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C K Abrass

Publications and source records attributed to C K Abrass.

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

Diabetic nephropathy. Mechanisms of mesangial matrix expansion.

Diabetic nephropathy, a major cause of morbidity and mortality in patients with diabetes mellitus, is characterized by the progressive expansion of mesangial matrix that ultimately occludes glomerular capillaries. Multiple factors in the abnormal metabolic milieu of diabetes contribute to the development of increased amounts of mesangial matrix. Glucose stimulates an increase in synthesis of most collagens and matrix glycoproteins normally expressed within the mesangium. Abnormal glycosylation of matrix proteins interferes with their degradation and turnover. Periods of hyperinsulinemia and alterations in angiotensin II induce changes in the phenotype of mesangial cells and the composition of matrix they secrete. Together, glucose, insulin, and angiotensin II conspire to produce an unrelenting increase in accumulation of mesangial matrix, with altered composition and function.

Diabetic Nephropathies↗
PubMed1995

Aging-associated changes in renal extracellular matrix.

The composition of renal extracellular matrices was examined in 6-, 12-, 18-, and 24-month-old rats by immunofluorescence microscopy. No change in composition of tubular basement membrane was detected. Increased immunostaining for laminin chains B1 and s-laminin and thrombospondin characterized the thickened glomerular basement membrane. Interstitial collagens I and III were not detected in globally sclerotic glomeruli. The major change noted in the aged rat kidney at 24 months was generalized expansion of the interstitium by thrombospondin and fibronectin. In areas of tubular atrophy there was new expression of extra domain A (EDA)+ fibronectin. Collagens I and III were detected focally in the interstitium adjacent to areas of tubular atrophy, but otherwise collagens I, III, and IV and laminin did not contribute to the interstitial fibrosis. Interstitial fibrosis was detectable at 18 months of age and preceded the development of sclerotic glomeruli, tubular atrophy, or accumulations of interstitial collagen. These changes in extracellular matrix composition distinguish the aging kidney from other sclerotic forms of renal disease.

Aging↗
PubMed1994

Insulin induces a change in extracellular matrix glycoproteins synthesized by rat mesangial cells in culture.

Extracellular matrix (ECM) accumulation within the glomerular mesangium is a hallmark of progressive forms of renal disease. We recently succeeded in propagating mesangial cells (MC) from the time of explant without supplemental insulin which exhibit a matrix profile analogous to normal mesangium in vivo. We used these cells to characterize insulin-induced changes in biosynthesis and accumulation of three important matrix glycoproteins, laminin, fibronectin, and thrombospondin. Two clones of MC derived from glomeruli from a single rat were compared. MC grown in the absence of supplemental insulin (SI-MC) assemble a matrix rich in fibronectin with much smaller accumulations of laminin and thrombospondin. In comparison, MC (SI+MC) grown chronically in the presence of 1 microM insulin have a greatly expanded ECM that immunostains less intensely with antibodies to fibronectin, but, it contains significant accumulations of laminin and thrombospondin. Following metabolic labeling of secreted proteins with 35S-methionine, total protein synthesis was measured, and specific ECM components were identified and quantitated by immunoprecipitation, SDS-PAGE and autoradiography. The rate of total protein synthesis was increased by 50% in SI+MC as compared to SI-MC, yet, individual proteins were increased or decreased. The rate of synthesis of fibronectin was decreased and the rate of synthesis of laminin and thrombospondin was increased by insulin. These changes were directionally correlated with the net accumulation of these proteins as shown by immunostaining. In addition to an increase in laminin synthesis, insulin treatment induced a change in the isoform of laminin expressed.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1991

Fc-receptor-mediated phagocytosis: abnormalities associated with diabetes mellitus.

The family of Fc receptors (FcR) for IgG play pivotal roles in affector, effector, and regulatory functions of cells of the immune system. Thus, changes in expression and activation of FcRs may contribute to a variety of disease manifestations that are the consequence of abnormalities in immune system function. Patients with diabetes mellitus are often plagued with recurrent bacterial and mycotic infections, as well as large and small vessel injury which may in part be immune mediated and which lead to organ dysfunction. Hormone-mediated changes in immune system function have been postulated to contribute to a variety of the complications experienced by patients with diabetes mellitus. It is the purpose of this review to summarize current knowledge regarding abnormalities in immune system function in diabetes mellitus with special emphasis on classical hormonal modulation of Fc receptor-mediated phagocytosis.

