Sanderson, N. et al. Hepatic expression of mature transforming growth factor 1 in transgenic mice results in multiple tissue lesions. Proc. Natl. Acad. Sci. USA 92, 2572-2576

Laboratory of Experimental Carcinogenesis, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 04/1995; 92(7):2572-6. DOI: 10.1073/pnas.92.7.2572
Source: PubMed


Aberrant expression of transforming growth factor beta 1 (TGF-beta 1) has been implicated in a number of disease processes, particularly those involving fibrotic and inflammatory lesions. To determine the in vivo effects of overexpression of TGF-beta 1 on the function and structure of hepatic as well as extrahepatic tissues, transgenic mice were generated containing a fusion gene (Alb/TGF-beta 1) consisting of modified porcine TGF-beta 1 cDNA under the control of the regulatory elements of the mouse albumin gene. Five transgenic lines were developed, all of which expressed the Alb/TGF-beta 1 transgene selectively in hepatocytes. The transgenic line 25 expressing the highest level of the transgene in the liver also had high (> 10-fold over control) plasma levels of TGF-beta 1. Hepatic fibrosis and apoptotic death of hepatocytes developed in all the transgenic lines but was more pronounced in line 25. The fibrotic process was characterized by deposition of collagen around individual hepatocytes and within the space of Disse in a radiating linear pattern. Several extrahepatic lesions developed in line 25, including glomerulonephritis and renal failure, arteritis and myocarditis, as well as atrophic changes in pancreas and testis. The results from this transgenic model strongly support the proposed etiological role for TGF-beta 1 in a variety of fibrotic and inflammatory disorders. The transgenic model may also provide an appropriate paradigm for testing therapeutic interventions aimed at neutralizing the detrimental effects of this important cytokine.

