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Biomedical subjects

W A Border

Publications and source records attributed to W A Border.

At least 37 records · Page 2Linked to original sources
PubMed1997

Transforming growth factor-beta in human glomerular injury.

Overexpression of the cytokine transforming growth factor-beta has been identified as the key mediator of chronic progressive kidney fibrosis in experimental and human kidney diseases. The renoprotective effects of angiotensin II blockade and low-protein diets have recently been linked to downregulation of transforming growth factor-beta production. Neutralizing the actions of transforming growth factor-beta by decorin gene therapy appears to be a highly effective new approach in the treatment of renal fibrosis.

Angiotensin II↗
PubMed1997

Angiotensin II in renal fibrosis: should TGF-beta rather than blood pressure be the therapeutic target?

A large body of data has now implicated elevations in the cytokine transforming growth factor-beta (TGF-beta) as a key mediator of tissue fibrosis. A number of mechanisms by which TGF-beta can be increased have been identified. Among them is the potent vasoconstrictor angiotensin II (ANG II). In vitro data indicate that ANG II, independent of blood pressure, increases synthesis and decreases degradation of pathological extracellular matrix components. These effects are largely, but not completely, mediated by ANG II induction of TGF-beta. In many models of renal fibrosis and in a number of human renal diseases, blockade of ANG II retards disease progression. Very recent studies indicate that ANG II blockade suppresses TGF-beta, whether the therapeutic agent is an angiotensin converting enzyme inhibitor or an ANG II type 1 receptor antagonist. These data suggest that an important antifibrotic, therapeutic effect of ANG II blockade is reduction of TGF-beta overexpression and raise the question of whether disease progression could be further retarded if ANG II blockade were optimized for maximal TGF-beta reduction rather than for normalization of systemic blood pressure.

Angiotensin II↗
PubMed1996

L-arginine metabolism in immune-mediated glomerulonephritis in the rat.

Low-protein diets slow the progression of some renal diseases. We recently found that dietary restriction of L-arginine markedly ameliorates disease in antithymocyte serum-induced glomerulonephritis in the rat, suggesting that L-arginine may play a key role in the beneficial effects of low-protein diets. L-arginine is metabolized by nitric oxide synthases to nitric oxide and L-citrulline or by arginase to urea and L-ornithine. L-ornithine is a precursor for polyamines, which are required for cell proliferation and for proline, an essential component of collagen. In a time course of disease, we found that inducible nitric oxide synthase gene expression and nitric oxide production were increased very early. Arginase activity was significantly increased until 5 days of disease. Ornithine decarboxylase, the rate-limiting step for polyamine synthesis, was increased at 3 days coincident with the onset of cell proliferation. Gene expression of ornithine aminotransferase, a proline synthetic enzyme, was increased from day 1, paralleling increased collagen synthesis. Thus, the three pathways of L-arginine metabolism are upregulated in a manner consistent with their possible roles in the cell lysis, cell proliferation, and collagen deposition, which characterize this model of glomerulonephritis.

Animals↗
PubMed1996

Role of transforming growth factor-beta 1 in experimental chronic cyclosporine nephropathy.

The pathogenesis of fibrosis in chronic cyclosporine (CsA) nephropathy remains unknown. Since TGF-beta 1 plays a key role in the fibrogenesis of a number of renal diseases, we studied a salt-depleted rat model of chronic CsA nephropathy which shows similarity to the structural and functional lesions described in patients. Pair fed rats were treated with either CsA (15 mg/kg/day s.c.) or an equivalent dose of olive oil and sacrificed at 7 and 28 days. Characteristic histologic changes of proximal tubular injury, tubulointerstitial fibrosis and arteriolopathy developed in CsA-treated rats at day 28. They were accompanied by physiologic changes of increased serum creatinine, decreased creatinine clearance, increased enzymuria and decreased concentrating ability. CsA-treated rats showed a progressive increase in mRNA expression of TGF-beta 1 and matrix proteins at days 7 and 28. Most of the changes were in the tubulointerstitial and vascular compartments by immunofluorescence with a predominant involvement of the medulla as compared to cortex. The mRNA expression of plasminogen activator inhibitor, a protease inhibitor stimulated by TGF-beta 1, followed TGF-beta 1 and matrix proteins, suggesting that the fibrosis of chronic CsA nephropathy likely involves the dual action of TGF-beta on matrix deposition and degradation.

Animals↗
PubMed1996

Expression of transforming growth factor-beta isoforms in human glomerular diseases.