Diabetes Mellitus↗
PubMed1990

Isolation and characterization of circulating immune complexes from rats with experimental membranous nephropathy.

Circulating immune complexes (CIC) were isolated from serum from controls and rats with active Heymann nephritis (n = 31) by two methods. CIC detected by the fluid phase Clq binding assay were precipitated from serum using Clq and polyethylene glycol. CIC were also isolated by sequential chromatography with anion exchange and lectin affinity supports. The isolated material was analyzed by PAGE and immunoblotting. The immune complex material isolated by both methods from rats with Heymann nephritis contained the same 60/65-kDa tubular Ag. By immunoblotting, the 60/65-kDa tubular Ag-bound antibodies from rats with active Heymann nephritis, but not antibodies to gp330. Antibody bound to the 60/65-kDa tubular protein in the CIC was isolated. This antibody bound to a similar Ag in glomerular eluates from rats with active Heymann nephritis when tested by immunoblotting. These observations suggest that glomerular immune deposits and CIC in rats with Heymann nephritis contain the same tubular Ag. The 60/65-kDa Ag was isolated from CIC by HPLC using anion exchange and hydrophobic interaction columns. Rats immunized with this Ag developed Heymann nephritis. These studies suggest that CIC contribute to the development of glomerular subepithelial immune deposits in this model of membranous nephropathy. These studies do not exclude the participation of other Ag-antibody systems in Heymann nephritis, including gp330. This report describes methods for isolation and characterization of Ag-antibody components of CIC that might be useful to studies of other immune complex-mediated diseases.

Animals↗
PubMed1988

Pathogenesis of membranous nephropathy.

Membraneous nephropathy is the most common cause of idiopathic nephrotic syndrome in adults. Recent studies of the pathogenesis of the subepithelial glomerular immune deposits that characterize this disease have revealed new mechanisms of glomerular immune deposit formation involving cell surface antigens and have documented the role of the C5b-9 membrane attack complex of complement in mediating renal injury. Understanding these mechanisms may help us understand the pathogenesis of several other immune-mediated diseases and has implications for possible therapeutic interventions in MN.

Animals↗
PubMed1988

Insulin and insulin-like growth factor I binding to cultured rat glomerular mesangial cells.

The potential effects of insulin and insulin-like growth factor I (IGF-I) on mesangial cell (MC) metabolism and growth were examined. Radiolabeled insulin or IGF-I were incubated with cell membranes from rapidly proliferating (subconfluent) or nonproliferating (confluent) MC in the presence of increasing concentrations of unlabeled heterologous and homologous ligands (0-10(-6) M). Insulin binding to MC was specific and saturable, with Scatchard analysis of binding data showing the characteristic curvilinear plot. The predicted insulin binding maximum of 4.2 X 10(-12) M/100 micrograms protein for a theoretical high affinity site was consistent with a relatively low density of receptors, which were the same in proliferating and nonproliferating cell preparations. Specific binding of IGF-I to MC was also demonstrated. Binding data for membranes from proliferating cultures generated a linear Scatchard plot, which predicted a binding maximum of 3.5-9.7 X 10(-11) M/100 micrograms protein and a Kd of 2.0-3.2 X 10(-9) M. In contrast, membranes from nonproliferating cultures had no demonstrable specific binding of IGF-I. Covalent cross-linking of radiolabeled IGF-I to membranes from subconfluent cells demonstrated specific binding to a 145K membrane protein. A 95K membrane protein from a partially purified receptor preparation demonstrated autophosphorylation when incubated with 5 X 10(-9) M IGF-I. Incubation of MC with 10(-9) M IGF-I doubled cellular growth rates, an effect that could be duplicated only with high concentrations (10(-6) M) of insulin. These observations indicate that MC express predominantly receptors for IGF-I, and that growth stimulatory effects of physiological concentrations of IGF-I and pharmacological concentrations of insulin are probably mediated through the IGF-I receptor.

Affinity Labels↗
PubMed1988

Phenotypic expression of collagen types in mesangial matrix of diabetic and nondiabetic rats.

