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.

†These authors contributed equally in this study.Recent findings in idiopathic membranous nephropathy (MN) suggest that in most patients, the disease is because of anti-phospholipase A 2 receptor (PLA 2 R1) autoantibodies. Our aim was to analyze the prevalence and significance of anti-PLA 2 R1 antibodies in recurrent and de novo MN after transplantation. We assessed circulating PLA 2 R1 autoantibodies by a direct immunofluorescence assay based on human embryonic kidney cells transfected with a PLA 2 R1 cDNA, and the presence of PLA 2 R1 antigen in immune deposits. We showed that PLA 2 R1 was involved in 5 of 10 patients with recurrent MN, but in none of the 9 patients with de novo MN. We also showed a marked heterogeneity in the kinetics and titers of anti-PLA 2 R1, which may relate to different pathogenic potential. We provide evidence that some patients with PLA 2 R1-related idiopathic MN and anti-PLA 2 R1 antibodies at the time of transplantation will not develop recurrence. Because PLA 2 R1 autoantibody was not always associated with recurrence, its predictive value should be carefully analyzed in prospective studies.

This study investigated the role of discoidin domain receptor 1 (DDR1), a collagen receptor that displays tyrosine-kinase activity, in the development of glomerulonephritis. Crescentic glomerulonephritis was induced in DDR1-deficient mice and their wild-type (WT) littermates as controls, by injection of alloimmune sheep nephrotoxic serum (NTS). Histological, functional and transcriptomic studies were performed. Glomerulonephritis produced a 17-fold increase of DDR1 expression, predominantly in glomeruli. DDR1 deletion protected NTS-treated mice against glomerular disease (proteinuria/creatininuria 5.5±1.1 vs. 13.2±0.8 g/mmol in WT, crescents 12±2 vs. 24±2% of glomeruli, urea 16±2 vs. 28±5 mM), hypertension (123±11 vs. 157±8 mmHg), and premature death (70 vs. 10% survival) (all P<0.05). Reciprocal stimulation between DDR1 and interleukin-1b expression in vivo and in cultured podocytes suggested a positive feed-back loop between DDR1 and inflammation. In NTS-treated WT mice, administration of DDR1-specific antisense oligodeoxynucleotides decreased DDR1 expression (-56%) and protected renal function and structure, including nephrin expression (4.2±1.4 vs. 0.9±0.4 arbitrary units, P<0.05), compared to control mice receiving scrambled oligodeoxynucleotides. The therapeutic potential of this approach was reinforced by the observation of increased DDR1 expression in glomeruli of patients with lupus nephritis and Goodpasture's syndrome. These results prompt further interest in DDR1 blockade strategies, especially in the treatment of glomerulonephritis.