Protein and mRNA expression of TGF-beta isoforms, TGF-beta 1, -beta 2 and -beta 3, and deposition of fibronectin containing extra domain A (fibronectin EDA+) and plasminogen activator inhibitor-1 (PAI-1) were studied in human chronic glomerulonephritis and diabetic nephropathy. Normal kidneys showed similar, weak immunostaining for all three TGF-beta isoforms. TGF-beta mRNA expression was weak for all isoforms with TGF-beta 1 > TGF-beta 3 >> TGF-beta 2. In thin basement membrane disease and minimal change disease, disorders where extracellular matrix accumulation is not a feature, immunoreactivity and mRNA expression did not differ from normal. In contrast, diseases characterized by extracellular matrix accumulation (IgA nephropathy, focal and segmental glomerulosclerosis, crescentic glomerulonephritis, lupus nephritis and diabetic nephropathy) all showed significantly increased expression of the three TGF-beta isoforms in glomeruli and the tubulointerstitium. While glomerular and tubulointerstitial deposition of two matrix components induced by TGF-beta, fibronectin EDA+ and PAI-1, was significantly elevated in all diseases with matrix accumulation, correlation analysis revealed a close relationship primarily with TGF-beta 1. We conclude that, for a spectrum of human glomerular disorders, increased protein expression of all three TGF-beta isoforms and proteins induced by TGF-beta is associated with pathological accumulation of extracellular matrix.

Antibody Specificity↗
PubMed1996

Gene therapy by skeletal muscle expression of decorin prevents fibrotic disease in rat kidney.

There are currently no effective therapies for progressive fibrotic diseases. Recent evidence has implicated overproduction of transforming growth factor-beta1 (TGF-beta1) as a major cause of tissue fibrosis. Furthermore, this evidence implies that inhibitors of TGF-beta1 may be clinically useful as antifibrotic agents. The proteoglycan decorin is a known inhibitor of TGF-beta1. In a rat model of glomerulonephritis we have shown that fibrosis is mediated by TGF-beta1. We report here that transfer of decorin cDNA into rat skeletal muscle increases the amount of decorin messenger RNA and protein present in skeletal muscle and decorin present in kidney, where it has a marked therapeutic effect on fibrosis induced by glomerulonephritis. Transfected glomerulonephritic rats showed a significant reduction in levels of glomerular TGF-beta1 mRNA and TGF-beta1 protein, extracellular matrix accumulation and proteinuria. These results demonstrate the potential of gene therapy as a novel treatment for fibrotic diseases caused by TGF-beta1.

Animals↗
PubMed1995

L-arginine may mediate the therapeutic effects of low protein diets.

We have previously shown beneficial effects of dietary protein restriction on transforming growth factor beta (TGF-beta) expression and glomerular matrix accumulation in experimental glomerulonephritis. We hypothesized that these effects result from restriction of dietary L-arginine intake. Arginine is a precursor for three pathways, the products of which are involved in tissue injury and repair: nitric oxide, an effector molecule in inflammatory and immunological tissue injury; polyamines, which are required for DNA synthesis and cell growth; and proline, which is required for collagen production. Rats were fed six isocaloric diets differing in L-arginine and/or total protein content, starting immediately after induction of glomerulonephritis by injection of an antibody reactive to glomerular mesangial cells. Mesangial cell lysis and monocyte/macrophage infiltration did not differ with diet. However, restriction of dietary L-arginine intake, even when total protein intake was normal, resulted in decreased proteinuria, decreased expression of TGF-beta 1 mRNA and TGF-beta 1 protein, and decreased production and deposition of matrix components. L-Arginine, but not D-arginine, supplementation to low protein diets reversed these effects. These results implicate arginine as a key component in the beneficial effects of low protein diet.

Animals↗
PubMed1995

Transforming growth factor-beta and angiotensin II: the missing link from glomerular hyperfiltration to glomerulosclerosis?

Both angiotensin II and TGF-beta are key mediators of glomerular and tubulointerstitial injury and fibrosis in progressive kidney diseases. It was thought that angiotensin II damages the kidney by increasing glomerular filtration pressure, whereas autocrine TGF-beta overexpression occurs from unidentified mechanisms. Recent studies reveal that angiotensin II is a potent inducer of TGF-beta synthesis in a variety of cells and that this mechanism exerts important biological effects including extracellular matrix accumulation, cell proliferation, and hypertrophy. Because these studies were performed in vitro, there is clear evidence that the biological effects were observed independently of the vasoconstrictive properties of angiotensin II. Although it is difficult to study angiotensin II-mediated effects in vivo without influencing systemic and glomerular blood pressure, further studies are needed to evaluate the ability of ACE-inhibitors and angiotensin II receptor blockers to suppress TGF-beta overexpression in selected models of chronic progressive kidney disease.

Angiotensin II↗
PubMed1995

Transforming growth factor-beta and matrix protein expression in acute and chronic rejection of human renal allografts.

