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V Cattell

Publications and source records attributed to V Cattell.

At least 37 records · Page 2Linked to original sources
PubMed1995

The nitric oxide pathway in glomerulonephritis.

Nitric oxide has fundamental roles in the modulation of many cell functions. In glomerulonephritis, generation of nitric oxide by the acutely inflamed glomerulus has recently been confirmed, with evidence that synthesis occurs through induction of the inducible form of nitric oxide synthase. Recent studies implicate infiltrating macrophages as a major source of this activity, although intrinsic glomerular cells may contribute as nitric oxide synthase has been found in cytokine-stimulated mesangial, endothelial and epithelial cells in culture. Cytokines, which are known to have a central role in glomerulonephritis, are the most probable stimulus of nitric oxide synthase induction in vivo, although this awaits confirmation. A role for nitric oxide in the pathophysiology of glomerulonephritis is not clearly defined at present but is strongly suggested by evidence for participation of nitric oxide in other immune and inflammatory diseases. The evidence evaluated in this review emphasizes that the role is certain to be complex. As yet it is not possible to predict whether the modulatory effects of nitric oxide on glomerular haemodynamics, vascular integrity, leucocyte infiltration and intrinsic glomerular cell responses are predominantly protective or cytotoxic. There are presently only two fully published reports of inhibition of nitric oxide in models of glomerulonephritis, one of which showed an exacerbation of acute heterologous nephrotoxic injury, and the other showed amelioration of chronic autoimmune glomerulonephritis. It is therefore premature to speculate on the effects of nitric oxide inhibition in glomerulonephritis. New insights await further understanding of the regulation of the inducible form of nitric oxide synthase in glomerulonephritis and the availability of specific inhibitors of this enzyme.

Animals↗
PubMed1995

Inducible nitric oxide synthase in inflammation.

Inflammation, the reaction of vascularized tissue to local injury, not only limits the effects of injury; it may also be the underlying pathological process which initiates or sustains disease. In this paper, the evidence is reviewed for a role for nitric oxide (NO) as a chemical indicator of inflammation and inflammatory diseases.

Animals↗
PubMed1994

Localization of inducible nitric oxide synthase in acute renal allograft rejection in the rat.

There is increasing evidence for a role for nitric oxide (NO) in the alloimmune response and induction of NO synthesis occurs during allograft rejection. The aim of this study was to investigate the source of NO synthesis in rejecting allografts. Localization of inducible nitric oxide synthase (iNOS) was studied by immunohistochemistry, in a rat model of acute renal allograft rejection, in unmodified Lewis recipients in which rejection is complete 7 days after transplantation of F1 hybrid Lewis-Brown Norway kidneys. High levels of iNOS expression were found in infiltrating mononuclear cells in glomeruli and interstitium of rejecting kidneys; there was no expression in parenchymal renal cells, or in control isografts of either rat strain. Expression of iNOS in the cortex was present from 4 to 6 days posttransplantation, and had declined by the 7th day, where expression was principally in the medulla. The pattern of iNOS staining was similar to ED1 staining, a marker for rat macrophages. These findings suggest that infiltrating macrophages in the graft reaction are a prominent source of NO; this iNOS expression supports a role for NO in the modulation of local allogeneic responses, and possibly as a mediator of cytotoxic graft damage.

Amino Acid Oxidoreductases↗
PubMed1994

Mycoplasma fermentans and HIV-associated nephropathy.

We describe a patient in whom HIV-associated nephropathy developed in association with the detection of Mycoplasma fermentans. This mycoplasma was found in renal tissue by means of a polymerase chain reaction when nephropathy was first evident, and subsequently in urine, blood and the throat. The evidence presented strengthens the causal association of this micro-organism with HIV-induced nephropathy.

AIDS-Associated Nephropathy↗
PubMed1994

Induction of nitric oxide synthase in rat immune complex glomerulonephritis.

Nitric oxide (NO) is a biological mediator which is synthesized from L-arginine by a family of nitric oxide synthases (NOS). Previously we have shown that NO is synthesized ex vivo by glomeruli obtained from animals with acute immune complex glomerulonephritis. We have now sought evidence for the in vivo induction of NOS in glomeruli by immunohistochemistry using specific antisera raised against a peptide sequence of inducible mouse macrophage NOS and by in situ hybridization. The expression of the enzyme was studied in kidneys of rats with acute unilateral immune complex glomerulonephritis, induced by cationized IgG, by immunohistochemistry. Inducible NOS (iNOS) was present in glomeruli in nephritic (left) kidneys at the time of maximum macrophage infiltration, both within intraglomerular mononuclear cells and cells emigrating into Bowman's space. iNOS expressing cells were also present in interstitial infiltrates. There was no expression in normal rat kidneys or in glomeruli in the non-nephritic (right) kidneys of experimental rats. In situ hybridization confirmed the immunohistochemical localization. These results provide the first direct evidence for the presence and localization of inducible NOS in glomeruli and support a significant role for NO in the pathogenesis of immune complex glomerulonephritis.

