Tissue Transglutaminase Contributes to Interstitial Renal Fibrosis by Favoring Accumulation of Fibrillar Collagen through TGF-β Activation and Cell Infiltration

Abstract

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.

Renal Allograft Fibrosis: Biology and Therapeutic Targets

“…Another profibrotic protein involved in the interaction of cells with the ECM is basigin (CD147) (347). Finally, syndecan-4 and the cross-linking enzyme tissue transglutaminase are also involved in renal fibrogenesis (348)(349)(350). Nothing is known about such mechanisms in the kidney allograft.…”

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“…In the extracellular environment, TG2 can also function through its Ca 2? -activated transamidating activity to increase the rate of deposition of ECM proteins such as FN and collagen I (Shweke et al 2008;Verderio et al 1999;Yuan et al 2007), leading to accumulation and changes in the ECM influencing both cell adhesion and differentiation (Chau et al 2005;Johnson et al 2007).…”