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      Involvement of Transglutaminase-2 in Pathological Changes in Renal Disease


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          Background: Transglutaminase (Tg)-2 is shown to be related to renal fibrosis. However, its roles in human kidney disease have not been fully studied. Methods: Using immunohistochemistry, we examined Tg-2 expression in renal biopsy specimens from 22 patients with IgA nephropathy (IgAN) and correlated the intensity of Tg-2 staining with clinical and histopathological parameters. We compared the distribution and intensity of Tg-2 staining with those of transforming growth factor (TGF)-β staining. Results: In normal human kidneys, Tg-2 staining was not significant. In IgAN kidneys, glomerular Tg-2 staining correlated with serum creatinine (S-Cr), creatinine clearance (Ccr), urinary protein excretion, glomerular sclerosis, and mesangial cell proliferation. Tubulointerstitial Tg-2 correlated with S-Cr, Ccr, N-acetyl-β-glucosaminidase, urinary β<sub>2</sub>-microglobulin, and tubulointerstitial injuries. Tg-2 staining in the vicinity of vascular poles of glomeruli preceded the development of mesangial lesions, and was more remarkable in cases with renal impairment. The distribution and intensity of Tg-2 staining were not consistent with those of TGF-β staining. In glomerular crescents, Tg-2 staining was remarkable. Conclusion: The present study showed a correlation between Tg-2 expression and renal function and pathological changes. Tg-2 expression in the vicinity of vascular poles was notable because that may be an initial marker of glomerular injury.

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          Most cited references21

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          Transglutaminase 2: an enigmatic enzyme with diverse functions.

          Transglutaminase 2 (TG2) is an inducible transamidating acyltransferase that catalyzes Ca(2+)-dependent protein modifications. It acts as a G protein in transmembrane signalling and as a cell surface adhesion mediator, this distinguishes it from other members of the transglutaminase family. The sequence motifs and domains revealed in the recent TG2 structure, can each be assigned distinct cellular functions, including the regulation of cytoskeleton, cell adhesion and cell death. Ablation of TG2 in mice results in impaired wound healing, autoimmunity and diabetes, reflecting the number and variety of TG2 functions. An important role for the enzyme in the pathogenesis of coeliac disease, fibrosis and neurodegenerative disorders has also been demonstrated, making TG2 an important therapeutic target.
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            Requirement for transglutaminase in the activation of latent transforming growth factor-beta in bovine endothelial cells

            A hitherto unknown function for transglutaminase (TGase; R-glutaminyl- peptide: amine gamma-glutamyltransferase, EC was found in the conversion of latent transforming growth factor-beta (LTGF-beta) to active TGF-beta by bovine aortic endothelial cells (BAECs). The cell- associated, plasmin-mediated activation of LTGF-beta to TGF-beta induced either by treatment of BAECs with retinoids or by cocultures of BAECs and bovine smooth muscle cells (BSMCs) was blocked by seven different inhibitors of TGase as well as a neutralizing antibody to bovine endothelial cell type II TGase. Control experiments indicated that TGase inhibitors and/or a neutralizing antibody to TGase did not interfere with the direct action of TGF-beta, the release of LTGF-beta from cells, or the activation of LTGF-beta by plasmin or by transient acidification. After treatment with retinoids, BAECs expressed increased levels of TGase coordinate with the generation of TGF-beta, whereas BSMCs and bovine embryonic skin fibroblasts, which did not activate LTGF-beta after treatment with retinoids, did not. Furthermore, both TGase inhibitors and a neutralizing antibody to TGase potentiated the effect of retinol in enhancing plasminogen activator (PA) levels in cultures of BAECs by suppressing the TGF-beta-mediated enhancement of PA inhibitor-1 (PAI-1) expression. These results indicate that type II TGase is a component required for cell surface, plasmin-mediated LTGF-beta activation process and that increased expression of TGase accompanies retinoid-induced activation of LTGF- beta.
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              Mechanisms involved in the pathogenesis of tubulointerstitial fibrosis in 5/6-nephrectomized rats.

              The 5/6 nephrectomy model is used to study pathogenetic mechanisms underlying chronic renal failure. We previously demonstrated that increased mesangial cell proliferation and glomerular PDGF B-chain expression precede glomerulosclerosis in this model. In the present study we have assessed the concomitant changes in the cortical tubulointerstitium. A wave of tubular and interstitial cell proliferation (as determined by immunostaining for PCNA) occurred at week 1 after 5/6 nephrectomy. This wave preceded the peak glomerular cell proliferation by one week. Tubulointerstitial cell proliferation decreased thereafter and reached control values by week 10. In situ hybridization and immunostaining for PDGF B-chain and beta-receptor in sham-operated controls showed labeling of distal tubules and collecting ducts, while no signal was present in the interstitium. PDGF B-chain mRNA and protein expression was markedly increased in tubules at weeks 2 and 4 after 5/6 nephrectomy and in the interstitium (particularly in areas of inflammatory infiltrates) at weeks 2 to 10. Similar changes occurred with PDGF receptor beta-subunit immunostaining. Interstitial expression of desmin and alpha-smooth muscle actin (markers of myofibroblasts) progressively increased after week 1. Interstitial influx of monocytes/macrophages with focal accentuation started at week 2. Counts of lymphocytes, neutrophils and platelets showed only minor changes. In parallel to the monocyte/macrophage influx, progressive interstitial accumulation of collagens I and IV, laminin, and fibronectin occurred. All of these changes were correlated with the increase in serum creatinine, proteinuria and an index of tubulointerstitial damage. We conclude that tubulointerstitial changes after 5/6 nephrectomy show similarities with those observed in the glomeruli. Tubular and interstitial overexpression of PDGF B-chain and its receptor may play a role in mediating fibroblast migration and/or proliferation in areas of tubulointerstitial injury.

                Author and article information

                Nephron Clin Pract
                Nephron Clinical Practice
                S. Karger AG
                February 2007
                16 January 2007
                : 105
                : 3
                : c139-c146
                aSecond Department of Internal Medicine, National Defense Medical College, Tokorozawa, Saitama, and bDepartment of Nephrology and Kidney and Dialysis Center, Shonan Kamakura General Hospital, Kamakura, Kanagawa, Japan
                98646 Nephron Clin Pract 2007;105:c139–c146
                © 2007 S. Karger AG, Basel

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                : 16 May 2006
                : 01 October 2006
                Page count
                Figures: 2, Tables: 2, References: 31, Pages: 1
                Self URI (application/pdf): https://www.karger.com/Article/Pdf/98646
                Self URI (text/html): https://www.karger.com/Article/FullText/98646
                Self URI (journal page): https://www.karger.com/SubjectArea/Nephrology
                Original Paper

                Cardiovascular Medicine,Nephrology
                Glomerular sclerosis,Transglutaminase-2,Tubulointerstitial injury,Vascular pole,Crescentic formation


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