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J Floege

Publications and source records attributed to J Floege.

At least 55 records · Page 3Linked to original sources
PubMed1998

C-type natriuretic peptide inhibits mesangial cell proliferation and matrix accumulation in vivo.

Local C-type natriuretic peptide (CNP) production and CNP receptor expression have been demonstrated in glomeruli. However, the glomerular (patho-)physiological functions of CNP are largely unknown. We therefore investigated the effects of CNP on mesangial cell proliferation and matrix accumulation in the rat mesangioproliferative anti-Thy 1.1 model. Over seven days rats received a continuous infusion (1 microgram/kg/min) of either CNP (N = 6), an irrelevant control peptide (N = 3) or buffer alone (N = 6). Kidney biopsies were performed on days 2, 4 and 8. Few significant differences between the groups were noted on days 2 and 4. Compared to buffer treated rats on day 8, those receiving CNP showed a 35% reduction of glomerular mitoses, a 62% reduction of glomerular uptake of the thymidine analogue BrdU and a significant reduction in glomerular expression of PDGF B-chain. Double immunoperoxidase staining also revealed blunting of proliferating, activated mesangial cells (515 reduction of alpha-smooth muscle actin-/BrdU-positive cells) and macrophage influx. Moreover, there was a marked reduction of mesangial collagen IV and fibronectin accumulation at the protein and mRNA level. Rats receiving the control peptide were indistinguishable from buffer treated rats. Systemic blood pressure was reduced by 10 to 20% in both CNP and control peptide treated rats on day 8, excluding that the findings were due to hemodynamic effects of CNP. Our findings demonstrate that CNP is involved in the regulation of mesangial cell proliferation and matrix production in vivo. The data suggest the existence of a glomerular natriuretic peptide system that may regulate tissue homeostasis and contribute to resolution of mesangioproliferative diseases.

Animals↗
PubMed1998

Alterations of synovial tissue and their potential role in the deposition of beta2-microglobulin-associated amyloid.

BACKGROUND: Beta-2-microglobulin-associated amyloidosis (AB2M) is a frequent complication of long-term dialysis treatment. Uraemic retention of beta2-microglobulin (beta2M) apparently constitutes the basis for AB2M. However, it is unclear why clinical manifestations are largely confined to osteoarticular tissues. It has been speculated that synovial inflammatory changes, induced by uraemia and/or dialysis therapy could predispose this tissue to amyloid deposition. METHODS: We investigated which local synovial alterations preceded or paralleled amyloid deposition. Using immunohistology we evaluated synovial leukocyte infiltration (B and T lymphocytes, monocytes/macrophages), cell proliferation, fibroblast activation (de novo expression of alpha-smooth-muscle actin), the expression of extracellular matrix components (heparan sulphate proteoglycan, collagen types I, III, IV), and advanced glycation end-products (AGEs). RESULTS: Synovial AB2M was detected in 20 of 36 chronic peritoneal and haemodialysis patients and none of eight non-uraemic controls. Notably, non-AB2M synovial amyloid was present in six additional dialysis and three control patients. Cellular infiltration was largely restricted to patients with advanced AB2M deposits. The infiltrates consisted mainly of macrophages and progressed with increasing degrees of AB2M deposition. In advanced cases they exhibited characteristics of a foreign-body reaction. Other infiltrating leukocyte types, altered cell proliferation, or fibroblast activation were absent or uncommon in periarticular tissue of dialysis patients with and without AB2M. Neither dialysis treatment nor the presence of AB2M deposits appreciably altered the qualitative matrix composition in periarticular tissue. AGEs were present in AB2M deposits, the extracellular synovial matrix of dialysis patients (of both, patients with and without AB2M) and, to a lesser degree, in synovia of controls. CONCLUSIONS: These data suggest that, except for AGE formation, alterations of none of the parameters assessed, and in particular no inflammatory tissue alterations, precede periarticular AB2M. Rather synovial tissue, possibly modified by AGEs, seems to have an intrinsic propensity for amyloid deposition and inflammatory changes appear to only arise secondary to amyloid deposition.