Amino Acid Oxidoreductases↗
PubMed1994

Cellular localization of inducible nitric oxide synthase in experimental endotoxic shock in the rat.

1. Endotoxin induces a shock-like syndrome with increased nitric oxide synthesis. To clarify the cellular source of NO in endotoxic shock we used immunohistochemistry and in situ hybridization to localize inducible NO synthase in rats given lipopolysaccharide or Corynebacterium parvum and lipopolysaccharide. Immunohistochemistry was carried out with an antibody raised against a synthetic peptide of mouse macrophage NO synthase. In situ hybridization was performed with 35S-labelled oligonucleotide probes corresponding to cDNA sequences common to mouse macrophage inducible NO synthase and rat vascular smooth inducible NO synthase. Monocytes and macrophages were identified by immunohistochemistry with the mouse monoclonal antibody ED1. 2. After lipopolysaccharide alone, the major site of NO synthase induction was monocytes and macrophages in multiple organs, principally liver and spleen. Bronchial, bile duct, intestinal and bladder epithelium and some hepatocytes also expressed inducible NO synthase. Expression peaked at 5 h and had returned to normal by 12 h except in spleen. 3. After priming with C. parvum, lipopolysaccharide led to a similar distribution of inducible NO synthase as lipopolysaccharide alone, but in addition there was more prominent hepatocyte staining, staining in macrophage granulomas in the liver and inducible NO synthase was present in some endothelial cells in the aorta. 4. These findings provide a direct demonstration of the cellular localization of inducible NO synthase after lipopolysaccharide.

Amino Acid Oxidoreductases↗
PubMed1994

Glomerular expression and cell origin of transforming growth factor-beta 1 in anti-glomerular basement membrane disease.

The glomerular expression (mRNA levels) of transforming growth factor-beta 1 (TGF-beta 1) was assessed in two forms of rat anti-glomerular basement membrane (GBM) disease, a macrophage-independent and a macrophage-dependent variant. After a single intravenous injection of rabbit anti-rat GBM immune serum, significant proteinuria and histopathologic changes developed in both variants. Increased TGF-beta 1 mRNA levels were found in isolated glomeruli of the macrophage-dependent variant only in which glomerular infiltration by macrophages also occurred. Macrophages isolated from glomeruli of animals with this variant demonstrated TGF-beta 1 mRNA levels comparable to those found in glomeruli isolated at the same time point after injection of the anti-GBM serum. The observations indicate that in anti-GBM disease, enhanced glomerular TGF-beta 1 expression occurs in the macrophage-dependent variant and suggest that infiltrating macrophages account for this event.

Animals↗
PubMed1994

Expression of the gene for inducible nitric oxide synthase in experimental glomerulonephritis in the rat.

Nitrite, a stable product of nitric oxide (NO), is synthesized in vitro by glomeruli in experimental glomerulonephritis. We have now studied the expression of the gene for inducible NO synthase (iNOS) in accelerated nephrotoxic nephritis (NTN). The purpose of the study was to confirm in vivo induction of iNOS in this model of immune complex disease, and to relate the onset of induction and the level of expression to pathogenic events in the model. Glomeruli from rats with NTN were isolated at 6 h, 24 h and 2, 4 and 7 days and total RNA extracted. RNA (10 micrograms) was reverse transcribed and polymerase chain reaction (PCR) was performed with primers homologous to rat vascular smooth muscle iNOS and rat beta actin. A 222-base PCR product corresponding to iNOS mRNA was present in all experimental animals. iNOS expression was also found in activated macrophages, neutrophils and IL-1-stimulated but not unstimulated mesangial cells. Quantitative competitive PCR was carried out on glomerular samples using a 514-bp mutant of a 735-bp PCR product. iNOS expression was present at low levels in normal glomeruli and was markedly enhanced at 6 h after the induction of glomerulonephritis and peaked at 24 h. Increased iNOS expression persisted to day 7. beta actin mRNA levels were similar in all glomerular specimens. This study demonstrates that there is in vivo induction of iNOS in immune complex glomerulonephritis, corresponding to the generation of nitrite we have previously reported. iNOS gene expression is detectable within 6 h of induction of NTN, indicating the onset of gene transcription is closely related to the initial formation of immune complexes.

Amino Acid Oxidoreductases↗
PubMed1994

Arginine metabolism in experimental glomerulonephritis: interaction between nitric oxide synthase and arginase.

