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Biomedical subjects

J Floege

Publications and source records attributed to J Floege.

At least 19 recordsLinked to original sources
PubMed2006

Upregulation of group IB secreted phospholipase A(2) and its M-type receptor in rat ANTI-THY-1 glomerulonephritis.

Treatment of rat glomerular mesangial cell (GMC) cultures with pancreatic secreted phospholipase A(2) (sPLA(2)-IB) results in an enhanced expression of sPLA(2)-IIA and COX-2, possibly via binding to its specific M-type sPLA(2) receptor. In the current study, we have investigated the expression and regulation of sPLA(2)-IB and its receptor during glomerulonephritis (GN). In vivo we used the well-established rat model of anti-Thy 1.1 GN (anti-Thy 1.1-GN) to study the expression of sPLA(2)-IB and the M-type sPLA(2) receptor by immunohistochemistry. In addition, in vitro we determined the interkeukin (IL)-1beta-regulated mRNA and protein expression in primary rat glomerular mesangial and endothelial cells as well as in rat peripheral blood leukocytes (PBLs). Shortly after induction of anti-Thy 1.1-GN, sPLA(2)-IB expression was markedly upregulated in the kidney at 6-24 h. Within glomeruli, the strongest sPLA(2)-IB protein expression was detected on infiltrated granulocytes and monocytes. However, at the same time, the M-type receptor was also markedly upregulated on resident glomerular cells. In vitro, the most prominent cytokine-stimulated secretion of sPLA(2)-IB was observed in monocytes isolated from rat PBLs. Treating glomerular endothelial cells (GECs) with cytokines elicited only weak sPLA(2)-IB expression, but treatment of these cells with exogenous sPLA(2)-IB resulted in a marked expression of the endogenous sPLA(2)-IB. Mesangial cells did not express sPLA(2)-IB at all. The M-type sPLA(2) receptor protein was markedly upregulated on cytokine-stimulated mesangial and endothelial cells as well as on lymphocytes and granulocytes. During anti-Thy 1.1 rat GN, sPLA(2)-IB and the M-type sPLA(2) receptor are induced as primary downstream genes stimulated by inflammatory cytokines. Subsequently, both sPLA(2)-IB and the M-type sPLA(2) receptor are involved in the autocrine and paracrine amplification of the inflammatory process in different resident and infiltrating cells.

Animals↗
PubMed2006

Biological responses to PDGF-BB versus PDGF-DD in human mesangial cells.

Platelet-derived growth factor (PDGF)-BB and PDGF-DD mediate mesangial cell proliferation in vitro and in vivo. While PDGF-BB is a ligand for the PDGF alpha- and beta-receptor chains, PDGF-DD binds more selectively to the beta-chain, suggesting potential differences in the biological activities. Signal transduction and regulation of gene expression induced by PDGF-BB and -DD were compared in primary human mesangial cells (HMCs), which expressed PDGF alpha- and beta-receptor subunits. The growth factor concentrations used were chosen based on their equipotency in inducing HMCs proliferation and binding to the betabeta-receptor. Both growth factors, albeit at different concentrations induced phosphorylation and activation of extracellular signal-regulated kinase 1 (ERK1) and ERK2. In addition, PDGFs led to the phosphorylation and activation of signal transducers and activators of transcription 1 (STAT1) and STAT3. HMCs proliferation induced by either PDGF-BB or -DD could be blocked by signal transduction inhibitors of the mitogen-activated protein kinase-, Janus kinase (JAK)/STAT-, or phosphatidyl-inositol 3-kinase pathways. Using a gene chip array and subsequent verification by real-time reverse transcriptase (RT)-polymerase chain reaction, we found that in HMC genes for matrix metalloproteinase 13 (MMP-13) and MMP-14 and, to a low extent, cytochrome B5 and cathepsin L were exclusively regulated by PDGF-BB, whereas no exclusive gene regulation was detected by PDGF-DD. However, at the protein level, both MMP-13 and -14 were equally induced by PDGF-BB and -DD. PDGF-BB and -DD effect similar biological responses in HMCs albeit at different potencies. Rare apparently differential gene regulation did not result in different protein expression, suggesting that in HMCs both PDGFs exert their biological activity almost exclusively via the PDGF beta-receptor.