Adult↗
PubMed1998

Improved survival and amelioration of nephrotoxic nephritis in intercellular adhesion molecule-1 knockout mice.

Intercellular adhesion molecule-1 (ICAM-1) expression is upregulated in nephrotoxic nephritis, a model of human rapidly progressive glomerulonephritis. To evaluate the pathogenetic relevance of ICAM-1 in this model, nephrotoxic nephritis was induced in ICAM-1 knockout mice and genetic controls. Mice were preimmunized with rabbit IgG in complete Freund's adjuvant. Seven days later they received rabbit anti-mouse glomerular basement membrane IgG. The early humoral immune responses (levels of circulating mouse anti-rabbit IgG, glomerular deposition of rabbit and mouse IgG and mouse C3c) were not altered in ICAM-1 knockout mice. During 28 d of follow-up, 3 of 19 control nephritic mice and 0 of 16 ICAM-1 knockout mice died. Proteinuria was high in nephritic control mice (means 10 to 12 mg/24 h at all time points investigated) and significantly reduced in nephritic ICAM-1 knockout mice (means <4.4 mg). Mean serum creatinine rose from 29 micromol/L at day -7 to 48 micromol/L (day 28) in nephritic control mice. This increase in serum creatinine was significantly lower in ICAM-1 knockout mice: 27 (day -7) and 36 micromol/L (day 28). Histologic analysis at day 28 revealed that ICAM-1 deficiency in nephrotoxic nephritis mice led to significantly reduced glomerular crescent formation (2+/-3% in ICAM-1 knockout mice versus 13+/-8% in nephritic controls) and tubulointerstitial injury (score 0.4+/-0.4 versus 2.0+/-1.1). By immunohistochemistry, ICAM-1 deficiency in nephritic mice led to significantly reduced (peri-)glomerular and/or interstitial macrophage influx, alpha-smooth muscle actin expression, and type IV collagen accumulation. These data indicate that ICAM-1 is a central mediator of glomerular and tubulointerstitial injury in murine nephrotoxic nephritis.

Animals↗
PubMed1998

Expression of PDGF alpha-receptor in renal arteriosclerosis and rejecting renal transplants.

Platelet-derived growth factor (PDGF) plays an important role in renal disease. We have recently demonstrated that in healthy mature human kidney, PDGF alpha-receptor expression is largely restricted to interstitial cells. The study presented here assesses the expression of PDGF alpha-receptor in 18 mature adult kidneys with arteriosclerosis from individuals with no clinically evident history of renal disease other than localized neoplasia, in 13 kidneys with irreversible transplant rejection, and in a series of renal transplant biopsies composed of examples of both severe and absent rejection, by in situ hybridization and immunocytochemistry. Strong focal or diffuse expression of PDGF alpha-receptor mRNA and protein was noted in some intimal cells of intrarenal arterial vessels exhibiting signs of arteriosclerosis and/or vascular rejection. By double immunostaining, it could be shown that these cells were neither endothelial cells nor infiltrating leukocytes. The cells were most often identified as smooth muscle by colabeling for the smooth muscle cell-specific protein SM22alpha and less commonly for alpha-smooth muscle actin. There was also a population of PDGF alpha-receptor-expressing cells that failed to colabel with any of these markers, and hence remain of uncertain histogenesis. These intimal cells were generally negative for several other markers of differentiated smooth muscle cells, i.e., calponin and desmin. Near these PDGF alpha-receptor-positive intimal cells, expression of PDGF A-chain, an alpha-receptor ligand, was demonstrated in endothelial, intimal, and/or medial cells. Prominent PDGF alpha-receptor mRNA and protein expression also was noted in areas of interstitial fibrosis and in some glomeruli, in particular those with segmental glomerulosclerosis or fibrotic crescents. Double immunolabeling for PDGF alpha-receptor and alpha-smooth muscle actin confirmed that most of these latter PDGF alpha-receptor-positive cells were interstitial myofibroblasts or mesangial cells, or both. In summary, these data demonstrate widespread expression of PDGF alpha-receptor in renal cell types involved in fibrotic and sclerosing processes. The data also show that PDGF alpha-receptor expression identifies a unique population of phenotypically altered vascular smooth muscle cells, which appear to be involved in the vascular response to injury.

