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Biomedical subjects

M A Kirschenbaum

Publications and source records attributed to M A Kirschenbaum.

At least 37 records · Page 2Linked to original sources
PubMed1994

Hematopoietic colony stimulatory factor formation by murine mesangial cells: gene expression and biological activity.

This study examined the ability of mesangial cells to synthesize colony-stimulating factors (CSF), cytoregulatory peptides associated with the differentiation and proliferation of hematopoietic cells. Conditioned media obtained from SV-40 transformed murine mesangial cells stimulated the growth of murine bone marrow progenitor cells of the myeloid series. Differential analysis of these cells showed the presence of both macrophages and granulocytes. Cellular identification of bone marrow colonies stimulated in response to mesangial cell conditioned media was examined by flow cytometric analysis and revealed the presence of F4/80 antigen positive macrophages (67%) and Gran-1 antigen positive granulocytes (21%). Neutralizing antibodies to macrophage colony-stimulating factor (M-CSF) and granulocyte-macrophage colony-stimulating factor (GM-CSF) but not antibody to interleukin-3 (IL-3), or stem cell factor (SCF) significantly inhibited the growth of the progenitor cells induced by mesangial cell conditioned media. Utilizing Northern blot analysis, murine mesangial cells expressed mRNA transcripts for M-CSF, GM-CSF, and granulocyte colony-stimulating factor (G-CSF). Further studies were performed to determine optimal incubation conditions for mesangial cell CSF gene expression. These studies revealed that both GM-CSF and G-CSF mRNA were maximally expressed at early time points (4 and 8 h of incubation), while M-CSF mRNA expression remained unchanged during the incubation of mesangial cells from 4-48 h. Incubation of mesangial cells with various concentrations of fetal bovine serum (FBS, 0.5-15%) markedly increased the mRNA expression of M-CSF, GM-CSF and G-CSF in a dose-dependent manner. These studies indicated that transformed murine mesangial cells are able to synthesize and secrete biologically active CSF that are associated with the migration and proliferation of circulating mononuclear cells in the glomerulus. Furthermore, observations regarding the role of duration of incubation and the media concentration of FBS on mesangial cell CSF mRNA expression may provide useful data to understand the optimal conditions for studies that examine the gene expression of basal or inducible CSF in mesangial cells.

Animals↗
PubMed1994

Uremic serum subfraction inhibits apolipoprotein A-I production by a human hepatoma cell line.

Abnormalities in lipoprotein metabolism are common in uremic patients and may represent an additional risk factor for the development of atherosclerosis. Despite the frequent occurrence of lipoprotein abnormalities, the role of various serum toxins and subfractions that accumulate in uremic patients on lipoprotein metabolism is not clearly understood. This study addressed the role of uremic toxins on lipoprotein metabolism by examining the effect of a 500 to 2,000-d subfraction obtained from the serum of uremic and control subjects on the synthesis of apolipoprotein (apo) A-I in a human hepatoma cell line (Hep-G2). Serum subfractions obtained from uremic patients inhibited apo A-I synthesis and secretion by Hep-G2 cells in a dose-dependent manner as measured by (3H)leucine incorporation into apo A-I, immunoprecipitation, and ELISA. The uremic serum subfraction decreased the mRNA expression for apo A-I in Hep-G2 cells when compared with controls. These observations suggest that a component of uremic serum can have the potential to inhibit hepatic apo A-I synthesis and may adversely influence high-density lipoprotein metabolism, thus increasing the risk for the development of atherosclerotic vascular complications in uremic patients.

Apolipoprotein A-I↗
PubMed1993

Association between very-low-density lipoprotein and glomerular injury in obese Zucker rats.

