Transforming Growth Factor-β: Importance in Long-Term Peritoneal Membrane Changes

2005 ◽  
Vol 25 (3_suppl) ◽  
pp. 15-17 ◽  
Author(s):  
Peter J. Margetts ◽  
Kook-Hwan Oh ◽  
Martin Kolb
Keyword(s):  
Peritoneal Dialysis ◽  
Growth Factor ◽  
Gene Transfer ◽  
Structural Changes ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Transforming Growth Factor Β1 ◽  
Peritoneal Membrane ◽  
Membrane Changes

We have provided evidence from adenovirus-mediated gene transfer to the peritoneum that transforming growth factor-β1 mimics many of the functional and structural changes in the peritoneum in patients on long-term peritoneal dialysis, including fibrosis, increased submesothelial thickness, angiogenesis, increased solute transport, and ultrafiltration dysfunction. We review several key properties of this important fibrogenic molecule.

scholarly journals Antiangiogenic and Antifibrotic Gene Therapy in a Chronic Infusion Model of Peritoneal Dialysis in Rats

2002 ◽  
Vol 13 (3) ◽  
pp. 721-728 ◽  
Author(s):  
Peter J. Margetts ◽  
Steve Gyorffy ◽  
Martin Kolb ◽  
Lisa Yu ◽  
Catherine M. Hoff ◽  
...  
Keyword(s):  
Peritoneal Dialysis ◽  
Growth Factor ◽  
Gene Transfer ◽  
Transforming Growth Factor ◽  
Angiogenesis Inhibitor ◽  
Transforming Growth Factor Β ◽  
Collagen Content ◽  
Peritoneal Membrane ◽  
Peritoneal Fibrosis ◽  
Membrane Function

ABSTRACT. To identify the relative importance of peritoneal fibrosis and angiogenesis in peritoneal membrane dysfunction, adenoviral mediated gene transfer of angiostatin, a recognized angiogenesis inhibitor, and decorin, a transforming growth factor-β–inhibiting proteoglycan, were used in a daily infusion model of peritoneal dialysis. A peritoneal catheter and subcutaneous port were inserted in rats. Five and fourteen d after insertion, adenovirus-expressing angiostatin, decorin, or AdDL70, a null control virus, were administered. Daily infusion of 4.25% Baxter Dianeal was initiated 7 d after catheter insertion and continued until day 35. Three initial doses of lipopolysaccharide were administered on days 8, 10, and 12 to promote an inflammatory response. Net ultrafiltration was used as a measure of membrane function, and peritoneum-associated vasculature and mesenteric collagen content was quantified. Ultrafiltration dysfunction, angiogenesis, and fibrosis were observed in daily infusion control animals. Animals treated with AdAngiostatin demonstrated an improvement in net ultrafiltration (−3.1 versus −7.8 ml for control animals; P = 0.0004) with a significant reduction in vessel density. AdDecorin-treated animals showed a reduction in mesenteric collagen content (1.8 versus 2.9 μg/mg; P = 0.04); however, AdDecorin treatment had no effect on net ultrafiltration. In a rodent model of peritoneal membrane failure, net ultrafiltration was significantly improved and peritoneal-associated blood vessels were significantly reduced by using adenovirus-mediated gene transfer of angiostatin. Decorin, a transforming growth factor-β–inhibiting proteoglycan, reduced collagen content but did not affect net ultrafiltration. Improvement in the function of the peritoneum as a dialysis membrane after treatment with angiostatin has implications for treatment of peritoneal membrane dysfunction seen in patients on long-term dialysis.

Adenovirus-Based Transient Expression Systems for Peritoneal Membrane Research

2006 ◽  
Vol 26 (5) ◽  
pp. 547-558 ◽  
Author(s):  
Catherine M. Hoff ◽  
Peter J. Margetts
Keyword(s):  
Peritoneal Dialysis ◽  
Gene Transfer ◽  
Transforming Growth Factor ◽  
Genetically Modify ◽  
Transforming Growth Factor Β ◽  
Laboratory Research ◽  
Peritoneal Membrane ◽  
Peritoneal Fibrosis ◽  
Necrosis Factor Alpha ◽  
Wide Range

