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Biomedical subjects

G Schieren

Publications and source records attributed to G Schieren.

12 recordsLinked to original sources
PubMed1997

Azotemia and extrarenal manifestations in old female Han:SPRD (cy/+) rats.

In humans suffering from polycystic kidney disease (PKD) a gender difference is seen with males exhibiting a faster rate of progression of chronic renal failure than females. The aim of this study was to examine renal function in female rats suffering from autosomal dominant PKD [Han:SPRD (cy/+)] and to look for the occurrence of extrarenal organ manifestations of PKD. In young (2 months) as well as in old female rats (21 months) relative kidney weight was greater in affected than unaffected animals. In contrast, only the old affected female rats developed azotemia (serum urea 95 +/- 124 mg/dl) and severe cystic kidney transformation. Furthermore, old affected female rats exhibited liver cysts (affected 42%; unaffected 3%) and pancreatic cysts (affected 69%; unaffected 15%). Liver cyst epithelia stained positive for cytokeratin 19, a marker for bile duct epithelia. By immunohistochemistry liver cysts exhibited a similar extracellular matrix composition as observed in renal cysts of the same animals (staining positive for laminin, fibronectin and heparan sulfate proteoglycan, but not collagen I). This study proves PKD in the Han:SPRD (cy/+) rat model to be a truly multiorgan disease with a close resemblance of the human disease.

Age Factors↗
PubMed1996

Murine models of polycystic kidney disease.

The current knowledge of human polycystic kidney disease (PKD)--its morphology as well as the current biochemical and molecular understanding of the disease- has been enormously aided by the existence of a variety of animal models. In mice, several spontaneous mutations have been identified that give rise to PKD. Furthermore, it has been possible to create experimental models of renal cystic disease by genetic manipulation. All these different models have been very informative in studying the role of growth hormones, cell differentiation and hyperplasia, ionic transport, oncogene expression and changes in extracellular matrix (ECM) composition during the development of PKD. Furthermore, they have allowed investigators to test different therapeutic approaches in vivo. This article will review the characteristics of the most common murine models of PKD, some of their current uses and the future role of these animal models in the understanding of human renal cystic disease.

Animals↗
PubMed1996

Rat models of autosomal dominant polycystic kidney disease.

Several rat models of polycystic kidney disease (PKD) have been published. The only rat model of autosomal dominant polycystic kidney disease currently used is the so-called Hannover rat (Han:SPRD cy/+). This model is characterized by a slow progression of uraemia, proteinuria and hyperlipidaemia. Histological changes clearly resemble those seen is human PKD. The localization of Na+/K(+)-ATPase correlating with the phenotype of the cysts--basal in moderately expanded and apical in highly expanded cysts--suggests that the mislocation of the Na+/K(+)-ATPase is involved in the mechanism of cyst expansion rather than formation, and a consequence of cell dedifferentiation rather than an initial event. Of note is a considerable gender difference in disease severity. Disease anticipation or genetic imprinting does not occur. In addition to gender, a number of interventions influence the progression rate: acceleration is noted after unilateral nephrectomy, the induction of acidosis, chloride feeding or an increased protein intake; slowing down of the course occurs after the induction of alkalosis and castration, and after treatment with lovastatin and methylprednisolone. Thus the Han:SPRD cy/+ rat represents the only well-documented rat model of autosomal dominant PKD resembling a number of features of the human disease.

Animals↗
PubMed1996

In vitro formation of cysts derived from a rat model of autosomal dominant polycystic kidney disease.

In this study, we report a model of spontaneous cyst formation in vitro and a procedure to obtain large quantities of cysts from polycystic rat kidney cells. Furthermore, we assess the effects of epidermal growth factor, a modulator of morphogenesis, and of taxol, a stabilizer of microtubules, which has recently been proposed as a useful treatment of human polycystic kidney disease (PKD). It is anticipated that data generated from in vitro studies using cysts from PKD-affected rat kidneys may yield further insights to the pathophysiological and cellular basis of fatal renal cyst formation processes, and may lead to specific therapeutic strategies directed at controlling the growth of cysts, thereby reducing the number of animal tests.

