Is mesangial cell proliferation required for extracellular matrix expansion in glomerular disease?
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Animals↗
Biomedical subjects
R J Johnson
Publications and source records attributed to R J Johnson.
Induction of beta-platelet-derived growth factor receptor in rat hepatic lipocytes during cellular activation in vivo and in culture.
A consistent response to liver injury is the activation of resident mesenchymal cells known as lipocytes (Ito, fat-storing cells) into a proliferating cell type. In cultured lipocytes, platelet-derived growth factor (PDGF) is the most potent proliferative cytokine, but requires the activation-dependent expression of its receptor protein (Friedman, S. L., and M. J. P. Arthur. 1989. J. Clin. Invest. 84:1780-1785); the role of PDGF receptor (PDGFR) in liver injury is unknown. We have examined PDGFR gene expression in freshly isolated lipocytes during liver injury and correlated these findings with a culture model of cellular activation. Whereas lipocytes from normal rats had no detectable transcript for the beta-PDGFR subunit, this mRNA was induced within 1 h after a dose of carbon tetrachloride (CCl4). In contrast, alpha subunit mRNA was detected in normal cells, but was unchanged after liver injury. Similar results were observed in lipocytes from bile duct-obstructed rats, although beta-PDGFR induction was less marked. By immunoblot, induction of beta-PDGFR protein in lipocytes isolated from CCl4-treated animals correlated with mRNA increases. In contrast to lipocytes, endothelial cells from normal liver expressed low levels of alpha- and beta-receptor subunit mRNA, which did not increase with injury. Using a beta-PDGFR antibody, receptor protein could be identified within fibrotic septa in CCl4-treated animals in regions where cells expressed proliferating cell nuclear antigen (PCNA). In cultured lipocytes activated by growth on uncoated plastic, beta-PDGFR transcripts appeared within 3 d after plating, which coincided with the onset of cellular proliferation. In contrast, quiescent cells in suspension culture had no detectable beta-PDGFR mRNA. These results indicate that beta-PDGF receptor induction by lipocytes is an early event during hepatic injury in vivo and in primary culture.
Adipocytes↗
Mesangial cell apoptosis: the major mechanism for resolution of glomerular hypercellularity in experimental mesangial proliferative nephritis.
Increases in mesangial cell number may herald glomerular scarring, but they are not irreversible. This study sought mechanisms by which surplus glomerular mesangial cells can be cleared. A small proportion of cultured mesangial cells exhibited typical morphological features of apoptosis (programmed cell death), which was increased by growth factor deprivation or exposure to cycloheximide, stimuli known to increase apoptosis in other cell types. Apoptosis was confirmed by typical internucleosomal chromatin cleavage. In vivo, clear morphological evidence of mesangial apoptosis leading to phagocytosis by neighboring mesangial cells was obtained in self-limited mesangial proliferation induced in rats by Thy1.1 antibody, apoptosis occurring approximately 10-fold more frequently than in the healthy rat glomerulus. Indeed, changes in glomerular cell number in Thy1.1 nephritis strongly suggested that apoptosis is the major cell clearance mechanism counterbalancing cell division, thereby mediating resolution of glomerular hypercellularity in experimental mesangial proliferation.
Animals↗
Human renal cortical interstitial cells with some features of smooth muscle cells participate in tubulointerstitial and crescentic glomerular injury.