This study was performed to evaluate the composition of the extracellular matrix of the mesangium in both diabetic and nondiabetic rats. Four groups of rats (n = 10 each) were studied. Nondiabetic rats were injected with saline (group 1) or insulin (3.5 U NPH daily) (group 2). Streptozocin-induced diabetic rats were similarly injected with saline (group 3) or insulin (group 4). Six weeks after initiation of study, glomerular diameter (micron) was increased in groups 2 (147 +/- 21), 3 (144 +/- 22), and 4 (150 +/- 7) compared with group 1 (104 +/- 12) (P less than .01). Glomerular hypertrophy was associated with an increase in the relative amount of mesangial matrix as determined by staining for fibronectin. By immunofluorescence microscopy (0-4+ scale), type I collagen antigen was not detected in the mesangium of any of the experimental groups. Staining for type V collagen and thrombospondin was similar between the experimental groups. Type III collagen antigen was not detected in the mesangium of control (group 1) or insulin-deficient diabetic rats (group 3); however, it was detected (2-3+) in the mesangium of both insulin-treated diabetic and nondiabetic rats (Mann-Whitney, P less than .01). Comparable intensity of staining (1+) for type IV collagen antigen was detected in the mesangium of animals from groups 1, 2, and 4; however, the staining intensity was markedly increased (3+) in insulin-deficient diabetic rats (group 3; Mann-Whitney, P less than .01).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1988

Characterization of renal injury initiated by immunization of rats with heparan sulfate.

To investigate the role of antibody to heparan sulfate (HS) in the development of glomerular injury, male Lewis rats were immunized with HS and compared with unimmunized controls. In HS-immunized rats circulating antibodies that bound to renal basement membranes, an increase in serum creatinine (0.8 mg/dl versus 0.6 in controls P less than 0.01), and a 40% decline in creatinine clearance developed. In no animal did abnormal proteinuria develop. By histologic examination there was glomerular and interstitial capillary engorgement with erythrocytes, modest infiltration by polymorphonuclear leukocytes, and no proliferation of intrinsic glomerular cells. Immunofluorescence microscopy demonstrated deposits of rat IgG along the glomerular basement membrane. Bowman's capsule, and peritubular capillaries. Electron-microscopic examination revealed capillary engorgement with erythrocytes that appeared adherent to each other and contained entrapped areas of rarefied material. These observations demonstrate that binding of antibody to HS in the glomerulus induces a mild inflammatory reaction and a reduction in glomerular filtration rate, but no abnormal proteinuria.

Animals↗
PubMed1988

Measurement of the rates of basal pinocytosis of horseradish peroxidase and internalization of heat-aggregated IgG by macrophages from normal and streptozotocin-induced diabetic rats.

The rates of basal pinocytosis and internalization of Fc receptor-bound model immune complexes by macrophages from control (Group 1, n = 9), insulin-treated non-diabetic (2, n = 9), insulin-deficient diabetic (3, n = 8) and insulin-treated diabetic (4, n = 8) rats were measured. Pinocytic rates, as determined by uptake of horseradish peroxidase (HRP), were comparable for all experimental groups (1, 19.6 +/- 5.3; 2, 18.6 +/- 6.0; 3, 18.7 +/- 5.5; 4, 24.5 +/- 9.1; mean +/- 1 SD, pg per min per 10(6) cells, analysis of variance P greater than 0.05). The rates of internalization of Fc receptor-bound model immune complexes were decreased in insulin-treated non-diabetic rats (2, 41.7 +/- 10) and both groups of diabetic rats (3, 39 +/- 5.6; 4, 44.6 +/- 6.9) compared with control animals (1, 54.4 +/- 7.2; mean +/- 1 SD, percentage internalized per 10 min per 10(6) cells, analysis of variance P less than 0.01). Under the conditions of study, comparable amounts of model immune complexes were bound by macrophages from each of the groups; thus, the amount of internalized material was decreased in all three experimental groups (2, 3 and 4). These data suggest that insulin treatment, as well as the diabetic environment, can contribute to a decreased rate of internalization of Fc receptor-bound immune complexes, and may thereby contribute to impaired phagocytosis that has been demonstrated to occur in diabetes. These changes appear to be specific to Fc receptor-mediated internalization, as no differences in the rates of basal pinocytosis were observed.

Animals↗
PubMed1987

Tamm-Horsfall protein coating of free cells in urine.

