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Biomedical subjects

W A Border

Publications and source records attributed to W A Border.

At least 55 records · Page 3Linked to original sources
PubMed1994

Sustained expression of TGF-beta 1 underlies development of progressive kidney fibrosis.

We found that TGF-beta 1 expression and increased matrix production is transient and self-limited in nephritic glomeruli from rats with acute, reversible glomerulonephritis induced by a single injection of an antibody reactive with glomerular mesangial cells. In contrast, in rats given a second antibody injection, one week later, the glomerular expression of TGF-beta 1 mRNA and TGF-beta 1 protein remained elevated through 18 weeks and was associated with a large infiltration of mononuclear cells, with staining features of fibroblastic/myofibroblastic cells, strongly expressing TGF-beta 1 in the tubulointerstitium of the kidney. By 18 weeks kidneys from animals receiving two antibody injections showed glomerulosclerosis and tubulointerstitial fibrosis with striking deposition of collagens type I and III, whereas kidney tissue from animals given one antibody injection was indistinguishable from normal control. The histological changes were accompanied by persistent proteinuria and elevated levels of blood urea nitrogen. Extracellular matrix markers of TGF-beta 1 activity, a special isoform of fibronectin, tenascin, biglycan and plasminogen activator inhibitor-1, were significantly elevated in kidneys undergoing fibrosis. These data suggest that sustained TGF-beta 1 expression contributes to the development of progressive kidney fibrosis.

Animals↗
PubMed1994

Transforming growth factor-beta and the pathogenesis of glomerular diseases.

Transforming growth factor-beta (TGF-beta) is a cytokine that is important in embryogenesis, development, carcinogenesis, and tissue repair. TGF-beta is unique among cytokines in its widespread actions on the regulation of extracellular matrix. In a model of acute mesangial proliferative glomerulonephritis, it was shown that overproduction of TGF-beta is the cause of pathologic matrix accumulation in the nephritic glomeruli. TGF-beta acted to increase matrix production, inhibit matrix degradation, and modulate matrix receptors in the glomerulonephritic rats. Elevated expression of TGF-beta was also found in other experimental glomerular diseases, including diabetic nephropathy. Studies of humans with glomerulonephritis and diabetic nephropathy also strongly implicated TGF-beta in the pathogenesis of glomerular matrix build-up. Recently, the proteoglycan decorin was shown to neutralize TGF-beta. When injected into glomerulonephritic rats, decorin markedly suppressed pathologic matrix deposition in the glomeruli. Thus, decorin offers hope as a treatment for progressive kidney diseases caused by the overproduction of TGF-beta.

Animals↗
PubMed1994

Increased expression of transforming growth factor-beta in renal disease.

Transforming growth factor-beta (TGF-beta) is a multifunctional cytokine and a major regulator of tissue repair and extracellular matrix. Recent studies show that TGF-beta overexpression in experimental and human kidney diseases leads to progressive glomerular and tubulointerstitial scarring and renal failure. New evidence suggests that angiotensin-converting enzyme inhibitors and a low-protein diet may slow the progression of chronic kidney diseases in part by suppressing TGF-beta overexpression. New therapies may prevent progressive fibrosis in chronic kidney disease by suppressing the action of TGF-beta.

Acute Disease↗
PubMed1994

Cytokines and L-arginine in renal injury and repair.

Advances in molecular biology have identified cytokines as mediators of pathophysiological changes in chronic renal disease. Transforming growth factor-beta (TGF-beta) plays an important role in the pathogenesis of glomerular and interstitial fibrosis, whereas platelet-derived growth factor (PDGF) is involved in proliferative changes in chronic progressive renal diseases. Tumor necrosis factor-alpha and interleukins are expressed in experimental models of renal disease and are causes of inflammation and cell migration. Cytokines act by many different mechanisms, and one target of their action may be L-arginine metabolism. Since the discovery of the effector molecule nitric oxide (NO), generated from L-arginine, knowledge of this pathway has increased dramatically. It became evident that the L-arginine/NO pathway is of major importance in the regulation of hemodynamics and neurotransmission, in host defense against intracellular microorganisms, and in immunologic tissue injury. This pathway is induced by proinflammatory cytokines and possibly regulated by TGF-beta and PDGF. L-Arginine is also metabolized to L-ornithine, which can be processed to polyamines or to L-proline. As polyamines are important mediators of cell growth and L-proline is a substrate for collagen synthesis, both pathways, once activated, may be important in repair processes. It is likely that cytokines and L-arginine metabolism are interconnected and that both are involved in the inflammation, tissue repair, and fibrogenesis processes in the kidney. Dietary protein restriction in progressive renal diseases may substantially affect both systems. This review summarizes current knowledge about interactions of cytokines and L-arginine metabolism and the relevance to renal diseases.