Adult↗
PubMed1998

Endogenous fibroblast growth factor-2 mediates cytotoxicity in experimental mesangioproliferative glomerulonephritis.

Fibroblast growth factor-2 (FGF-2) is released from mesangial cells in experimental mesangioproliferative glomerulonephritis induced with anti-Thy 1.1 antibody. To investigate the functional role of released FGF-2, rats received either neutralizing anti-FGF-2 IgG or a functional peptide antagonist of FGF-2 (FGF119-126) before or shortly after induction of anti-Thy 1.1 nephritis. In additional experiments, rats were treated with bolus injections of FGF-2 from 2 to 6 h after disease induction. The data showed that anti-FGF-2 therapy led to significant reductions of early mesangial cell injury (mesangiolysis, microaneurysm formation) and the subsequent mesangioproliferative changes (glomerular de novo expression of alpha-smooth muscle actin, mesangial cell proliferation, matrix accumulation, and platelet influx). Conversely, injections of FGF-2 augmented both mesangial injury and the subsequent mesangioproliferative changes. Studies on the mechanisms underlying the amplification of mesangial cell injury by FGF-2 showed that anti-FGF-2 therapy reduced cell death at 2 and 8 h after disease induction by 58 and 54%, respectively. This was associated with significant reductions in the number of glomerular H2O2- and OH -producing cells, as well as reduced glomerular production of nitric oxide. These data suggest that release of constitutively expressed FGF-2 after immune-mediated cell injury contributes to glomerular cell damage and thus identify FGF-2 as a novel mediator of cytotoxicity.

Animals↗
PubMed1997

Recurrent immunoglobulin A nephropathy after renal transplantation: a significant contributor to graft loss.

BACKGROUND: Although most transplanted patients with underlying IgA nephropathy (IgAN) develop histological recurrence, its clinical relevance is considered low. METHODS: We performed a single-center analysis of 61 renal transplant patients with IgAN. RESULTS: Forty-four percent of the patients showed a stable graft function. Progressive graft dysfunction apparently due to recurrent IgAN occurred in 23% of the patients (16% required dialysis). Five patients were retransplanted, and three again developed dialysis-dependent renal failure apparently due to recurrent IgAN. In 20% of the patients, chronic transplant dysfunction was due to other reasons, whereas no reason was identified in 13% of the patients. Neither findings before transplantation, the ACE genotype, the type of immunosuppression, nor the course after transplantation predicted transplant dysfunction due to recurrent IgAN. Follow-up after transplantation was longer in the group with dysfunction due to recurrent disease than in the group with dysfunction due to chronic rejection or in the stable group. CONCLUSION: Recurrent IgAN is a clinically relevant problem in renal transplant patients. Its importance may have been underestimated in the past due to inadequate lengths of follow-up.

Adult↗
PubMed1997

Localization of PDGF alpha-receptor in the developing and mature human kidney.

Using in situ hybridization and immunocytochemistry we describe the renal localization of the PDGF alpha-receptor. PDGF alpha-receptor mRNA was uniformly present in human metanephric kidney in interstitial cells and vascular arcades that course through the blastema. PDGF alpha-receptor mRNA was present in some mesangial structures in early glomeruli, but was largely lost as glomeruli matured. It was present in adventitial fibroblasts, but usually not in vascular smooth muscle cells or endothelial cells of the fetal vasculature. This pattern persisted in adult kidneys, with extensive expression of mRNA by interstitial cells and only occasional expression by mesangial cells. All in situ hybridization findings were corroborated by immunocytochemistry. Double immunolabeling confirmed the rare expression of the PDGF alpha-receptor protein by vascular smooth muscle cells and the absence of its expression by endothelial cells. Given that both PDGF A- and B-chain can promote smooth muscle cell and fibroblast migration and proliferation and that both signal through the PDGF alpha-receptor, these data suggest that PDGF alpha-receptor may play important roles in the early vasculogenesis of the fetal kidney as well as in the pathogenesis of renal interstitial fibrosis.