Angiogenesis Inducing Agents↗
PubMed2005

[Renovascular hypertension--diagnosis and therapy].

Atherosclerotic renal artery stenosis accounts for most cases of renovascular hypertension (RVH). Hypertensive patients with clinical features suggesting RVH should be submitted to further noninvasive evaluation including duplex Doppler ultrasonography, CT- or MR angiography. Invasive evaluation by contrast-enhanced angiography confirms the diagnosis of renal artery stenosis. However, neither diagnostic test reliably predicts the course of hypertension after revascularisation. The therapeutic approach in hypertensive patients with hemodynamically important renal artery stenosis includes medical or invasive therapy (renal percutaneous transluminal angioplasty, PTRA; renal arterial stent placement, PTRAS; surgical revascularisation). Randomized trials comparing invasive and conservative approaches demonstrated no differences in blood pressure control or renal function. Only patients with clear clinical indications should be submitted to interventional procedures as PTRA, PTRAS and surgical vascular intervention.

Angioplasty, Balloon↗
PubMed2005

COX-2 inhibitor induced anuric renal failure in a previously healthy young woman.

Side effects of nonsteroidal anti-inflammatory drugs (NSAIDs) most commonly affect the gastrointestinal tract and the kidney. The recent release of selective cyclooxygenase-2 (COX-2) inhibitors has been associated with a decrease in adverse gastrointestinal effects. However, the nephrotoxic potential of these drugs still remains controversial. Here, we report the case of a previously healthy woman with reversible acute renal failure associated with eight days of anuria following the administration of valdecoxib, a newly released selective cyclooxygenase-2 inhibitor, during an episode of acute febrile pyelonephritis. We suggest that selective COX-2 inhibitors should not be used in patients with volume contraction and underlying renal disease.

Acute Disease↗
PubMed2004

Tacrolimus- (FK 506) based immunosuppression in severe systemic lupus erythematosus.

In a 30-year-old male patient systemic lupus erythematosus was diagnosed based on the presence of 8 out of 11 ARA criteria. Disease onset was acute and included renal function impairment with biopsy-proven lupus nephritis (WHO class IV) requiring renal replacement therapy. Although conventional immunosuppressive therapy regimens proved effective in controlling disease activity, all of the administered drugs were accompanied by serious side effects: bilateral femur head necrosis with corticosteroids, allergic skin reaction in response to azathioprine, nephrotoxicity with cyclosporine, nausea and abdominal pain with mycophenolate mofetil and life-threatening septicemia with cyclophosphamide treatment. In search for alternative treatment options, tacrolimus (FK506, trough serum levels 3-6 ng/ml) was started. FK506 was well-tolerated and lupus activity completely resolved within 7 months after initiation of therapy. During 36 months of follow-up no arthritic complaints occurred and renal function stabilized at a serum creatinine of 2.1 mg/dl with negative anti-ds-DNA antibodies and ANA titers. In conclusion, FK506 may be considered as alternative immunosuppressive for maintenance treatment in patients with severe lupus erythematosus and side effects to conventional regimens.

Adult↗
PubMed2003

[Therapy and prophylaxis of renal failure].

The number of patients with end-stage renal disease is constantly growing. If patients at risk are identified early enough, currently available therapeutic options allow a potent primary and secondary prevention of progressive renal failure. If the underlying disease can not be eliminated, the mainstay of the therapy are supportive measures such as antihypertensive and, in case of an underlying diabetes mellitus, antidiabetic therapy, dietary restrictions as well as avoidance of additional nephrotoxic agents. Furthermore, even a mild renal insufficiency has been identified as a potent cardiovascular risk factor. The second major goal of supportive therapy therefore is a reduction of the markedly increased cardiovascular morbidity of these patients. This can be achieved through treatment of various consequences of renal failure, such as hyperparathyroidism, renal anemia etc. Supportive therapy thus represents a highly complex and interdisciplinary treatment, which should prompt an early inclusion of a nephrologist into the therapeutic strategy.

Diabetes Complications↗
PubMed2003

[IgA nephropathy: frequent, but rarely diagnosed].