Animals↗
PubMed1992

Enhanced expression of the complement-regulatory factor C8 binding protein (C8bp) on U937 cells after stimulation with IL-1 beta, endotoxin, IFN-gamma, or phorbol ester.

C8 binding protein (C8bp) is a 65-kDa membrane glycoprotein that inhibits complement-mediated lysis by homologous C5b-9. C8bp was first identified on human erythrocytes, but could also be detected on peripheral blood cells, platelets, glomerular cells and synovial fibroblasts. Lack of C8bp as seen in patients with paroxysmal nocturnal hemoglobinuria type III results in enhanced susceptibility of the cells toward C5b-9. We studied C8bp expression on the promonocytic cell line U937. In addition to the membrane-bound C8bp, a cytoplasmic form of C8bp could also be identified by immunofluorescence, blotting, and precipitation. Stimulation of the cells with IL-1 beta, endotoxin, IFN-gamma, or phorbol ester increased C8bp surface expression. Because cycloheximide did not inhibit enhanced surface expression, it was most probably mobilized from cytoplasmic reservoirs. Thus, resistance of nuclear cells to complement attack seems to be based on two events: 1) the removal of the C5b-9 complex from the membrane; and 2) expression of regulatory surface proteins such as C8bp, which inhibit C5b-9-mediated lysis. We propose that the C8bp mobilization by cytokines might provide an additional protection against complement attack by its known interference with the C5b-9 assembly.

Blood Proteins↗
PubMed1992

Hair removal by a depilatory does not affect survival in rodent experimental flaps.

The current study looked at the effect of topically applied hair depilatory agent Nair on flap survival. In a 10 x 3-cm dorsal rat flap model, there were no statistically significant differences in survival noted on postoperative day 7 between control skin and flaps receiving 6 to 24 minutes of Nair preoperatively. Therefore, hair depilation by Nair can be used safely in this model.

Administration, Cutaneous↗
PubMed1992

Immune damage to the mesangium: antibody- and complement-mediated stimulation and destruction of mesangial cells.

The deposition of immune complexes in the tissue results in complement activation leading to the formation of the lytic C5b-9 complex. Tissue cells are relatively resistant to complement attack due to cellular mechanisms such as removing C5b-9 from the surface and the expression of membrane proteins, which regulate complement activation and attack on the cell surface. Hence, cell killing is not an important consequence of complement activation on nucleated cells. On the other hand, the sublethal C5b-9-membrane interaction leads to various cellular responses, among them the synthesis of eicosanoids, cytokines, matrix-degrading proteases, and extracellular matrix, resulting in the modification of cell proliferation, leukocyte function, matrix degradation, and the formation of scar tissue. Thus, the complement-dependent immune damage is caused by secondary mediators, either derived from leukocytes or mesangial cells, rather than by a direct C5b-9-mediated killing.

Animals↗
PubMed1989

The beneficial effect of chlorpromazine on dorsal skin flap survival.

A 3 x 10-cm dorsal rat skin flap contains a distal portion that is poorly perfused. The dorsal flap served as a useful model to test hemodynamic properties of the vasodilatory drug chlorpromazine. A control group of flaps were treated with saline and the test group with chlorpromazine (15 mg/kg intraperitoneally). Eight days postoperatively, the surface area of the flaps that necrosed was 27.3% for the treated group and 36.5% for the controls. Using Student's t-test this difference was significant (p less than 0.001). Nutrient blood flow determined by the penetration of fluorescein dye into the flap was consistently greater in the chlorpromazine-treated group compared with the control group in the first 24 hours postoperatively. The adenosine triphosphate (ATP) levels measured at 0 and 24 hours postoperatively were consistently lower in the distal parts of the flap, treated or control, compared with proximal parts of the flap (p less than 0.001, analysis of variance). However, there were no significant differences in ATP levels between treated and control biopsies at any one site on the flap. In conclusion, chlorpromazine had a beneficial effect on rat skin survival, and increased blood flow appears to be one of the major reasons.

Animals↗
PubMedDate not supplied

A new in vitro bioassay for cyst formation by renal cells from an autosomal dominant rat model of polycystic kidney disease.