Because the increased tissue expression of TGF-beta underlies fibrosis in many diseases, it was hypothesized that sustained elevated transforming growth factor (TGF)-beta overexpression might be responsible for fibrosis in chronic rejection of the renal allograft. To test this hypothesis, biopsies were obtained from 5 patients with acute rejection, 5 patients with chronic rejection, 10 normal individuals, and 10 patients with kidney disease. The tissues were examined by immunofluorescence for the three TGF-beta isoforms (1, 2, and 3) and the two matrix proteins induced by TGF-beta that serve as markers of fibrosis: fibronectin extradomain A positive (EDA+) and plasminogen activator inhibitor-1 (PAI-1). The tubulointerstitium from all cases of acute rejection and chronic rejection showed highly significant increases in immunostaining for the three TGF-beta isoforms (P < 0.001), fibronectin EDA+ (P < 0.005), and PAI-1 (P < 0.001). In the glomeruli, only TGF-beta 1 expression achieved statistical significance (P < 0.005) in acute rejection, whereas in chronic rejection, all three TGF-beta isoforms (p < 0.001) in addition to fibronectin EDA+ (p < 0.001) and PAI-1 (p < 0.001) were elevated. There was both cellular and matrix staining of the TGF-beta isoforms. In striking contrast, control kidney tissues were negative or only weakly positive. Because TGF-beta was present both in acute and in chronic rejection but not in control tissues and because acute rejection episodes are a good predictor for chronic rejection, these results suggest that TGF-beta may play a role in the pathogenesis of fibrosis in chronic rejection.

Acute Disease↗
PubMed1995

Nitric oxide mediates immunologic injury to kidney mesangium in experimental glomerulonephritis.

BACKGROUND: Nitric oxide (NO), produced from L-arginine by an inducible NO synthase, is an important effector molecule in inflammatory and immunologic tissue injury. The role of NO generation in immunologic injury to glomerular mesangial cells and the effect of dietary restriction of L-arginine on this injury was investigated. EXPERIMENTAL DESIGN: Acute glomerulonephritis was induced by injection of anti-thymocyte serum (ATS) which binds to an antigen on the glomerular mesangial cell. Complement-mediated mesangial cell lysis follows. The effect of blocking NO production in vivo by administration of the NOS inhibitor NG-monomethyl-L-arginine (L-NMMA) 60 minutes before ATS injection on mesangial cell lysis, and on the severity of disease was assessed. The effect of dietary restriction of L-arginine on mesangial cell lysis in response to ATS injection was also determined. RESULTS: We report here that blocking NO production in vivo with L-NMMA prevented mesangial cell lysis by 90%. Injection of L-NMMA caused transiently elevated systolic blood pressure, but did not diminish ATS binding to mesangial cells or recruitment of monocyte/macrophages into glomeruli indicating that L-NMMA pretreatment did not limit injury by insufficient glomerular perfusion. ATS-induced proteinuria and increases in urinary nitrite excretion were prevented. Glomerular expression of transforming growth factor-beta and accumulation of extracellular matrix were suppressed by the L-NMMA treatment. Low protein diet (6%), but also selective dietary L-arginine restriction, given for 7 days before induction of the disease mimicked L-NMMA treatment, significantly decreasing mesangial cell lysis. The effect of a low protein diet was abolished by dietary L-arginine supplementation. CONCLUSIONS: This study strongly implicates NO as a mediator in immune-mediated mesangial cell lysis. The data suggest that limiting NO production by limiting arginine intake might decrease glomerular injury and subsequent glomerulosclerosis.

Animals↗
PubMed1994

Interaction of the small interstitial proteoglycans biglycan, decorin and fibromodulin with transforming growth factor beta.

We have analysed the interactions of three proteoglycans of the decorin family, decorin, biglycan and fibromodulin, with transforming growth factor beta (TGF-beta). The proteoglycan core proteins, expressed from human cDNAs as fusion proteins with Escherichia coli maltose-binding protein, each bound TGF-beta 1. They showed only negligible binding to several other growth factors. Intact decorin, biglycan and fibromodulin isolated from bovine tissues competed with the fusion proteins for the TGF-beta binding. Affinity measurements suggest a two-site binding model with Kd values ranging from 1 to 20 nM for a high-affinity binding site and 50 to 200 nM for the lower-affinity binding site. The stoichiometry indicated that the high-affinity binding site was present in one of ten proteoglycan core molecules and that each molecule contained a low-affinity binding site. Tissue-derived biglycan and decorin were less effective competitors for TGF-beta binding than fibromodulin or the non-glycosylated fusion proteins; removal of the chondroitin/dermatan sulphate chains of decorin and biglycan (fibromodulin is a keratan sulphate proteoglycan) increased the activities of decorin and biglycan, suggesting that the glycosaminoglycan chains may hinder the interaction of the core proteins with TGF-beta. The fusion proteins competed for the binding of radiolabelled TGF-beta to Mv 1 Lu cells and endothelial cells. Affinity labelling showed that the binding of TGF-beta to betaglycan and the type-I receptors in Mv 1 Lu cells and to endoglin in endothelial cells was reduced, but the binding to the type-II receptors was unaffected. TGF-beta 2 and 3 also bound to all three fusion proteins. Latent recombinant TGF-beta 1 precursor bound slightly to fibromodulin and not at all to decorin and biglycan. The results show that the three decorin-type proteoglycans each bind TGF-beta isoforms and that slight differences exist in their binding properties. They may regulate TGF-beta activities by sequestering TGF-beta into extracellular matrix.

Biglycan↗