Adult↗
PubMed1997

Activated complement C3: a potentially novel predictor of progressive IgA nephropathy.

In the search for a serologic marker of disease activity, we measured concentrations of activated C3 (actC3, that is, neoantigens developing after C3 activation on breakdown products), C4-C3 complexes and soluble C5b-9 (sC5b-9) in one or two plasma samples from adult patients with IgA nephropathy (IgAN, N = 50) or Henoch-Schönlein purpura (HSP, N = 4). As controls, 20 patients with non-immune renal disease, but comparable age, degree of proteinuria, renal dysfunction and prevalence of hypertension were studied. Compared to controls, actC3 levels were elevated in 30% of the patients with IgAN and one of the HSP patients. C4-C3 complexes were elevated in only 8% of the IgAN patients, and sC5b-9 levels were within the control range in all IgAN and HSP patients. In IgAN patients with elevated actC3 levels, proteinuria and hematuria were more pronounced than in those with normal levels. Elevated plasma concentrations of actC3 at the first presentation correlated with subsequent deterioration of renal function both in patients with initially normal and already impaired renal function (r = -0.56, N = 44, P = 0.003). The five IgAN patients with elevated actC3 on both occasions of obtaining plasma showed the most rapid loss of renal function. We conclude that mainly alternative pathway complement activation can be demonstrated in patients with IgAN and HSP. In IgAN patients the presence of complement activation is associated with more severe renal disease. Further studies are warranted to examine the clinical usefulness of actC3 as a predictor of the subsequent course of IgAN.

Adolescent↗
PubMed1997

Age-related glomerulosclerosis and interstitial fibrosis in Milan normotensive rats: a podocyte disease.

In Milan normotensive (MNS) rats glomerulosclerosis and interstitial fibrosis develop spontaneously in the absence of hypertension. Renal changes were sequentially assessed in these rats between 2 and 10 months of age. At 10 months, rats were characterized by heavy proteinuria, increased serum creatinine, focal or global glomerulosclerosis in 51 +/- 12% of the glomeruli as well as tubulointerstitial injury involving > 25% of the section area. Cell injury in podocytes (evidenced as increased expression of desmin and by electron microscopy) and interstitial fibroblasts (increased expression of alpha-smooth muscle actin) and mild glomerular hypertrophy were witnessed as early as three to four months of age and preceded glomerulosclerosis and interstitial fibrosis. Only minor evidence of mesangial cell activation (as assessed by glomerular (de novo alpha-smooth muscle actin or type I collagen expression or increased cell proliferation) was noted throughout the observation period. Later stages of the disease were characterized by glomerular and/or tubulointerstitial macrophage influx and osteopontin expression (a chemoattractant), mild accumulation of lymphocytes, platelets, fibrinogen, as well as by a progressive accumulation of various matrix proteins. Progressive renal disease in MNS rats is thus noteworthy for the relative lack of mesangial cell activation. Rather, early podocyte damage, induced by yet unknown mechanisms, may underlie the development of glomerulosclerosis and subsequent interstitial fibrosis.

Actins↗
PubMed1997

Cyclin kinase inhibitors are increased during experimental membranous nephropathy: potential role in limiting glomerular epithelial cell proliferation in vivo.