Obese Zucker rats spontaneously develop lipoprotein abnormalities, proteinuria, mesangial expansion and glomerulosclerosis. Previous studies have implicated these lipoprotein abnormalities in the pathogenesis of the progressive renal injury which these rats develop. The present study was designed to examine the chronological development of very-low-density lipoprotein (VLDL) abnormalities and renal injury. Obese and lean Zucker rats were maintained on a standard rat diet and sacrificed at 6, 11, 17, 23, 28, and 34 weeks of age. Renal tissue was examined histologically, serum was assayed for lipoproteins, and 24-hour urinary protein excretion determined. Hypertriglyceridemia, elevated VLDL-cholesterol and VLDL-triglycerides were seen at as early as 6 weeks of age in obese rats at a time when other lipoprotein fractions were normal. By 23 weeks, proteinuria developed in obese animals and renal tissue showed increased mesangial matrix, hypercellularity and glomerulosclerosis with lipid deposition noted in the mesangium. All of these abnormalities worsened during the 34 weeks of study at a time when almost all of the total circulating cholesterol was carried by VLDL rather than low-density lipoprotein (LDL), the predominant carrier of circulating cholesterol. These data suggest that increased lipoproteins with atherogenic potential, specifically cholesterol-rich VLDL and triglyceride-rich VLDL particles, correlated positively with the development of renal injury and glomerulosclerosis in obese Zucker rats. They further support a hypothesis that the increased appearance of atherogenic lipoproteins, particularly cholesterol-rich VLDL, may be associated with proteinuria and progressive glomerular injury.

Animals↗
PubMed1993

Effect of dietary cholesterol on rat glomerular cholesterol esterase.

The accumulation of tissue cholesterol and cholesteryl esters is commonly seen during the development of both atherosclerosis and glomerulosclerosis. The intracellular cholesterol content is regulated, in part, by the hydrolysis of cholesteryl esters to cholesterol, a reaction catalyzed by cholesterol esterase. Decreased cholesterol esterase has been linked to cholesteryl ester accumulation in vascular cells and has been postulated to be an important factor in the progression of atherosclerosis and, possibly, glomerulosclerosis. In order to determine whether cholesterol esterase regulates glomerular cholesterol accumulation, the effect of cholesterol feeding on the cholesterol content and the activity of cholesterol esterase was examined in rat glomeruli. Cholesterol esterase was measured using a cholesteryl[1-14C]oleate-lecithin liposome substrate. Total and free glomerular cholesterol was measured spectrofluorometrically. Feeding rats 4% cholesterol for 2 months decreased total glomerular (acid plus neutral) cholesterol esterase activity when compared to glomeruli from similar rats fed a normal chow (1.8 +/- 0.1 versus 1.48 +/- 0.2 nmol/mg protein/h, p < 0.05). Total, free and esterified cholesterol concentrations were higher in glomeruli from cholesterol-fed rats than from controls, consistent with decreased cholesterol esterase activity. Thus, glomerular cholesterol accumulation appears to be regulated by cholesterol esterase. This finding is similar to that in other vascular tissues which have been investigated and which are prone to accumulate cholesterol during the development of atherosclerosis.

Animals↗
PubMed1992

Comparative studies on acid cholesterol esterase in renal blood vessels and aorta of control and hypercholesterolemic rabbits.

Decreased acid cholesterol esterase has been linked to cholesteryl ester accumulation and may be fundamental in the development of atherosclerosis. The present study compared cholesterol esterase activity with the accumulation of cholesterol and its esters in aorta, renal artery and renal preglomerular microvessels. Tissue was obtained from white New Zealand rabbits fed either a control or 2%-cholesterol diet for 1 month. Cholesterol esterase was increased in microvessels from cholesterol-fed animals when compared to aorta and renal artery. Cholesterol feeding generally produced an increase in cholesterol and cholesteryl ester accumulation in all vascular tissues. The percent distribution of esterified/total cholesterol in renal microvessels was decreased consistent with the concomitant increase in cholesterol esterase. In contrast, aorta and renal artery exhibited an increase in cholesterol and cholesteryl ester accumulation and an increase in the percent of esterified cholesterol consistent with a decrease in acid cholesterol esterase after cholesterol feeding. The data suggest that renal microvessels, when compared to aorta and renal artery, may be relatively protected from developing atherosclerotic microvascular lesions through an organ-specific increase in acid cholesterol esterase activity.

Animals↗
PubMed1991

Effect of nifedipine on renal microvascular cholesterol accumulation and prostacyclin biosynthesis in cholesterol-fed rabbits.

