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Originally published online as doi:10.2353/ajpath.2008.070726 on January 17, 2008

Published online before print January 17, 2008
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(American Journal of Pathology. 2008;172:288-298.)
© 2008 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2008.070726

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{dagger}, 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,{dagger}School of Medicine, University of California, Davis, Sacramento, California

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 β-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-{gamma}/lipopolysaccharide. In addition, absence of galectin-3 does not affect transforming growth factor-β 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.






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Copyright © 2008 by the American Society for Investigative Pathology.