The inadequate proliferative response of the visceral glomerular epithelial cell (GEC) following injury in vivo may contribute to the development of progressive glomerulosclerosis in many forms of glomerular disease. Cell proliferation is ultimately controlled by cell-cycle regulatory proteins, including cyclins that bind to cyclin dependent kinases (CDK), and the active complex formed is necessary for progression through the cell-cycle. By inhibiting cyclin-CDK complexes, cyclin kinase inhibitors arrest the cell-cycle and prevent proliferation. To determine the mechanisms that may be responsible for the lack of GEC proliferation in vivo, we examined GEC expression of specific cell-cycle proteins in normal rats and in the passive Heymann nephritis (PHN) model of membranous nephropathy, where the GEC are the target of complement-mediated injury. Following antibody deposition and complement activation there was a marked up-regulation in the cyclin kinase inhibitors p21 and p27 in rats with PHN. By associating with cyclin A-CDK2 complexes, p21 and p27 limited the kinase activity of CDK2. Giving bFGF to rats with PHN was associated with an increase in GEC mitosis and ploidy and a decrease in expression of p21, but not CDK2 or p27. Furthermore, apoptosis was not present in PHN, but was increased in rats given bFGF. In conclusion, this study shows that the low proliferative capacity of the GEC in vivo in response to immune injury may be due to an increase in the expression of specific cyclin kinase inhibitors. The increase in mitosis in PHN rats given bFGF may be due to a decrease in p21. Thus, changes in cell cycle regulatory proteins may regulate the response of GEC to injury and underlie the development of progressive glomerulosclerosis in diseases of the GEC.

Animals↗
PubMed1997

Beta 2-microglobulin associated amyloidosis: a vanishing complication of long-term hemodialysis?

Beta 2-microglobulin associated amyloidosis (A beta 2m amyloidosis) is considered an inevitable complication of chronic hemodialysis, particularly in hemodialysis with cellulose based membranes. We performed a single center study to assess the prevalence of A beta 2m amyloidosis in 1988 versus 1996. Randomly selected patients, studied in 1988, were matched for time on hemodialysis (mean 71 months, range 3 to 207) and age (mean 51 years, range 22 to 80) with patients of the 1996 population. Compared to 1988 patients, the 1996 patients exhibited a lower prevalence of carpal tunnel syndrome (7 of 43 in 1988 vs. 1 of 43 in 1996; P < 0.001) and radiological evidence of A beta 2m amyloidosis (13 of 34 patients vs. 3 of 34 patients positive; P < 0.001; and 33 of 272 possible sites affected in 1988 vs. 7 of 272 sites in 1996 patients; P < 0.05). Compared to the 1988 population, the 1996 population exhibited significantly lower serum aluminum levels, lower average serum creatinine (but not urea) levels, more frequent therapy with erythropoietin, less home hemodialysis, longer hemodialysis time using high-flux synthetic dialysis membranes (mean of 13% vs. 6% of the total hemodialysis time in the 1988 group), and more frequent usage of reverse osmosis water plus bicarbonate buffer for dialysate preparation. We conclude that the prevalence and severity of A beta 2m amyloidosis unexpectedly decreased by about 80% in our center between 1988 and 1996. Given the relatively short times spent on high flux hemodialysis in both groups, increased beta 2-microglobulin removal is unlikely to account for this phenomenon. Rather, other factors, for example, dialysate composition and purity, may be involved.

Adult↗
PubMed1997

Role of interleukin-6 in mediating mesangial cell proliferation and matrix production in vivo.

Mesangial cell proliferation and matrix overproduction characterize many progressive glomerular diseases. Based on currently available data, the role of interleukin-6 (IL-6) in mediating mesangial cell proliferation and matrix production is controversial. The present study attempts to clarify this issue by showing that: (1) IL-6 knock out mice develop a normal glomerular architecture and in particular a normal mesangium. (2) Mesangioproliferative glomerulonephritis induced by Habu snake venom is equally severe in IL-6 knock out mice as in control mice. (3) A continuous seven-day intraperitoneal infusion of 50 micrograms recombinant human IL-6 into rats with a prior minimal (subnephritogenic) injury to mesangial cells does not induce glomerular cell activation, cell proliferation, matrix production, leukocyte influx, platelet influx or proteinuria. (4) A continuous seven-day IL-6 infusion into rats with mesangioproliferative nephritis (anti-Thy 1.1 nephritis) increases matrix protein transcription in the absence of detectable effects on matrix protein accumulation and otherwise has no effect on the natural course of the disease. We conclude from these findings that IL-6 is not an important mediator of mesangial cell proliferation and matrix overproduction in vivo, and that currently little rationale exists to advocate anti-IL-6 therapy in mesangioproliferative disease states.