Autosomal dominant polycystic kidney disease (ADPKD) is one of the most frequent human inherited diseases. The main feature of the disease is the development of renal cysts, first occurring in the proximal tubules, and with time, dominating all segments of the nephron, leading to end-stage renal disease in 50% of the patients in their fifth decade of life. A therapy for polycystic kidney disease (PKD) has not yet been developed. Patients coming to end-stage ADPKD require long-term dialysis and/or transplantation. A suitable animal model to study ADPKD is the spontaneously mutated Han:SPRD (cy/+) rat, but a method to cultivate Han:SPRD (cy/+) derived renal cells which preserves their ability to form cyst-like structures in vitro has previously not been reported. Based on this well-characterized animal model, we developed a cell culture model of renal cyst formation in vitro. When renal cells of the Han:SPRD (cy/+) rat were isolated and cultured under conditions that prevent cell-substratum adhesion, large amounts of cyst-like structures were formed de novo from Han:SPRD (cy/+) derived renal cells, but only a few from control rat renal cells. In contrast, when cultivated on plastic as monolayer cultures, Han:SPRD (cy/+)-derived and control rat-derived renal cells were indistinguishable and did not form cyst-like structures. Immunohistochemical characterization of the cyst-like structures suggests tubular epithelial origin of the cyst-forming cells. The amount of cysts formed from Han:SPRD (cy/+)-derived renal cells grown in a stationary suspension culture is susceptible to modulation by different conditions. Human cyst fluid and epidermal growth factor both stimulated the formation of cysts from Han:SPRD (cy/+)-derived renal cells whereas taxol inhibited cystogenesis. In contrast, neither human cyst fluid nor epidermal growth factor affected the amount of cysts formed by control rat renal cells. As the culture model reported here allows not only the distinction of PKD-derived tubular epithelium from its normal counterpart, but also the modulation of cyst formation especially by Han:SPRD (cy/+)-derived renal cells, it might be a useful prescreening protocol for potential treatments for PKD and thus reduce the need for animal experiments.

Animals↗
PubMedDate not supplied

Expression of the complement regulator factor C8 binding protein on human glomerular cells protects them from complement-mediated killing.

The complement-regulatory factor C8 binding protein (C8bp) was first identified on human erythrocyte membranes by its affinity for the complement component C8 and its ability to inhibit lysis by homologous complement. Cultured human glomerular mesangial or epithelial cells (GEC) expressed C8bp on the cell surface and in the cytoplasm. Following stimulation of the glomerular cells with interleukin 1 beta, C5b-9 or with endotoxin, a transient, protein synthesis-independent increase in C8bp surface expression was seen. Blocking of C8bp function with F(ab)2 fragment of an antibody to C8bp rendered GEC susceptible to complement-mediated killing, indicating that C8bp contributes to the cellular defense against complement attack.

Blood Proteins↗
PubMedDate not supplied

Fibronectin modulates interleukin 6 and fibronectin synthesis of human glomerular mesangial cells in culture.

In this paper we report that fibronectin (FN) and its proteolytic 120-kD fragment regulate synthesis and secretion of interleukin 6 (IL-6) and of FN by human glomerular mesangial cells. While intact FN and a fragment derived from the heparin-binding domain had no effect on IL-6 secretion, the 120-kD FN fragment containing the cell attachment site stimulated secretion by 40-fold. The same FN fragment reduced FN secretion and the steady state mRNA level by 80%. The intact FN showed only a weak inhibitory effect (+/- 30%); the 30-kD fragment containing the heparin-binding domain had no effect. The effects of the 120-kD FN were inhibited by the peptide RGDS, implying participation of the cell attachment site in signal transduction. An antibody to the alpha-chain of VLA-3 mimicked the effect of the 120-kD FN, whereas an antibody to the alpha-chain of VLA-5 was partly inhibitory. Taken together, the data suggest that FN by interacting with its receptors differentially regulates the protein synthesis of glomerular mesangial cells, promoting IL-6 secretion and inhibiting FN synthesis.

Antibodies↗