Studies, performed in rabbits, examined the effect of feeding a high cholesterol diet and/or a calcium antagonist, nifedipine, on renal microvascular prostacyclin biosynthesis and cholesterol accumulation. After 30 days, cholesterol-fed rabbits had elevated serum and tissue cholesterol levels associated with decreased microvascular prostacyclin biosynthesis and histologic evidence of microvascular and glomerular lipid accumulation. Nifedipine reduced tissue cholesterol levels, enhanced prostacyclin biosynthesis, and reduced the histologic evidence for lipid accumulation in renal microvessels and glomeruli. These studies suggest that calcium antagonists may have a beneficial effect in preventing the tissue cholesterol accumulation associated with a high-cholesterol diet and further suggest that these agents may have beneficial effects in the treatment of renal diseases associated with microvascular or glomerular lipid accumulation.

6-Ketoprostaglandin F1 alpha↗
PubMed1991

Characterization and physiologic regulation of atrial natriuretic factor receptors in rabbit preglomerular renal microvessels.

There has been no direct demonstration of the presence of guanylate cyclase-linked atrial natriuretic factor receptors in renal preglomerular microvasculature. Using [125I]ANF, we have demonstrated the presence of high affinity (Kd = 80 pM) and low affinity (Kd = 7.2 nM) ANF receptors in membranes derived from rabbit renal preglomerular microvessels (afferent arterioles and interlobular arteries). These microvessels also exhibited the presence of particulate bound ANF-sensitive guanylate cyclase. The density of the high affinity ANF receptor in desoxycorticosterone-treated rabbits on a high-salt diet (31 +/- 3 fmol/mg protein) was nearly half of that seen in rabbits on a normal diet (53 +/- 4 fmol/mg protein; p less than 0.01, n = 4). Data from this study demonstrated the presence of renal preglomerular ANF receptors and suggested that these receptors (perhaps in addition to glomerular ANF receptors) may participate in the regulation of extracellular volume.

Animals↗
PubMed1991

Cholesterol esterase in preglomerular microvessels from normal and cholesterol-fed rabbits.

Feeding cholesterol to rabbits produces an atherosclerotic model sharing common metabolic features with the disease in humans, including the vascular lipid accumulation. In coronary vascular cells, this lipid accumulation has been associated with decreased prostacyclin (PGI2) biosynthesis and acid cholesterol esterase activity. Unlike the coronary vascular bed, renal microvasculature appears relatively resistant to atherosclerotic injury. This study examined whether renal microvessels from cholesterol-fed rabbits demonstrated similar metabolic changes in coronary vascular cells. Rabbits were fed either a 0% or 2% cholesterol diet for 1 mo. Similar to coronary vascular cells, in renal microvessels from cholesterol-fed rabbits PGI2 biosynthesis decreased and tissue concentrations of cholesterol and cholesteryl esters increased. However, unlike coronary vascular cells, renal microvascular cholesterol esterase activity increased. Light and electron microscopy revealed sporadic lipid deposits in renal microvessels from cholesterol-fed rabbits and no foam cells or occlusive lesions. In vitro addition of prostanoids to normal renal microvessels had no effect on cholesterol esterase activity. It is inviting to speculate that the increased acid cholesterol esterase activity in renal microvessels from cholesterol-fed rabbits protected them from developing extensive microvascular lesions. These biochemical events may explain the relative resistance of human renal microvessels to the development of occlusive atherosclerotic microvascular lesions.

Animals↗
PubMed1991

Renal magnesium wasting associated with therapeutic agents.

Renal magnesium wasting is an important cause of hypomagnesemia observed in hospitalized patients. The purpose of this review is to present an index case of symptomatic hypomagnesemia associated with renal magnesium wasting during capreomycin therapy, and to survey the available literature regarding the various therapeutic agents associated with the causation of this syndrome. Finally, we have considered the pathophysiologic mechanisms that may contribute to the development of the multiple electrolyte abnormalities observed in these patients, and have outlined the current strategies to treat this syndrome.

Aminoglycosides↗
PubMed1990

Biochemical evidence for PGI2 and PGE2 receptors in the rabbit renal preglomerular microvasculature.