Animals↗
PubMed1997

Cationic dextran induces mesangioproliferative nephritis in rats independent of glomerular IgA deposition.

BACKGROUND: Dextran-induced mesangioproliferative glomerulonephritis in mice and, as recently reported, in rats is used as a model of IgA nephropathy. The pathogenetic role of the glomerular IgA deposits in this model, however, is unclear since IgG is often deposited in parallel. METHODS: Lewis rats were immunized with cationic DEAE-dextran. Following this, rats received 5 x/week i.v. injections of 3 mg DEAE-dextran each, from days 20 to 80 and were then followed until day 120. RESULTS: Rats developed transient proteinuria (range 63-152 mg/24 h) and haematuria on day 80. Renal biopsies obtained at days 60, 80, 100 and 120 showed mild to severe mesangioproliferative changes at days 80 and 100 which did not persist at day 120. Electron-microscopy revealed mesangial immune deposits, signs of endothelial activation and vacuoles in mesangial cells and podocytes. Compared to normal, age-matched controls, in the nephritic rats significant (P < 0.05) increases were noted for glomerular total cellularity, alpha-smooth-muscle actin expression (a marker of activated mesangial cells), monocyte/macrophage counts, and matrix proteins. Using three different antibodies, no evidence of glomerular IgA deposition was detected at any time point. In contrast, glomerular IgG, IgM, C3, and occasional small C5b-9 deposits were present in nephritic rats. Circulating IgG but not IgA anti-dextran antibodies could be demonstrated in nephritic rats. CONCLUSIONS: The data confirm that mesangioproliferative glomerulonephritis can be induced in rats by immunization and chronic challenge with cationic dextran. Our data also show that in rats glomerular IgG deposition rather than IgA, appears to play an important pathogenetic role in this mesangioproliferative glomerulonephritis model.

Animals↗
PubMed1997

Treatment of experimental mesangioproliferative glomerulonephritis with non-anticoagulant heparin: therapeutic efficacy and safety.

Treatment with conventional heparin is effective in experimental mesangioproliferative glomerulonephritis. However, the long-term effects and safety of this therapy, in particular in the presence of mesangiolysis, have not been assessed. In addition, this therapy has been hampered by bleeding complications. In the present study, therefore, we investigated the long-term effects of a short course of non-anticoagulant (NA) heparin treatment in the anti-Thy 1.1 mesangioproliferative glomerulonephritis, in which early immune-mediated mesangiolysis subsequently leads to mesangial hyperproliferation. Rats received continuous ip NA-heparin or vehicle during the active mesangioproliferative phase (Days 2 to 9; early treatment) or during the early resolution phase (Days 10 to 17; late treatment). Whereas NA-heparin in the early treatment group did not affect the glomerular macrophage, lymphocyte, or platelet influx, it did lead to significantly decreased glomerular cellularity, mesangial cell proliferation, alpha-smooth muscle actin, desmin expression (ie, markers of activated mesangial cells), and matrix accumulation as well as to persistent mesangiolytic lesions including microaneurysms. Despite this latter finding, at Day 120, NA-heparin-treated rats of the early treatment group showed significantly better renal function and less proteinuria and glomerulosclerosis than vehicle-infused rats. In contrast, late therapy with NA-heparin neither accelerated resolution of the nephritis or otherwise affected the course of the disease. We conclude that transient NA-heparin therapy is effective in mesangioproliferative glomerulonephritis, both acutely and long term, when it is initiated during the active phase of the disease. Also, NA-heparin therapy is safe even in glomerular diseases accompanied by mesangiolysis.

Aneurysm↗