In most forms of renal injury, even those due to a primary glomerular process, the extent of tubulointerstitial scarring is a critical determinant of renal functional reserve and prognosis. Yet, little is known about the functional characteristics of the interstitial cells that mediate the processes of chronic tubulointerstitial injury. In this study, tissues from normal kidney (N = 7), from nephrectomies removed for allograft rejection (N = 14) and chronic pyelonephritis (N = 2), and from a cohort of 128 biopsies exhibiting a range of glomerulopathies and tubulointerstitial injury were characterized with antibodies to mesenchymal cells (alpha-smooth muscle actin, desmin) by immunohistology. Selected normal kidneys were also studied by immunoelectron microscopy. Normal adult kidneys contain a widespread population of cortical interstitial cells that constitutively express alpha-smooth muscle actin but not desmin. Immunoelectron microscopy shows that these cells are fibroblasts and not capillary endothelial cells or leukocytes. It has previously been shown that these cells constitutively express platelet-derived growth factor receptor beta and the p75 nerve growth factor receptor. Accumulations of cells expressing smooth muscle actin were identified at sites of chronic tubulointerstitial injury in allograft and pyelonephritic kidneys. The cohort of 128 renal biopsies also revealed accumulations of muscle actin-expressing cells at sites of interstitial injury. These findings demonstrate that a population of interstitial cells with some muscle-like features can be identified in normal kidneys.(ABSTRACT TRUNCATED AT 250 WORDS)
Actins↗
An in vivo comparison between intraoperative isometric measurement and local elongation of the graft after reconstruction of the anterior cruciate ligament.
This study was designed to determine if isometric measurement can be used to predict the pattern of elongation (the change in length) of a bone-patellar ligament-bone graft during passive flexion-extension of the knee at the time of reconstruction of the anterior cruciate ligament in vivo. A standard operative reconstruction technique was performed on nine patients. The tunnel sites for the grafts were selected, and the change in the distance between these sites was measured, with use of a CA-5000 drill-guide isometer as the knee was subjected to passive flexion-extension. After the reconstruction was completed, a Hall-effect transducer was implanted in the graft to measure the local displacement in the mid-substance of the graft that was produced by passive flexion-extension of the knee. For comparison, the isometric measurements and the values for local displacement of the graft were normalized by calculation of the percentage change in the length. With the knee in 10 to 30 degrees of flexion, the average isometric measurements and the measurements of local displacement demonstrated a decrease in length; however, the two techniques of measurement deviated at angles of flexion of 40 degrees and more. On the average, the isometric measurement of elongation between the trial insertion sites predicted that the graft would increase in length in flexion relative to extension, in contrast to the response of the graft after fixation. There was no significant correlation between the isometric measurements and the local elongation of the graft (r2 = 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)
Adolescent↗
The measurement of elongation of anterior cruciate-ligament grafts in vivo.
Many investigators who have studied the mechanical behavior of anterior cruciate-ligament grafts have attributed the increase in anterior translation of the tibia relative to the femur (an increase in the anterior laxity of the knee joint) to the temporal changes in the material behavior (strength and elastic properties) of the graft that occur throughout the process of remodeling. However, with the onset of motion of the joint, it is unclear whether the repeatable mechanical behavior of the graft remains unchanged immediately after fixation, if the fixation slips, or if the length of the graft changes and produces an increase in anterior translation of the tibia relative to the femur. It is also unknown if procedures performed by different surgeons, using similar graft material and similar operative techniques, can produce similar mechanical behavior of the graft, or if the behavior of the graft is similar to that of the normal anterior cruciate ligament. In an effort to address these questions, two surgeons performed a reconstruction of the anterior cruciate ligament on ten patients each (groups 1 and 2) with use of a bone-patellar ligament-bone graft. Immediately after fixation of the graft, a Hall-effect transducer was implanted to measure the changes in the length of the mid-substance of the graft while the knee was moved through twenty cycles of passive flexion-extension. Unlike the length pattern of the normal anterior cruciate ligament, the length pattern of the graft changed during the initial cycles of passive motion of the knee. We defined this phenomenon as the cyclic response of the graft and characterized it by calculation of the changes in the length of the graft at fixed positions of the knee across the multiple cycles of passive motion. In some patients, the length of the graft increased through the initial passive-motion cycles, while in others, it decreased. With the knee nearly extended, the predicted increase in anterior translation of the tibia relative to the femur, resulting from the increase in the length of the graft, was a maximum of 1.0 millimeter. This indicates that increases in anterior translation of the tibia relative to the femur can occur immediately after reconstruction of the anterior cruciate ligament and that changes in the length of the graft occur after fixation at loads that are less than the ultimate failure load of the graft or of the fixation.(ABSTRACT TRUNCATED AT 400 WORDS)
Adolescent↗
Mechanisms of cyclosporine-induced interstitial fibrosis.