The origin of free cells in urine is difficult to determine in the absence of cellular casts. Using fluorescein-conjugated antibody to human Tamm-Horsfall protein (THP), it was demonstrated that some free cells in urine are coated with THP. To evaluate the usefulness of this observation in the differentiation of upper from lower urinary tract disease, the presence of THP coating of cells was correlated with the clinical diagnosis in 141 subjects. The percentage of THP-coated cells for each group (mean +/- SD) was Healthy volunteers (n = 10), 4% +/- 2%; hospitalized controls (n = 20), 3% +/- 3%; glomerulonephritis (n = 21), 61% +/- 6%; chronic interstitial nephritis (n = 26), 56% +/- 5%; other renal parenchymal diseases (n = 14), 50% +/- 8%; bladder disease (n = 14), 8% +/- 2%; and hypertension (n = 36), 24% +/- 33%. Based on the results from the bladder disease group, 12% coating was set as the 95% confidence limit for lower urinary tract disease. The results in this group were not different from control subjects. By analysis of variance and chi 2 analysis, subjects with renal parenchymal disease could be distinguished from those with hypertension and bladder disease (P less than .001 and P less than .0001, respectively). The presence of cellular coating by THP in renal parenchymal disease and its absence in bladder disease suggests that this simple test may be of use in determining the origin of free cells observed in the routine microscopic urinalysis.

Adsorption↗
PubMed1987

Accelerated glomerulosclerosis in diabetic rats with immune complex injury.

Immune complex-mediated injury has been postulated to contribute to diabetic microangiopathy. To test this hypothesis, immune complex disease was induced in both insulin-deficient (I-) and insulin-treated (I+) rats with streptozocin-induced diabetes mellitus (DM), and the rats were compared with their respective controls. Heymann nephritis (HN), an animal model of membranous nephropathy, was induced in rats by immunization with proximal renal tubular brush border antigen. In addition to the homogeneous mesangial deposits of IgG that developed in diabetic rats, diabetic rats with immune injury also developed immune deposits of IgG and tubular antigen. Diabetic animals with Heymann nephritis developed more intense granular mesangial and capillary wall immune deposits, detected by immunofluorescence (ranked-sums test, P = .002) and electron microscopy. Mesangial immune deposits were associated with mesangial hypercellularity, determined by counting nuclei per glomerular cross section. Diabetic animals with immune injury had an increased number of nuclei (DM, I-, HN: 70 +/- 4; DM, I+, HN: 65 +/- 3) compared with animals with only Heymann nephritis (55 +/- 4) or only diabetes [DM, I-: 52 +/- 4; DM, I+: 54 +/- 3 (mean +/- SE); P less than .05, ANOVA]. An increase in the accumulation of mesangial matrix in diabetic animals with Heymann nephritis was also apparent by light microscopy and immunofluorescence staining of the mesangium for fibronectin. Insulin treatment and control of hyperglycemia did not prevent the development of these changes. Animals with only Heymann nephritis had lesser amounts of immune deposits, which were limited to the subepithelial space and not associated with structural alterations of the mesangium.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1987

Alterations in plasma clearance and tissue localization of model immune complexes in rats with streptozotocin-induced diabetes.

In order to study the in vivo clearance of model immune complexes, radiolabelled aggregated rat gamma globulin (ARG), aggregated human serum albumin (AHSA) and 59Fe-tagged erythrocytes were intravenously injected into control, and insulin-deficient and insulin-treated rats with streptozotocin-induced diabetes. Plasma clearance and organ uptake were measured. The rate of plasma clearance of ARG was studied at trace (18 micrograms) and near-saturating (10 mg) doses. AHSA was cleared slowly from the circulation, and there were no observed differences between the study groups. At trace doses of ARG, plasma clearance was similar in the three animal groups; however, at the higher dose, clearance was significantly slowed in both insulin-deficient and insulin-treated diabetic rats as compared to control animals (P less than 0.01). Organ uptake of AHSA was similar in all study groups. Hepatic uptake at 10 min after injection of ARG was comparable in control and insulin-deficient rats; however, the rate of removal from the liver was significantly slowed in these diabetic rats. Insulin-treated diabetic rats had less hepatic-associated ARG, as compared to the other animals, throughout the study. Splenic uptake of ARG was comparable in both control and insulin-treated animals, but was significantly less in insulin-deficient diabetic animals. These alterations in plasma clearance and tissue localization of ARG in diabetic animals suggest that abnormal phagocytosis may contribute to the elevated levels of circulating immune complexes that have been demonstrated in diabetic subjects.

Animals↗
PubMed1987

Differentiation of renal from non-renal hematuria by microscopic examination of erythrocytes in urine.