L-Arginine is metabolized by two pathways: 1) by nitric oxide synthase (NOS) to nitric oxide (NO) and 2) by arginase forming urea and L-ornithine. Inflammatory responses may involve a balance between the pathways, as NO is cytotoxic and vasodilatory and L-ornithine is a promoter of cell proliferation and matrix synthesis. In experimental glomerulonephritis we have previously shown that NOS is activated in nephritic glomeruli. We have now examined both pathways of L-arginine metabolism to study competition for L-arginine, temporal variation, and the sources of NOS and arginase. Acute in situ glomerulonephritis was induced in rats, and glomeruli were studied at 1, 4, and 7 days. Both NOS and arginase activities were present. There was temporal variation: NOS activity was highest on day 1 and arginase activity on day 4; both declined by day 7. Competition between the pathways was demonstrated by increased urea synthesis in the presence of NG-monomethyl-L-arginine, an inhibitor of NOS. Measurement of NOS and arginase activities in macrophages isolated from nephritic glomeruli showed that these cells were a major source of glomerular NOS but not arginase activity. In contrast, high arginase activity but low NO production was identified in cultured rat glomerular mesangial cells. These studies show differential temporal variation in expression of NOS and arginase pathways of arginine metabolism in experimental glomerulonephritis. We have found two factors that may contribute to this: 1) competition for substrate L-arginine between the two pathways and 2) different cellular sources. We hypothesize that the balance between these pathways is a mechanism regulating injury, hemodynamics, and mesangial cell proliferation.

Amino Acid Oxidoreductases↗
PubMed1994

Proliferating cell nuclear antigen (PCNA) as a diagnostic marker of acute cellular rejection in routinely processed biopsies of renal allografts.

Seventy-eight renal allograft biopsies taken for the management of graft dysfunction were analysed retrospectively by labelling with antibodies to proliferating cell nuclear antigen (PCNA) to assess whether this marker could distinguish episodes of rejection. Routinely processed, paraffin-embedded biopsies with focal or diffuse cellular infiltrates were selected and the percentage of infiltrating cells in the cortical interstitium which stained with PCNA antibody were counted (PCNA index). The area of cellular infiltration was also estimated by a morphometric point-counting technique. The biopsies were divided into two groups based on standard clinical criteria; those with acute rejection (n = 31) and those with other causes of graft dysfunction (n = 47). The PCNA index was significantly higher in episodes of acute rejection (7.9%) compared to non-rejection (2.1%). This was independent of time after transplantation. The PCNA index was also greater in rejecting kidneys containing only focal cellular infiltrates (percentage area of cellular infiltration < 13.1%). Thus PCNA staining may be of use in the differential diagnosis of rejection in routinely processed biopsies of renal allografts where there are only focal inflammatory infiltrates, otherwise not diagnostic of cellular rejection.

Acute Disease↗
PubMed1992

Arginase is a major pathway of L-arginine metabolism in nephritic glomeruli.

L-arginine can be metabolized to nitric oxide (NO) by nitric oxide synthase (NOS) and to urea and L-ornithine by arginase. Competition between these pathways for L-arginine in inflammatory sites has been suggested. In experimental glomerulonephritis glomeruli produce nitrite; a major source is macrophages. We hypothesized that arginase is present in glomeruli and may compete for substrate with NOS in glomerulonephritis. Therefore we examined both pathways in isolated nephritic glomeruli and peritoneal macrophages. Arginase activity was present in glomeruli, increased by > 500% in nephritic glomeruli compared to controls, and was predominant over NOS. Activity increased with L-NMMA (a NOS inhibitor), but this trend did not reach statistical significance. In macrophages both pathways were present; NOS predominated basally but this was reversed by L-NMMA. In contrast with glomeruli macrophage arginase activity increased after LPS stimulation. Levels of macrophage arginase activity could not account for activity in nephritic glomeruli, suggesting another source of arginase. This is the first demonstration of high arginase activity of nephritic glomeruli. Competition between arginase and NOS pathways suggests a regulatory mechanism of L-arginine metabolism within the glomerulus, with implications for the pathogenesis of injury and scarring in glomerulonephritis.

Amino Acid Oxidoreductases↗
PubMed1992

Urinary excretion of nitrite and nitrate in experimental glomerulonephritis reflects systemic immune activation and not glomerular synthesis.