It has been proposed that a portion of the biologic actions of vasodilator prostaglandins occurs via an interaction with specific adenylate cyclase-linked receptors. This hypothesis was explored further in the renal microvasculature by examining the effects of PGI2, PGE1, and PGE2 on rabbit preglomerular microvascular adenylate cyclase. A membrane preparation derived from freshly isolated rabbit renal preglomerular microvessels was used in these studies. NaF, forskolin, or 5'-guanylyl imidodiphosphate were found to be effective in increasing adenylate cyclase activity in the absence of exogenous guanosine-5'-triphosphate. A dose-dependent stimulation of adenylate cyclase was also observed with guanosine-5'-triphosphate. PGE1, PGE2, and PGI2 produced a dose-dependent stimulation of adenylate cyclase activity only in the presence of guanosine-5'-triphosphate suggesting that this nucleotide is essential for prostaglandin-induced stimulation of the enzyme. PGI2 exhibited a time-dependent increase in adenylate cyclase activity and this increased activity reached a plateau at 20-25 min. When PGE1 and PGE2 were added together, no additive effect on adenylate cyclase stimulation was noted whereas PGI2 and PGE2 when added together produced an additive stimulatory effect. When viewed together, these data suggest the presence of separate PGI2 and PGE adenylate cyclase-linked receptors in rabbit renal preglomerular microvessels. These findings also suggest that in the renal microvasculature, cyclic AMP may be a second messenger mediating the vasodilatory effects of both PGI2 and PGE2.

Adenylyl Cyclases↗
PubMed1990

Cyclic AMP does not inhibit A23187-induced prostaglandin biosynthesis in cultured rabbit renal microvascular endothelial cells.

We have previously shown that cultured rabbit renal preglomerular microvascular endothelial cells have the ability to synthesize a number of common prostaglandins. In the present study we have examined whether endogenous cyclic AMP is involved in the regulation of PGI2 and PGE2 biosynthesis in these cultured cells. Isoproterenol and forskolin produced an increase in cyclic AMP accumulation in these cells but had no effect on PGI2 or PGE2 biosynthesis either in the presence or absence of A23187. Similar results were noted in the presence of 3-isobutyl-1-methylxanthine, a cyclic AMP-phosphodiesterase inhibitor. These studies suggested that endogenous cyclic AMP does not regulate the biosynthesis of PGI2 or PGE2 in cultured renal preglomerular microvascular endothelial cells either under basal or A23187-stimulated condition. They further suggested that the effect of 3-isobutyl-1-methylxanthine on prostaglandin biosynthesis in these cultured cells was not secondary to its effects on phosphodiesterase.

1-Methyl-3-isobutylxanthine↗
PubMed1990

Prostanoid biosynthesis in cultured rabbit renal microvascular smooth muscle cells. Effect of arachidonic acid, calcium, and A23187.

It is known that prostanoids are local regulators of vascular tone. Since Ca2+ is known to stimulate prostanoid biosynthesis, we examined this interaction in cultured smooth muscle cells derived from rabbit renal preglomerular microvessels by methods developed in this laboratory. These cells produced prostaglandin (PG)I2, PGE2, PGF2 alpha, and thromboxane A2 under in vitro conditions and biosynthesis was augmented in response to arachidonic acid, A23187, and Ca2+, and diminished in the presence of either mepacrine, aspirin, indomethacin, or meclofenamate. These data indicated that smooth muscle cells cultured in this laboratory were metabolically active and the data suggested that the effect of Ca2+ may be modulated by vasodilator prostanoids produced by the smooth muscle cells. These data failed to explain the greater ratio of the production of PGI2:PGE2 observed in freshly isolated rabbit renal preglomerular microvessels when compared with that seen in cultured endothelial cells derived from the same tissue which was previously reported by this laboratory.

Animals↗
PubMed1990

Peritoneal leucocyte response to bacterial peritonitis in patients receiving peritoneal dialysis.

We evaluated the quantitative peritoneal leucocyte response to antibiotic therapy in 25 CAPD patients with 57 episodes of bacterial peritonitis. Eighty-eight percent of the peritonitis episodes were initially treated with a first generation cephalosporin, but results of microbial sensitivity studies led to a change in the initial antibiotic regimen in 23 episodes. Overall, 47/57 (82%) episodes were cured by antibiotic therapy alone (responders), while 10/57 (18%) required removal of the peritoneal catheter as a curative procedure (nonresponder). Neither the duration of symptoms on initial presentation nor the status of being a nonresponder could be related to the baseline peritoneal leucocyte values, either the total (PLC) or polymorphonuclear counts (PMN). Since the baseline PLC and PMN showed a 500-fold variation, subsequent changes were expressed as a percent [PLC (%) and PMN-PLC (%)] of the baseline value. On day 3 of peritonitis, PLC (%) and PMN-PLC (%) were less in responders (26% and 10%) than nonresponders (251% and 254%) (p less than 0.001). Differentiation between responders and nonresponders based on PLC (%) and PMN-PLC (%) was associated with a high degree of sensitivity (90%) and specificity (90%). Similar results were obtained for day 4. These data suggest that the temporal pattern of PLC and PMN, when expressed as a percentage of the baseline value, may be useful in predicting those episodes of peritonitis which require removal of the peritoneal catheter.