IgA nephropathy (IgAN) is the most common type of glomerulonephritis in the western world. In the majority of cases, it manifests in adolescence or early adulthood as recurrent macrohematuria, frequently triggered by infections, or persistent microhematuria as well as mild proteinuria, hypertension and/or renal insufficiency. In view of the later, it is not surprising that IgAN is often a chance finding. The majority of affected persons probably never come to medical attention, since in autopsies a prevalence of up to 1% of the population has been reported. About 20-30% of patients with a diagnosis of IgAN suffer from chronic, slowly progressive renal failure. Predictors include the degree of proteinuria and arterial hypertension as well as the established renal impairment at the time of diagnosis. Early identification of this risk group is of particular importance, since adequate therapy can stop or at least retard the progression of renal failure. When end stage renal failure has developed and a renal transplant is performed, about 25% of the patients will experience a clinically relevant recurrence of IgAN with progressive graft dysfunction.

Diagnosis, Differential↗
PubMed2002

Inhibition of the renin-angiotensin system ameliorates genetically determined hyperinsulinemia.

This study was performed in order to assess the potentially different effects of the angiotensin-converting enzyme inhibitor captopril and of the angiotensin II receptor antagonist irbesartan on the metabolic syndrome in an animal model. Male NZO/BL6 F1 mice were treated with captopril, irbesartan, or placebo for 10 months: Control animals treated with placebo developed a metabolic syndrome with obesity (55.5+/-6.3 g), hypertension (146+/-10 mm Hg), hyperinsulinemia (7.2+/-5.7 ng/ml), hypercholesterolemia (5.1+/-0.7 mmol/l), cardiac hypertrophy (269+/-44 mg) and atherosclerotic plaques in the ascending aorta (3.6+/-1.5 microm(2)). Treatment with angiotensin-converting enzyme inhibitor or angiotensin II receptor antagonist significantly (p<0.001) reduces hypertension (73+/-5 and 78+/-11 mm Hg), cardiac hypertrophy (203+/-26 and 202+/-18 mg) and atherosclerosis (2.2+/-0.9 and 1.8+/-0.8 microm(2)). In addition, they prevented the development of obesity (42.2+/-3.5 and 38.3+/-2.8 g) and hyperinsulinemia (3.6+/-1.5 and 1.8+/-0.4 ng/ml). In conclusion, long-term treatment with an angiotensin-converting enzyme inhibitor or an angiotensin II receptor antagonist can ameliorate obesity and hyperinsulinemia in a genetically determined mouse model.

Angiotensin Receptor Antagonists↗
PubMed2001

Role of contact system activation in hemodialyzer-induced thrombogenicity.

BACKGROUND: The contact system is generally believed to be the main trigger of the coagulation cascade during extracorporeal circulation. However, the extent of contact activation, its role for intradialytic thrombin generation as well as the influence of different dialyzer membranes have not been well established. METHODS: In a novel full-scale ex vivo recirculation dialysis model, we investigated the thrombogenicity of three widely used hemodialyzers (Cuprophan Renak RA15-U, Polysulfone F6HPS and AN69XT Nephral 200). The activation of the contact system was evaluated using a newly developed ELISA for factor XIIa-C1-inhibitor complexes. Additionally, we determined free FXIIa (ELISA), thrombin-antithrombin (TAT) complexes, platelet factor 4 (PF4), complement activation (C5a), granulocyte elastase and blood cell counts. The findings in blood from normal volunteers were compared with factor XII-deficient blood. RESULTS: With normal blood AN69 exhibited the highest thrombogenicity in comparison to Cuprophan and Polysulfone, as assessed by TAT generation and platelet consumption. AN69 caused a rapid increase of the FXIIa-C1-inhibitor complexes and of free FXIIa. Despite significant TAT generation with Cuprophan and Polysulfone free FXIIa remained unchanged and the FXIIa-C1-inhibitor complexes stayed below the detection limit. With factor XII-deficient blood Polysulfone exhibited the same TAT generation, whereas the thrombogenicity of AN69 was greatly reduced. CONCLUSIONS: Our data challenge the common assumption that activation of the contact system with generation of FXIIa is the main trigger for coagulation and thrombus formation in hemodialysis. Only the negatively charged AN69 membrane with enhanced thrombogenicity strongly induced contact activation.

Adult↗
PubMed2001

Kidney protection against autoreactive CD8(+) T cells distinct from immunoprivilege and sequestration.