Animals↗
PubMed1994

Angiotensin II stimulates extracellular matrix protein synthesis through induction of transforming growth factor-beta expression in rat glomerular mesangial cells.

Angiotensin II (Ang II) has been implicated in the development of progressive glomerulosclerosis, but the precise mechanism of this effect remains unclear. In an experimental model, we have shown previously that TGF-beta plays a key role in glomerulosclerosis by stimulating extracellular matrix protein synthesis, increasing matrix protein receptors, and altering protease/protease-inhibitor balance, thereby inhibiting matrix degradation. We hypothesized that Ang II contributes to glomerulosclerosis through induction of TGF-beta. Ang II treatment of rat mesangial cells in culture increased TGF-beta and matrix components biglycan, fibronectin, and collagen type I at both the mRNA and protein levels in a time- and dose-dependent manner. Saralasin, a competitive inhibitor of Ang II, prevented the stimulation. Ang II also promoted conversion of latent TGF-beta to the biologically active form. Coincubation of mesangial cells with Ang II and neutralizing antibody to TGF-beta blocked the Ang II-induced increases in matrix protein expression. Continuous in vivo administration of Ang II to normal rats for 7 d resulted in 70% increases in glomerular mRNA for both TGF-beta and collagen type I. These results indicate that Ang II induces mesangial cell synthesis of matrix proteins and show that these effects are mediated by Ang II induction of TGF-beta expression. This mechanism may well contribute to glomerulosclerosis in vivo.

Angiotensin II↗
PubMed1994

Integrins.

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Amino Acid Sequence↗
PubMed1993

Expression of transforming growth factor beta is elevated in human and experimental diabetic nephropathy.

Diabetes is now the most common cause of progressive kidney failure leading to dialysis or transplantation. The central pathological feature of diabetic nephropathy is accumulation of extracellular matrix within the glomeruli. The factors in the diabetic milieu responsible for extracellular matrix accumulation are not understood. Here we report that in glomeruli of rats made diabetic there is a slow, progressive increase in the expression of transforming growth factor beta (TGF-beta) mRNA and TGF-beta protein. A key action of TGF-beta is induction of extracellular matrix production, and specific matrix proteins known to be induced by TGF-beta were increased in diabetic rat glomeruli. These proteins include an alternatively spliced form of fibronectin, tenascin, and the proteoglycan biglycan. TGF-beta has not previously been implicated in the matrix accumulation that occurs in the diabetic kidney. Glomeruli from humans with diabetic nephropathy also showed a striking increase in immunoreactive TGF-beta protein and deposition of the special form of fibronectin, whereas glomeruli from normal subjects or from individuals with other glomerular diseases (where extracellular matrix accumulation is not a feature) were negative or barely positive. These results implicate TGF-beta in the pathogenesis of diabetic nephropathy.

Animals↗
PubMed1993

Cytokines in kidney disease: the role of transforming growth factor-beta.

