Tissue transglutaminase contributes to interstitial renal fibrosis by favoring accumulation of fibrillar collagen through TGF-beta activation and cell infiltration.
Renal fibrosis is defined by the exaggerated accumulation of extracellular matrix proteins. Tissue transglutaminase (TG2) modifies the stability of extracellular matrix proteins and renders the extracellular matrix resistant to degradation. In addition, TG2 also activates transforming growth factor-beta (TGF-beta). We investigated the involvement of TG2 in the development of renal fibrosis using mice with a knockout of the TG2 gene (KO). These mice were studied at baseline and 12 days after unilateral ureteral obstruction, which induced a significant increase in interstitial TG2 expression in wild-type mice (P < 0.001). Interstitial fibrosis was evident in both groups, but total and fibrillar collagen was considerably lower in KO mice as compared with wild-type (P < 0.001). Similarly, mRNA and protein expression of collagen I were significantly lower in KO animals (P < 0.05). A statistically significant reduction in renal inflammation and fewer myofibroblasts were observed in KO mice (P < 0.01). Free active TGF-beta was decreased in KO mice (P < 0.05), although total (active + latent) TFG-beta concentration did not differ between groups. These results show that mice deficient in TG2 are protected against the development of fibrotic lesions in obstructive nephropathy. This protection results from reduced macrophage and myofibroblast infiltration, as well as from a decreased rate of collagen I synthesis because of decreased TGF-beta activation. Our results suggest that inhibition of TG2 may provide a new and important therapeutic target against the progression of renal fibrosis.
Shweke
Nasim
N
INSERM UMR, Paris, France.
Boulos
Nada
N
Jouanneau
Chantal
C
Vandermeersch
Sophie
S
Melino
Gerry
G
Dussaule
Jean-Claude
JC
Chatziantoniou
Christos
C
Ronco
Pierre
P
Boffa
Jean-Jacques
JJ
D000818:Animals; D017209:Apoptosis / Q000502:physiology; D018450:Disease Progression; D004797:Enzyme-Linked Immunosorbent Assay; D024022:Fibrillar Collagens / Q000096:biosynthesis*; D005355:Fibrosis; D005455:Fluorescent Antibody Technique; D019204:GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D007150:Immunohistochemistry; D007668:Kidney / Q000201:enzymology* / Q000473:pathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D020133:Reverse Transcriptase Polymerase Chain Reaction; D053773:Transforming Growth Factor beta1 / Q000378:metabolism; D011503:Transglutaminases / Q000235:genetics / Q000378:metabolism*
D024022:Fibrillar Collagens; D053773:Transforming Growth Factor beta1; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D011503:Transglutaminases; D019204:GTP-Binding Proteins