Background Peritoneal membrane research has provided important insights into the physiology and pathophysiology of this tissue that is of vital importance for peritoneal dialysis patients. Among the various tools and methodologies used to study the peritoneum, we have extensively used adenovirus-mediated gene transfer. Methods A literature review was carried out. Information from reviewed papers was combined with the authors’ experience and results. Results We have used first-generation adenoviruses that are simple to construct and can infect a wide range of dividing and nondividing cell types. These vectors are restricted, however, in that they provide only a short duration of transgene expression and may elicit an inflammatory response. Modifications to this technology with helper-dependent adenovirus may circumvent these problems but with increased complexity of construction. Adenovirus-mediated gene transfer has been used to evaluate the effect of several cytokines and growth factors on peritoneal membrane physiology. We have used intraperitoneal delivery of transforming growth factor-β to generate an experimental model system of resolving peritoneal fibrosis and epithelial mesenchymal transdifferentiation. We have studied the effects of the inflammatory cytokines interleukin-1β and tumor necrosis factor alpha on the peritoneum, and have shown that antiangiogenic factors such as sFLT-1 and angiostatin can reduce the damaging effects of exposure to peritoneal dialysis solutions in an animal model. Conclusions The use of recombinant adenoviruses to genetically modify cells and tissues is now a common laboratory research tool. This technique has provided important advances in our understanding of the peritoneal membrane.

A Chronic Inflammatory Infusion Model of Peritoneal Dialysis in Rats

2001 ◽  
Vol 21 (3_suppl) ◽  
pp. 368-372 ◽  
Author(s):  
Peter J. Margetts ◽  
Martin Kolb ◽  
Lisa Yu ◽  
Catherine M. Hoff ◽  
Jack Gauldie
Keyword(s):  
Peritoneal Dialysis ◽  
Growth Factor ◽  
Gene Transfer ◽  
Peritoneal Fluid ◽  
Transforming Growth Factor ◽  
Membrane Damage ◽  
Intraperitoneal Administration ◽  
Peritoneal Membrane ◽  
Ultrafiltration Failure ◽  
Physiologic Saline

Objectives Peritoneal membrane changes are related to daily exposure to non physiologic dialysate and recurrent acute inflammation. We modified a daily infusion and inflammation model and evaluated it for fibrotic and angiogenic features. The feasibility of adenovirus-mediated gene transfer in the model was also assessed. Methods Peritoneal catheters were implanted in rats. Over a period of 4 weeks, the animals received a daily infusion of Dianeal 4.25% (Baxter Healthcare Corporation, Deerfield, IL, U.S.A.) with an initial three doses of lipopolysaccharide (LPS) or physiologic saline. Peritoneal fluid was assayed for transforming growth factor beta (TGFβ) and vascular endothelial growth factor (VEGF). Animals were humanely killed at week 5. Net ultrafiltration was then measured, and tissue samples were immunostained for factor VIII. Mesenteric tissue was assayed for hydroxyproline content. Adenovirus-mediated gene transfer of β-galactosidase was assayed by intraperitoneal administration of the virus, 4 days before the end of the experiment. Results Animals treated with either Dianeal or physiologic saline showed peritoneal membrane thickening and increased vascularity. Fibrosis was demonstrated by increased hydroxyproline concentration. Ultrafiltration was impaired. We found increased concentrations of VEGF and TGFβ in the peritoneal fluid of animals treated with LPS and daily infusion. Adenovirus-mediated gene transfer to the peritoneal membrane was demonstrated in the model. Conclusions Exposure to LPS and daily Dianeal or physiologic saline leads to peritoneal fibrosis and neoangiogenesis. Vascularization and glucose transport correlate with ultrafiltration failure. The present animal model mimics changes seen in humans on peritoneal dialysis and may be valuable for evaluating short-term interventions to prevent membrane damage.

Increased aortic stiffness in the insulin-resistant Zucker fa/fa rat

2005 ◽  
Vol 289 (2) ◽  
pp. H845-H851 ◽  
Author(s):  
Akhilesh K. Sista ◽  
Mary K. O'Connell ◽  
Tomoya Hinohara ◽  
Santosh S. Oommen ◽  
Brett E. Fenster ◽  
...  
Keyword(s):  
Growth Factor ◽  
Aortic Stiffness ◽  
Transforming Growth Factor ◽  
Longitudinal Direction ◽  
Transforming Growth Factor Β ◽  
Transforming Growth Factor Β1 ◽  
Vascular Stiffness ◽  
Molecular Evidence ◽  
Mechanical Stiffness ◽  
Insulin Resistant