Cytokines such as transforming growth factor-beta (TGF-beta) are peptide factors that regulate embryogenesis, development, inflammation, tissue repair, and carcinogenesis. Growing evidence indicates that dysregulation of cytokine actions may underlie the pathogenesis of serious autoimmune, degenerative, and fibrotic diseases. Studies in a model of acute mesangial proliferative glomerulonephritis show that overproduction of TGF-beta is the cause of pathologic accumulation of extracellular matrix in the nephritic glomeruli. Transforming growth factor-beta acts to increase matrix production, inhibit matrix degradation, and modulate matrix receptors in the glomerulonephritic rats. It may also play a role in the glomerular matrix build-up that is a central feature of diabetic nephropathy. Elevated expression of TGF-beta mRNA and TGF-beta protein were found in the glomeruli of diabetic rats along with increased levels of proteoglycans and other matrix components that are known to be induced by TGF-beta. The study of human diabetic glomeruli has also showed markedly elevated levels of TGF-beta protein. Glomeruli from normal kidneys and nonprogressive kidney disorders were negative. The striking ability of TGF-beta to cause exuberant matrix formation may be due to the fact that TGF-beta can induce its own production by resident cells at a site of injury. Thus, the potential for TGF-beta to do harm may be due to this autoinduction mechanism whereby TGF-beta expression can become chronic, creating a vicious circle. As the role that TGF-beta plays in chronic fibrotic diseases becomes better understood, it is likely that TGF-beta inhibitors will become important future drugs for treating these conditions.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1993

Role of proteoglycans and cytoskeleton in the effects of TGF-beta 1 on renal proximal tubule cells.

Transforming growth factor-beta (TGF-beta) is a critical cell regulatory protein which influences cell growth, cell differentiation and cell chemotaxis. TGF-beta 1 has been previously shown to promote a migratory and adherent transformation of monolayers of renal proximal tubule cells in primary culture to form solid clusters of cells. To better understand the cellular basis of this TGF-beta 1 effect, these studies evaluated the influence of TGF-beta 1 on the synthesis of proteoglycans and on cytoskeleton rearrangement in rabbit renal proximal tubule cells in primary culture, and their role in this transformation effect of TGF-beta 1. Biosynthetic labeling of proteoglycans with 35S sulfate and enzyme digestion studies demonstrated that TGF-beta 1 promoted the synthesis of heparan sulfate proteoglycans in these cells. The importance of proteoglycan synthesis induced by TGF-beta 1 in this migration and aggregation process was demonstrated with the use of two chemically-dissimilar proteoglycan synthesis inhibitors: xyloside and galactosamine. Both compounds inhibited TGF-beta 1 stimulation of proteoglycan synthesis and diminished TGF-beta 1 promoted transformation of proximal tubule cells as assessed by quantitative morphometry. Further experiments evaluated the influence of TGF-beta 1 on actin microfilaments with the use of rhodamine conjugated phalloidin staining and immunofluorescent microscopy, and demonstrated that TGF-beta 1 provoked a dramatic rearrangement of actin microfilaments into stress fibers. The use of actin microfilament disrupting agents, cytochalasin B and D, attenuated the stress fiber formation promoted by TGF-beta 1 and inhibited the TGF-beta 1-induced morphologic transformation of these cells. Further studies evaluated these effects on the rate of DNA synthesis in these cells, as assessed with 3H-thymidine incorporation. Proteoglycan synthesis inhibitors significantly diminished the maximal proliferative response of these epithelial cells to epidermal growth factor (EGF). In contrast, actin microfilament disaggregation with cytochalasin B or D did not change the rate of DNA synthesis in response to EGF but did attenuate the antiproliferative effect of TGF-beta 1 on EGF-induced DNA synthesis cells. These studies demonstrate that the TGF-beta 1 promoted synthesis cells. These studies demonstrate that the TGF-beta 1 promoted an increase in the production of proteoglycans and a higher ordered structure of the cytoskeleton. Both effects were instrumental in the adhesive migratory response of proximal tubule cells to TGF-beta 1 as well as the DNA synthesis rate response to both EGF and TGF-beta 1.

Actins↗
PubMed1993

Coordinated expression of beta 1 integrins and transforming growth factor-beta-induced matrix proteins in glomerulonephritis.