Download full-text


Available from: Lalage M Wakefield,
    • "Direct evidence for a role of TGF-β1 in renal fibrosis comes from studies reporting that, injection of human recombinant TGF-β1 in rats and rabbits leads to glomerular fibrosis (Terrell et al., 1993) and that overexpression of TGF-β in the kidney by administration of exogenous cDNA in rat renal artery lead to glomerulosclerosis characterized by ECM expansion (Isaka et al., 1993). Furthermore, transgenic mice overexpressing an active form of TGF-β1 in the liver develop progressive liver and renal fibrosis (Sanderson et al., 1995; Kopp et al., 1996). "
    [Show abstract] [Hide abstract]
    ABSTRACT: The understanding of renal fibrosis in chronic kidney disease (CKD) remains as a challenge. More than 10% of the population of developed countries suffer from CKD. Proliferation and activation of myofibroblasts and accumulation of extracellular matrix proteins are the main features of kidney fibrosis, a process in which a large number of cytokines are involved. Targeting cytokines responsible for kidney fibrosis development might be an important strategy to face the problem of CKD. The increasing knowledge of the signaling pathway network of the transforming growth factor beta (TGF-β) superfamily members, such as the profibrotic cytokine TGF-β1 or the bone morphogenetic proteins (BMPs), and their involvement in the regulation of kidney fibrosis, has stimulated numerous research teams to look for potential strategies to inhibit profibrotic cytokines or to enhance the anti-fibrotic actions of other cytokines. The consequence of all these studies is a better understanding of all these canonical (Smad-mediated) and non-canonical signaling pathways. In addition, the different receptors involved for signalling of each cytokine, the different combinations of type I-type II receptors, and the presence and function of co-receptors that can influence the biological response have been also described. However, are these studies leas to suitable strategies to block the appearance and progression of kidney fibrosis? In this review, we offer a critical perspective analyzing the achievements using the most important strategies developed up till now: TGF-β antibodies, chemical inhibitors of TGF-β receptors, miRNAs and signaling pathways and BMP agonists with a potential role as therapeutic molecules against kidney fibrosis.
    Pharmacology [?] Therapeutics 10/2015; DOI:10.1016/j.pharmthera.2015.10.003 · 9.72 Impact Factor
  • Source
    • "Using PLA of the Smad complexes in the salivary glands from these mice, we found no change in the number of BMP Smad complexes as compared with the control (Fig. 4A, 4D) but a slight increase in canonical TGF-β Smad complexes (Fig. 4B, 4E) and a substantial increase in the mixed Smad complexes (Fig. 4C, 4F). In the second model, active TGF-β1 is under the control of regulatory elements of the mouse albumin gene, which is expressed in the liver (Sanderson et al. 1995). In these mice, the resultant increase in plasma TGF-β levels leads to severe glomerulosclerosis and an accumulation of extracellular matrix in the kidney (Mozes et al. 1999). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Transforming growth factor-β (TGF-β) is an important regulator of cellular homeostasis and disease pathogenesis. Canonical TGF-β signaling occurs through Smad2/3-Smad4 complexes; however, recent in vitro studies suggest that elevated levels of TGF-β may activate a novel mixed Smad complex (Smad2/3-Smad1/5/9), which is required for some of the pro-oncogenic activities of TGF-β. To determine if mixed Smad complexes are evident in vivo, we developed antibodies that can be used with a proximity ligation assay to detect either canonical or mixed Smad complexes in formalin-fixed paraffin-embedded sections. We demonstrate high expression of mixed Smad complexes in the tissues from mice genetically engineered to express high levels of TGF-β1. Mixed Smad complexes were also prominent in 15-16 day gestation mouse embryos and in breast cancer xenografts, suggesting important roles in embryonic development and tumorigenesis. In contrast, mixed Smad complexes were expressed at extremely low levels in normal adult mouse tissue, where canonical complexes were correspondingly higher. We show that this methodology can be used in archival patient samples and tissue microarrays, and we have developed an algorithm to quantitate the brightfield read-out. These methods will allow quantitative analysis of cell type-specific Smad signaling pathways in physiological and pathological processes.
    Acta histochemica et cytochemica official journal of the Japan Society of Histochemistry and Cytochemistry 08/2014; 62(12). DOI:10.1369/0022155414550163 · 1.39 Impact Factor
  • Source
    • "The three isoforms for TGF-β are β1,  β2, and β3. TGF-β1 is an important profibrogenic cytokine in liver injury and it is biologically active with multiple pharmacological actions [41]. A balance among these actions is required to maintain tissue homeostasis. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The antifibrotic effects of traditional medicinal herb Caesalpinia sappan (CS) extract on liver fibrosis induced by thioacetamide (TAA) and the expression of transforming growth factor β 1 (TGF- β 1), α -smooth muscle actin ( α SMA), and proliferating cell nuclear antigen (PCNA) in rats were studied. A computer-aided prediction of antioxidant and hepatoprotective activities was primarily performed with the Prediction Activity Spectra of the Substance (PASS) Program. Liver fibrosis was induced in male Sprague Dawley rats by TAA administration (0.03% w/v) in drinking water for a period of 12 weeks. Rats were divided into seven groups: control, TAA, Silymarin (SY), and CS 300 mg/kg body weight and 100 mg/kg groups. The effect of CS on liver fibrogenesis was determined by Masson's trichrome staining, immunohistochemical analysis, and western blotting. In vivo determination of hepatic antioxidant activities, cytochrome P450 2E1 (CYP2E1), and matrix metalloproteinases (MPPS) was employed. CS treatment had significantly increased hepatic antioxidant enzymes activity in the TAA-treated rats. Liver fibrosis was greatly alleviated in rats when treated with CS extract. CS treatment was noted to normalize the expression of TGF- β 1, α SMA, PCNA, MMPs, and TIMP1 proteins. PASS-predicted plant activity could efficiently guide in selecting a promising pharmaceutical lead with high accuracy and required antioxidant and hepatoprotective properties.
    The Scientific World Journal 02/2014; 2014:301879. DOI:10.1155/2014/301879 · 1.73 Impact Factor
Show more