Accumulating clinical evidence indicates increased aortic stiffness, an independent risk factor for cardiovascular and all-cause mortality, in type 2 diabetic and glucose-intolerant individuals. The present study sought to determine whether increased mechanical stiffness, an altered extracellular matrix, and a profibrotic gene expression profile could be observed in the aorta of the insulin-resistant Zucker fa/fa rat. Mechanical testing of Zucker fa/fa aortas showed increased vascular stiffness in longitudinal and circumferential directions compared with Zucker lean controls. Unequal elevations in developed strain favoring the longitudinal direction resulted in a loss of anisotropy. Real-time quantitative PCR and immunohistochemistry revealed increased expression of fibronectin and collagen IVα3 in the Zucker fa/fa aorta. In addition, expression of transforming growth factor-β and several Smad proteins was increased in vessels from insulin-resistant animals. In rat vascular smooth muscle cells, 12–18 h of exposure to insulin (100 nmol/l) enhanced transforming growth factor-β1 mRNA expression, implicating a role for hyperinsulinemia in vascular stiffness. Thus there is mechanical, structural, and molecular evidence of arteriosclerosis in the Zucker fa/fa rat at the glucose-intolerant, hyperinsulinemic stage.

Abstract 297: Cardiac Transforming-growth-factor β-stimulated Clone 22 Gene Expression By Hypertrophic Stimuli

2013 ◽  
Vol 113 (suppl_1) ◽  
Author(s):  
Annina Kelloniemi ◽  
Jani Aro ◽  
Elina Koivisto ◽  
Heikki Ruskoaho ◽  
Jaana Rysä
Keyword(s):  
Growth Factor ◽  
Gene Transfer ◽  
Transforming Growth Factor ◽  
Pressure Overload ◽  
Transforming Growth Factor Β ◽  
Left Ventricular ◽  
Neonatal Rat ◽  
Mrna Levels ◽  
Ang Ii ◽  
Sd Rats

Objectives: Transforming-growth-factor β-stimulated clone 22 (TSC-22) is a leucine zipper protein expressed in many tissues and possessing various transcription-modulating activities. However, its function in the heart remains largely unknown. The aim of the present study was to characterize the cardiac TSC-22 expression. Methods: Acute pressure overload was accomplished in conscious Sprague-Dawley (SD) rats by intravenous infusion of arginine 8 -vasopressin (AVP, 0.05 μg/kg/min) for 4 hours and subcutaneous infusion of angiotensin II (Ang II, 33 μg/kg/h) with and without Ang II receptor type 1 blocker losartan (400 μg/kg/h) by using osmotic minipumps for 2 weeks. Adenovirus-mediated intramyocardial gene transfer of TSC-22 was performed into left ventricle (LV) of SD rats. Experimental myocardial infarction (MI) was produced by ligation of the left anterior descending coronary artery. Cultured neonatal rat ventricular myocytes (NRVM) were treated with endothelin-1 (ET-1, 100 nM). Results: A significant 1.6-fold increase ( P <0.05) in LV TSC-22 mRNA levels was noted already after 1 hour AVP infusion. Moreover, Ang II infusion markedly upregulated TSC-22 expression, LV mRNA levels being highest at 6 hours (11-fold, P <0.001). Simultaneous infusion of losartan completely abolished Ang II-induced increase in TSC-22 mRNA levels. Adenovirus-mediated gene transfer of TSC-22 into LV resulted a 1.9-fold ( P <0.001) increase in TSC-22 mRNA levels, accompanied by upregulated BNP mRNA levels (1.4-fold, P <0.01). In response to experimental MI, TSC-22 mRNA levels were elevated 4.1-fold ( P <0.001) at 1 day and 1.9-fold ( P <0.05) at 4 weeks. In cultured NRVM, ET-1 treatment increased TSC-22 mRNA levels from 1 h to 24 h, the greatest increase being observed at 12 h (2.7-fold, P <0.001). TSC-22 protein levels were upregulated from 4 h to 24 h with the highest increase at 24 h (4.7-fold, P <0.01). Conclusion: These results indicate that TSC-22 expression is rapidly activated in response to pressure overload, MI and in ET-1 treated cultured NRVM. Moreover, adenovirus-mediated overexpression of TSC-22 mRNA was associated with elevated left ventricular BNP mRNA levels.

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