BACKGROUND: Extracellular matrix remodeling after tissue injury involves both cell-cell and cell-matrix interactions. Integrins are matrix receptors that play a central role in such interactions, and transforming growth factor-beta (TGF-beta) is known to be a strong modulator of their expression. Our previous work has shown that in the anti-thymocyte serum-induced model of glomerulonephritis in the rat, elevated glomerular production of TGF-beta is a causal factor in matrix accumulation. Here we present data on the expression and distribution of glomerular beta 1 integrins in experimental glomerulonephritis. EXPERIMENTAL DESIGN: Metabolic labeling, immunohistochemical, and immunoprecipitation techniques were used on kidney glomeruli from normal rats and from rats over the course of glomerulonephritis induced by administration of anti-thymocyte serum. Changes in beta 1 subunit-containing integrins and the extracellular matrix components that serve as ligands for these integrins were characterized. RESULTS: The data indicate that expression in glomeruli of alpha 1, alpha 5, and beta 1 subunits paralleled both mesangial content of the ligands for the alpha 1 beta 1 and alpha 5 beta 1 integrins, laminin, collagen and fibronectin, and TGF-beta 1 protein; increasing on day 7 of disease and decreasing toward normal by day 28. The alpha 3 subunit displayed the opposite pattern. Exogenous TGF-beta, but not other cytokines, stimulated synthesis of alpha 1 beta 1 and alpha 5 beta 1 integrins by normal glomeruli. CONCLUSIONS: The data indicate that glomerular beta 1 integrin expression is altered in a manner that would promote cell adhesion to the matrix proteins known to accumulate in this disease model. The data further suggest that TGF-beta is responsible for these changes.

Acute Disease↗
PubMed1992

Natural inhibitor of transforming growth factor-beta protects against scarring in experimental kidney disease.

The central pathological feature of human kidney disease that leads to kidney failure is the accumulation of extracellular matrix in glomeruli. Overexpression of transforming growth factor-beta (TGF-beta) underlies the accumulation of pathological matrix in experimental glomerulonephritis. Administration of an antibody raised against TGF-beta to glomerulonephritic rats suppresses glomerular matrix production and prevents matrix accumulation in the injured glomeruli. One of the matrix components induced by TGF-beta, the proteoglycan decorin, can bind TGF-beta and neutralize its biological activity, so decorin may be a natural regulator of TGF-beta (refs 3, 4). We tested whether decorin could antagonize the action of TGF-beta in vivo using the experimental glomerulonephritis model. We report here that administration of decorin inhibits the increased production of extracellular matrix and attenuates manifestations of disease, confirming our hypothesis. On the basis of our results, decorin may eventually prove to be clinically useful in diseases associated with overproduction of TGF-beta.

Animals↗
PubMed1992

The 260-kDa transforming growth factor (TGF)-beta binding protein in rat glomeruli is a complex comprised of 170- and 85-kDa TGF-beta binding proteins.

In a previous study (MacKay, K., Robbins, A. R., Bruce, M. D., and Danielpour, D. (1990) J. Biol. Chem. 265, 9351-9356) we showed that rat glomeruli contain transforming growth factor (TGF)-beta 1 binding proteins with apparent molecular masses of 260, 170, and 85 kDa (Gl-260, Gl-170, Gl-85) as determined by electrophoresis under nonreducing conditions. We demonstrate here that Gl-260 is a complex of 170- and 85-kDa TGF-beta binding proteins. Under denaturing conditions the integrity of Gl-260 is maintained through the cross-linking of one monomer of the disulfide-linked TGF-beta 1 homodimer to Gl-85 and of the other monomer to the 100-kDa subunit of Gl-170. In addition, some Gl-260 complexes are maintained by direct cross-linking of Gl-85 to the 100-kDa subunit of Gl-170. One-dimensional peptide maps of Gl-85 and the 100-kDa subunit of Gl-170 indicate that they have distinctly different ligand binding domains. In contrast, peptide maps of Gl-85 and the type II receptor of normal rat kidney fibroblasts are similar. The biological responses of isolated glomeruli to TGF-beta appear to parallel those of cultured glomerular cells which are without detectable Gl-170 and Gl-260 binding proteins.

Affinity Labels↗
PubMed1992

In vivo interactions of TGF-beta and extracellular matrix.