Recent studies indicate that hematuria of renal parenchymal origin can be differentiated from hematuria of other origin by the presence of dysmorphic urinary erythrocytes (cells exhibiting irregular membranes or small surface blebs). We investigated the utility of this simple screening assay in a routine clinical laboratory. Dysmorphic erythrocytes in urine from 69 patients (18 with renal-parenchymal disease) were quantified on unstained slides by medical technologists using phase-contrast microscopes. Samples stored at 4 degrees C or 23 degrees C for up to 5 h had no significant changes in percentages of dysmorphic erythrocytes (PDE). PDE was also not modified by urea nitrogen concentration, osmolality, or pH over the physiological ranges of these variables. Receiver-operating characteristic (ROC) curves indicated an optimal sensitivity of 88% and specifity of 94% at a decision level of 14% dysmorphic erythrocytes per high-power field. Thus, the presence of fewer than 14% dysmorphic cells is suggestive of extra-renal disease; more than 14% is suggestive of intra-renal disease.

Diagnosis, Differential↗
PubMed1986

Evaluation of sequential glomerular eluates from rats with Heymann nephritis.

This study was undertaken to characterize the antigen-antibody content of sequential glomerular eluates from rats with Heymann nephritis. Serum and renal tissue were harvested every 2 wk after immunization with renal tubular antigen (Fx1A). Circulating antibody to the tubular antigen was detectable in the circulation from days 7 to 98. Direct immunofluorescence of renal tissue demonstrated an increase in IgG deposits through day 49 with stabilization thereafter. Tubular antigen deposits peaked at day 49 and then declined. One-hour and 3-hr acid eluates of isolated glomeruli were analyzed for IgG content, antibody specificity, and antigen content. Antibody from the 1-hr eluate bound to the tubular brush border but not the glomerulus, whereas the 3-hr eluate demonstrated binding to the glomerulus and not to the tubular brush border. In addition to rat IgG, the 1-hr eluate demonstrated a 70 kD band and the 3-hr eluate demonstrated a 45 kD band by polyacrylamide gel electrophoresis. By Western blot, antibody to the brush border bound to the 70 kD band. Anti-idiotypic antibody to anti-Fx1A, which binds to the glomerulus by indirect immunofluorescence, bound to the 45 kD band. The 3-hr eluate, but not the 1-hr eluate, precipitates radiolabeled F(ab')2 fragments from anti-Fx1A antibody but not from normal rat IgG. Quantitative analysis of the sequential eluates demonstrated that the 70 kD-anti-Fx1A system predominated early in the course of disease, whereas the 45 kD-anti-idiotype antigen-antibody system predominated late in the course of the disease. These observations confirm that two antigen-antibody systems contribute to the immune deposits in Heymann nephritis.

Animals↗
PubMed1986

The role of circulating antigen in the formation of immune deposits in experimental membranous nephropathy.

To investigate the role of circulating antigen in the formation of subepithelial immune deposits in the Heymann rat model of membranous nephropathy, the renal uptake and site of renal deposition of intravenously injected renal tubular antigen (F X 1A) was studied. F X 1A, (15, 30, 60, and 600 micrograms) radiolabeled with 125I, and bovine serum albumin (BSA; 15 micrograms) labeled with 131I were intravenously injected into naive rats. Plasma clearance and organ uptake of brush border antigens were determined. Of the injected F X 1A, 75% was cleared from the circulation by 1 hr as compared to 10% of the BSA. Uptake of F X 1A by heart, lung, and spleen was less than 1% at all doses studied. Renal uptake of F X 1A (29.8 micrograms/g tissue) was greater than that for liver (4.75 micrograms/g), spleen, heart, and lung (each less than 1 microgram/g tissue). Evaluation of washed renal homogenate and isolated glomeruli confirmed specific tissue-associated F X 1A antigen. Direct immunofluorescence demonstrated deposits of F X 1A antigen along the glomerular capillary wall in animals injected with F X 1A. Small scattered electron dense deposits were demonstrated in the subepithelial space. Similar binding could be reproduced in vitro by incubating cryostat sections of normal rat kidney or isolated glomeruli with solubilized F X 1A antigens. Direct binding of a tubular antigen to a constituent of the glomerulus could initiate in situ immune complex formation, and may explain the variably demonstrable "cross-reactivity" of the Heymann antibody with the glomerular capillary wall.

Animals↗