Tubular atrophy and interstitial fibrosis after renal transplantation is dependent on galectin-3.
BACKGROUND
Chronic allograft injury (CAI), characterized by interstitial fibrosis and tubular atrophy, leads to a progressive decline in graft function, resulting in the loss of 5% of renal transplants per annum, and eludes specific therapies. Galectin-3 (gal-3) is a β-galactoside-binding lectin expressed in diverse fibrotic tissue, and mice deficient in gal-3 have reduced fibrosis in kidney, liver, and lung models. The role of gal-3 in CAI is examined in this study.


METHODS
We adopted a murine model of CAI, characterized by a single class II mismatch between BM12 donor and C57BL/6 recipient strains. Syngeneic transplants served as controls (C57BL/6). Transplants were then performed between BM12 donors and gal-3 null recipients on a C57BL/6 background.


RESULTS
Transplantation of BM12 kidneys into C57BL6 mice was associated with interstitial fibrosis (P<0.0001), tubular atrophy (P<0.0001), and upregulation in gal-3 expression (P=0.002), compared with syngeneic controls. Transplanting BM12 kidneys into gal-3 null mice resulted in significant preservation of tubules (P=0.008) and reduced interstitial fibrosis (P=0.01), with decreased myofibroblast activation (P=0.01) and collagen I expression (P=0.04), compared with wild type controls. The number of infiltrating leukocytes was unaltered by abrogation of gal-3, but reduced expression of YM1 (P=0.0001), a marker of alternative macrophage activation, along with a reduction in the number of circulating CD4-positive T cells (P=0.01), and reduced expression of interleukin-4 (P=0.02) in gal-3 null mice suggest possible mechanisms by which gal-3 may promote renal transplant fibrosis.


CONCLUSIONS
Our results suggest a potential role for gal-3 in CAI, and this represents a potentially exciting therapeutic target.
Centre for Inflammation Research, Queen's Medical Research Institute, Little France Crescent, Edinburgh, United Kingdom.
Zexu
Z
Dang
Alison
A
MacKinnon
Lorna P
LP
Marson
Tariq
T
Sethi
D000818:Animals; D001284:Atrophy; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D005355:Fibrosis; D037502:Galectin 3 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D006085:Graft Survival; D006648:Histocompatibility; D000949:Histocompatibility Antigens Class II / Q000276:immunology; D015847:Interleukin-4 / Q000378:metabolism; D007674:Kidney Diseases / Q000276:immunology / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control; D016030:Kidney Transplantation / Q000276:immunology*; D007684:Kidney Tubules / Q000378:metabolism* / Q000473:pathology; D008262:Macrophage Activation; D008264:Macrophages / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D013997:Time Factors; D014185:Transplantation, Isogeneic
D037502:Galectin 3; D000949:Histocompatibility Antigens Class II; C485095:Lgals3 protein, mouse; D015847:Interleukin-4