed. E-mail: t.sethi{at}ed.ac.uk.

	Abstract

Macrophages have been proposed as a key cell type in the pathogenesis of renal fibrosis; however, the mechanism by which macrophages drive fibrosis is still unclear. We show that expression of galectin-3, a -galactoside-binding lectin, is up-regulated in a mouse model of progressive renal fibrosis (unilateral ureteric obstruction, UUO), and absence of galectin-3 protects against renal myofibroblast accumulation/activation and fibrosis. Furthermore, specific depletion of macrophages using CD11b-DTR mice reduces fibrosis severity after UUO demonstrating that macrophages are key cells in the pathogenesis of renal fibrosis. Disruption of the galectin-3 gene does not affect macrophage recruitment after UUO, or macrophage proinflammatory cytokine profiles in response to interferon-/lipopolysaccharide. In addition, absence of galectin-3 does not affect transforming growth factor- expression or Smad 2/3 phosphorylation in obstructed kidneys. Adoptive transfer of wild-type but not galectin-3^-/- macrophages did, however, restore the fibrotic phenotype in galectin-3^-/- mice. Cross-over experiments using wild-type and galectin-3^-/- macrophage supernatants and renal fibroblasts confirmed that secretion of galectin-3 by macrophages is critical in the activation of renal fibroblasts to a profibrotic phenotype. Therefore, we demonstrate for the first time that galectin-3 expression and secretion by macrophages is a major mechanism linking macrophages to the promotion of renal fibrosis.