BACKGROUND: The kidney tubulointerstitium has been reported to be protected from T-cell--mediated damage by sequestration from the T-cell compartment. We examined the ability of autoreactive T cells to infiltrate the kidney in a transgenic mouse model. METHODS: RIP-mOVA transgenic mice express the model autoantigen, membrane-bound ovalbumin (mOVA), in kidney proximal tubular cells and pancreatic beta cells. OVA-specific CD8(+) T cells (OT-I cells) were transferred into these recipient mice and their immune response against pancreas and kidney tissue was compared. RESULTS: When OVA-specific CD8(+) T cells (OT-I cells) were injected into RIP-mOVA mice, they were activated in the renal and pancreatic lymph nodes by cross-presentation. These in vivo-activated OT-I cells caused the destruction of pancreatic islets leading to autoimmune diabetes, but did not infiltrate the kidney. Neither CD95--CD95 ligand interactions, which have been proposed to induce apoptosis in T cells infiltrating immunologically privileged sites, nor CD30 signaling was responsible for the lack of kidney infiltration. When OT-I cells were activated in vitro prior to injection, they could infiltrate the kidney and caused acute renal failure when injected in high numbers. CONCLUSIONS: A mechanism distinct from previously described organ-specific protective mechanisms such as sequestration of antigen or CD95-mediated immunoprivilege contributes to the protection of the kidney tubulointerstitium from infiltration by autoreactive CD8(+) T cell.

Animals↗
PubMed2001

beta2-microglobulin-derived amyloidosis: an update.

The present review attempts to summarize recent developments in the field of beta2-microglobulin-derived amyloidosis (A(beta2)m amyloidosis) in patients on chronic dialysis therapy. A key factor in the pathogenesis is the uremic retention of the precursor molecule, beta2-microglobulin (beta2m). However, secondary modifications of the molecule such as limited proteolysis, conformational changes, and the formation of advanced glycation end products have also been described. Finally, in order to explain the striking predilection of the disease for synovial and periarticular structures, a role of local predisposing factors within the synovial membrane (for example, of the particular constituents of the extracellular matrix) must also be postulated. With respect to clinical symptomatology, recent data have confirmed that clinically manifest signs of the amyloidosis represent only the tip of the iceberg, since histologically amyloid deposition is much more widespread. Noninvasive diagnosing of the disease has been advanced by technical changes of the beta2m scintigraphy. Finally, there is accumulating evidence that prevention of the disease not only includes the usage of high-flux synthetic membranes for hemodialysis or hemodiafiltration, but that other factors contribute to the clinical manifestations of amyloidosis such as the dialysate composition and its microbacteriological quality. Such factors, which have changed over the last years as part of general improvements in dialysis care, may explain why the prevalence of the amyloidosis appears to decrease.

Amyloidosis↗
PubMed2001

Association of prolonged hyperglycemia with glomerular hypertrophy and renal basement membrane thickening in the Goto Kakizaki model of non-insulin-dependent diabetes mellitus.

The aim of the current study was to characterize the effects of prolonged hyperglycemia on renal structure and function using a model of non-insulin-dependent diabetes mellitus: the Goto Kakizaki (GK) rat, which does not have confounding variables, such as hyperlipidemia, obesity, or elevated blood pressure. The data show that hyperglycemia in this model was not associated with the development of significant proteinuria, but it was associated with the development of definitive age-dependent renal structural changes. These changes consisted of thickening of glomerular basement membrane at 35 weeks and tubular basement membrane. This thickening was accompanied by marked glomerular hypertrophy resulting from a parallel increase in total capillary luminal volume and mesangial volume, but fractional capillary and mesangial volumes remained unchanged. There was evidence of podocyte injury, as assessed by de novo expression of desmin. In contrast, there was no evidence of mesangial cell activation, as assessed by their de novo expression of alpha-SMA. Interstitial monocyte/macrophage influx increased significantly in GK rats at 12 weeks compared with Wistar controls. Glomerular macrophage infiltration was elevated significantly in 35-week GK rats. The structural changes described in the GK rat are similar to those described in prolonged non-insulin-dependent diabetes mellitus patients who have not developed overt renal disease. This model allows us to investigate further the mechanisms involved in the pathogenesis of the consequences of prolonged hyperglycemia.

Aging↗