Galectin-3 expression and secretion links macrophages to the promotion of renal fibrosis.
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 beta-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-beta 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.
Henderson
Neil C
NC
The Queen's Medical Research Institute, University of Edinburgh, Edinburgh EH16 4TJ, UK.
Mackinnon
Alison C
AC
Farnworth
Sarah L
SL
Kipari
Tiina
T
Haslett
Christopher
C
Iredale
John P
JP
Liu
Fu-Tong
FT
Hughes
Jeremy
J
Sethi
Tariq
T
D019264:Adoptive Transfer; D000818:Animals; D015153:Blotting, Western; D005347:Fibroblasts / Q000378:metabolism; D005355:Fibrosis; D005455:Fluorescent Antibody Technique; D037502:Galectin 3 / Q000378:metabolism*; D015870:Gene Expression; D007150:Immunohistochemistry; D007668:Kidney / Q000276:immunology / Q000378:metabolism* / Q000473:pathology*; D008264:Macrophages / Q000378:metabolism*; D051379:Mice; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014517:Ureteral Obstruction / Q000150:complications
D037502:Galectin 3