TGF-beta, a multifunctional cytokine, plays an important role in embryogenesis and in regulating repair and remodeling following tissue injury. Many of the biological actions of TGF-beta are mediated by widespread effects on deposition of extracellular matrix. TGF-beta stimulates the synthesis of individual matrix components including proteoglycans, collagens and glycoproteins. TGF-beta also blocks matrix degradation by decreasing the synthesis of proteases and increasing the synthesis of protease inhibitors. Finally, TGF-beta increases the synthesis of matrix receptors and alters their relative proportions on the surface of cells in a manner that could facilitate adhesion to matrix. All of these events have largely been demonstrated in vitro in cultured cells. In an experimental model of glomerulonephritis we have shown that TGF-beta is responsible for the accumulation of pathological matrix in the glomeruli following immunological injury. Furthermore, all three of TGF-beta's actions on extracellular matrix--increased synthesis, decreased degradation and modulation of receptors--have now been documented to be involved in matrix deposition in vivo in this model. Administration of the proteoglycan decorin suppressed TGF-beta-induced matrix deposition in the nephritic glomeruli, thus confirming a physiological role for decorin as a regulator of TGF-beta. Inhibitors of TGF-beta may be important future drugs in treating fibrotic diseases caused by overproduction of TGF-beta.

Animals↗
PubMed1992

Production of extracellular matrix by glomerular epithelial cells is regulated by transforming growth factor-beta 1.

Transforming growth factor-beta (TGF-beta) has widespread effects on extracellular matrix production by many cultured cell lines and appears to play a role in the pathological accumulation of extracellular matrix that accompanies inflammatory and fibrotic diseases such as glomerulonephritis. Earlier experiments have shown that mesangial cells respond to TGF-beta 1 with a marked increase in the production of two chondroitin/dermatan sulfate proteoglycans, decorin and biglycan, but their production of other matrix components elevated in glomerulonephritis is not substantially affected by TGF-beta 1. Since the glomerular epithelial cells are also thought to contribute to matrix production in the glomerulus, we examined the ability of these cells to produce some of the nonproteoglycan matrix components in response to TGF-beta 1. Exposure of glomerular epithelial cells to TGF-beta 1 increased the production of fibronectin and type IV collagen, in addition to biglycan. Enhancement of the cell layer accumulation of laminin was also observed. These results show that TGF-beta 1 has a differential effect on extracellular matrix production by epithelial and mesangial cells from glomeruli. TGF-beta 1 released in the glomerulus secondary to injury could thus affect both cell types and lead to increased intraglomerular production of proteoglycans, whereas the increased fibronectin, type IV collagen, and laminin may primarily originate from the epithelial cells.

Animals↗
PubMed1992

Glomerular matrix accumulation is linked to inhibition of the plasmin protease system.

TGF-beta plays a pivotal role in the pathological accumulation of extracellular matrix in experimental glomerulonephritis. Increased TGF-beta expression leads to increased synthesis and deposition of extracellular matrix components while administration of anti-serum to TGF-beta suppresses the major manifestations of the disease. We hypothesized that TGF-beta might also enhance matrix accumulation by decreasing matrix turnover via effects on protease/protease inhibitor balance. Plasmin is a potent protease capable of degrading a variety of matrix molecules. Plasmin generation from plasminogen is regulated by plasminogen activator(s) (PA) and plasminogen activator inhibitor(s) (PAI). In this study PA activity was markedly reduced and PAI-1 synthesis dramatically increased when TGF-beta was added to normal glomeruli. Diseased glomeruli also showed decreased PA activity, increased PAI-1 synthesis and increased PAI-1 deposition into matrix. Administration of anti-TGF-beta serum to glomerulonephritic rats blocked the expected increase in glomerular PAI-1 deposition. Thus changes in the PA/PAI balance favoring accumulation of matrix are induced by TGF-beta in normal glomeruli and are present in nephritic glomeruli when endogenous TGF-beta production is high. Our findings implicate the plasmin protease system in tissue repair following acute glomerular injury and suggest another mechanism by which TGF-beta enhances the matrix accumulation characteristic of many glomerular diseases.

Animals↗