In immune-induced glomerulonephritis (gn), glomeruli (gl) synthesize nitric oxide (NO), and urinary nitrite (NO2-) excretion is increased. In mammals on a low nitrate (NO3-) diet, urinary NO3- is a measure of endogenous NO3- synthesis. Excretion is increased after administration of macrophage activators, reflecting induction of NO production. To determine whether increased urinary NO2- gn is due to glomerular synthesis we studied urinary NO2-/NO3- in accelerated nephrotoxic nephritis induced by preimmunization with rabbit immunoglobulin G (IgG), followed by rabbit anti-rat nephrotoxic globulin, and in control rats similarly preimmunized with rabbit IgG, but followed by normal rabbit serum. Both urinary NO2- and NO3- were increased by i.p. preimmunization with rabbit IgG (peak 463 +/- 171 nmol NO2-/60.3 +/- 9.4 nmol NO3-/24 h, P < 0.001 for both NO2- and NO3- compared with preimmunization levels). Repeat immunization with i.v. rabbit anti-rat nephrotoxic globulin (nephritic rats) or normal rabbit globulin (control rats) again increased urinary NO2- and NO3-. There was no statistically significant difference in urinary NO2- and NO3- levels between nephritic rats where globulin had nephrotoxic activity and the control rats injected with normal rabbit globulin, despite increased NO2- synthesis in ex vivo nephritic glomeruli after nephrotoxic globulin (7.9 +/- 1.9 nmol/2000 gl/48 h; controls 3.2 +/- 1.0 nmol/2000 gl/48 h). Thus neither urinary NO2- nor NO3- levels reflect local activation of the NO pathway in glomeruli. As reported for other stimulants, we show here that systemic stimulation with foreign antigen increased NO synthesis.

Animals↗
PubMed1991

Glomeruli synthesize nitrite in active Heymann nephritis; the source is infiltrating macrophages.

Glomeruli synthesize nitrite (NO2-) in experimental nephrotoxic nephritis, a model of glomerulonephritis where infiltrating macrophages are pathogenic. NO2- synthesis was studied in active Heymann nephritis (AHN), a model of membranous glomerulonephritis in which macrophages have not been implicated. Active Heymann nephritis (AHN) was induced with purified renal tubular epithelial antigen and adjuvants. Glomeruli isolated at seven to eight weeks after induction (proteinuria 183 +/- 28 mg/24 hr, N = 6; adjuvant controls, 1.2 +/- 0.8 mg/24 hr, N = 6) produced NO2- in culture spontaneously (7.1 +/- 1.4, adjuvant controls 2.1 +/- 0.9 nmol/2000 g/48 hours; P = 0.021) and in increased amount following LPS stimulation (12.1 +/- 2.8, controls 4.2 +/- 1.6 nmol/2000 g/48 hours; P = 0.047). Synthesis was inhibited by L-NMMA, a competitive inhibitor of NO synthase. Enzymic digestion of glomeruli plus staining with mouse anti-rat macrophage monoclonal antibody ED1 showed macrophage infiltration (32 +/- 6, adjuvant controls 14 +/- 2 macrophages/glomerulus; P = 0.002). Whole body irradiation (XR) suppressed NO2- production (LPS stimulated: 1.0 +/- 0.4, N = 5; non-XR controls 7.2 +/- 4.6 nmol/2000 g/48 hours; N = 5, P = 0.016) and macrophage infiltration (1.1 +/- 0.5; non-XR controls 30 +/- 12 macrophages/glomerulus; P = 0.008) but had no effect on proteinuria. Irradiation with renal shielding confirmed the close correlation between glomerular NO2- synthesis and glomerular macrophage numbers (rs = 0.837, P less than 0.001). These results show that macrophages infiltrate glomeruli in AHN; they are the source of NO2- in this model. Neither macrophages nor NO2- are the cause of proteinuria.

Animals↗
PubMed1990

Glomeruli synthesize nitrite in experimental nephrotoxic nephritis.

Activated macrophages synthesize nitric oxide (NO) from L-arginine. In culture, the major stable end product is nitrite (NO2). Activated macrophages accumulate in glomeruli and are responsible for injury in experimental immune complex glomerulonephritis. We examined NO2- production by isolated glomeruli and urinary NO2- in accelerated nephrotoxic nephritis in the rat. Normal glomeruli did not produce NO2- spontaneously or when stimulated with lipopolysaccharide (LPS) (1 microgram/ml) or A23187 (2 microgram/ml). Cultured mesangial cells at first or seventh passage did not produce NO2- spontaneously or when stimulated. Nephritic glomeruli spontaneously produced NO2 at all times studied; this production was maximal at 24 hours after induction of glomerulonephritis (158.4 +/- 8.4 nmol/48 hr/ml, N = 3). The production of NO2- was inhibited 75 to 100% by NG-monomethyl-L-arginine (L-NMMA), and this inhibition was reversed by L-arginine, indicating NO2- production from L-arginine via NO. The production of NO2- was increased by LPS (1 microgram/ml) at 2, 7 and 21 days. NO2- was undetectable in normal rat urine; however, it was present in urine of rats with glomerulonephritis (Day 0 to 1:8161 +/- 2605 nmol/24 hr. N = 12). The production of NO in nephritic glomeruli may have implications for both the mechanism of glomerular injury and glomerular hemodynamics.

Animals↗