Adult↗
PubMed1989

Decreased atrial natriuretic factor receptors and impaired cGMP generation in glomeruli from the cardiomyopathic hamster.

To determine a possible basis for the decreased action of atrial natriuretic factors (ANF) in congestive heart failure, we compared the cardiomyopathic hamster (CMH) in frank congestive failure, and the age-matched, normal, F1B strain of Golden Syrian Hamsters. Scatchard analysis of competitive binding studies revealed two classes of glomerular receptors. The CMH exhibited decreased binding overall and a markedly decreased number of high affinity receptors but comparable receptor affinity compared to the F1B. In contrast, the low affinity receptor population in the CMH had a much greater affinity compared to the F1B while receptor number was similar. Plasma ANF levels were substantially elevated in the CMH compared to the F1B and in-vitro generation of cGMP was significantly lower in the CMH. Such abnormalities could contribute to the resistance to ANF in this disease.

Animals↗
PubMed1989

Decreased renal preglomerular microvascular PGI2 and PGE2 biosynthesis in cholesterol-fed rabbits.

Although atherosclerosis is a common disease afflicting the kidney, few studies have examined the biochemical disturbances associated with this process directly in the renal microvasculature. Using a technique developed in this laboratory to isolate renal preglomerular microvessels, we have examined whether these vascular segments have a reduced capacity to synthesize vasodilator prostanoids (i.e., PGI2 and PGE2), an observation which has been made in atherosclerotic blood vessels from other vascular beds. The synthesis of these two prostanoids was assessed by radioimmunoassay in a group of white New Zealand rabbits fed a 2% cholesterol diet for 30 days and the results compared to that obtained in a similar group of rabbits fed a normal diet. The results of these studies showed the development of hypercholesterolemia in the cholesterol-fed rabbits which was associated with a 35% decrease in the biosynthesis of PGI2 and a 51% decrease in PGE2 in freshly isolated renal preglomerular microvessels. These findings are similar to those observed in non-renal major blood vessels and suggest that common biochemical mechanisms may operate in the development of atherosclerosis in many organ systems.

Animals↗
PubMed1989

PGI2 is not a major prostanoid produced by cultured rabbit renal microvascular endothelial cells.

The microvasculature is known to be a source of a number of vasoregulatory prostanoids. In the kidney, these prostanoids have been proposed to influence vascular, tubular, and glomerular function. A rapid method for isolation of large numbers of preglomerular renal microvessels (interlobular arteries and afferent arterioles) from the rabbit kidney has recently been developed in this laboratory. In the current report, we describe methods to culture endothelial cells derived from these isolated renal microvessels. Endothelial cells in primary and continuous cultures were grown in monolayers on culture dishes and plates. These cells demonstrated morphology consistent with that described for other endothelial cells in culture including the presence of Weibel-Palade bodies as seen by electron microscopy. The presence of factor VIII immunofluorescence and angiotensin converting-enzyme activity was also observed. The cultured endothelial cells synthesized a number of common prostanoids under in vitro conditions and the hierarchy of biosynthesis was PGE2 greater than PGF2 alpha greater than PGI2 greater than TxA2. The ratio of the in vitro biosynthesis of PGI2:PGE2 was approximately 1:5, as compared with a 3-5:1 ratio seen in freshly isolated intact microvessels. Prostanoid biosynthesis increased in the cultured endothelial cells in the presence of arachidonic acid (1 and 10 microM), A23187 (10 microM), thrombin (5 U/ml), or bradykinin (1 microM) and decreased with mepacrine (10 microM)-or indomethacin (100 microM), suggesting that these cells were metabolically responsive to a variety of prostanoid stimulators and inhibitors. In summary, endothelial cells can be cultured from freshly isolated preglomerular renal microvessels and have the ability to produce a number of vasoregulatory prostanoids under in vitro conditions.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