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Animals↗
Complement activation during extracorporeal therapy: biochemistry, cell biology and clinical relevance.
Complement is a principal mediator of the acute inflammatory response and contributes to the non-specific recognition and elimination of foreign substances from the body. The system evolved to protect the host from invasion by various pathogens. However, due to the non-selective nature of the alternative pathway, biomaterial surfaces in any medical device used in contact with blood will also activate the system. This review summarizes our current understanding of the biochemistry and cell biology of complement. The relationship of this basic information to clinical observations is discussed in order to affirm the relevance of complement as a critical parameter of biocompatibility.
Biocompatible Materials↗
Does extracellular matrix expansion in glomerular disease require mesangial cell proliferation?
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Animals↗
Tubulointerstitial disease in glomerulonephritis. Potential role of osteopontin (uropontin).
Interstitial inflammation and tubular injury accompany most types of glomerulonephritis and are likely to mediate progressive renal injury. We hypothesized that the interstitial monocyte/macrophage accumulation in nephritis involves osteopontin, a cell attachment glycoprotein that avidly binds macrophages in vitro and induces a macrophage-rich infiltrate on subcutaneous injection in mice (Singh et al, J Exp Med, 1990, 171: 1931). In this study, we demonstrate that osteopontin messenger RNA and protein levels are up-regulated in a proportion of proximal and distal tubules in three experimental models of glomerulonephritis. In all three models, the expression of osteopontin initially precedes histological evidence of tubular injury, but is correlated with subsequent sites of monocyte/macrophage accumulation and tubular damage. Osteopontin expression also correlates with the severity of the tubulointerstitial injury, being greatest in amino-nucleoside nephrosis. These data suggest that 1) osteopontin is up-regulated in tubules in glomerular disease; 2) osteopontin may be important for macrophage accumulation at specific sites in diseased tissue; and 3) osteopontin may therefore have a role in the pathogenesis of the tubulointerstitial injury that accompanies glomerulonephritis.
Animals↗
Comparison of cDNAs from bovine brain coding for two isoforms of calreticulin.
Calreticulin is a major calcium-binding protein of the endoplasmic reticulum of non-muscle cells. In addition to a 1.9-kb calreticulin mRNA, some evidence has suggested the existence of another transcript of 3.75 kb, which is very similar to calreticulin. We report here the isolation and sequencing of cDNA clones from a bovine brain lambda gt11 cDNA library, two of which appear to code for calreticulin and a third for a novel isoform of calreticulin. The deduced amino-acid sequence of the novel clone shares high similarity with mouse calreticulin in the C-terminal 318 amino acids. However, its N-terminal sequence is completely divergent. Northern blot analysis of bovine cerebral cortex RNA indicates that the conserved region of the clone hybridizes to two messages of 1.9 kb and 3.75 kb. The divergent region of this clone hybridizes to the 3.75-kb message, but not to the 1.9-kb message. We believe that this novel clone corresponds to an alternate form of calreticulin which is identical to calreticulin toward the C-terminus, but completely different at the N-terminal region, and that this isoform is encoded by a much larger message.
Amino Acid Sequence↗
Non-age related differences in thrombin responses by platelets from male patients with advanced Alzheimer's disease.
Alzheimer's Disease(AD), characterized by a deposition of beta-amyloid peptide (beta/A4) in the brain and in the cerebral microvasculature of affected individuals, is derived from its precursor protein (beta APP) via proteolytic processing by enzyme(s) which have not yet been characterized or localized. Since platelets carry APP in one of their granules, they have been implicated as a source of the beta/A4 deposits in the microvasculature of AD patients, attributable to either an abnormality in the platelets' stimulus response, in the quantity or nature of the APP they release upon activation and/or in the processing of that protein. We show here that platelets from patients with severe AD have abnormal stimulus responses to alpha-thrombin. Specifically, these cells hyperacidify. While it is not clear why this abnormality occurs, it may contribute to aberrant granule secretion since we have demonstrated earlier that release of platelet granule contents is partially controlled by the cytoplasmic pH.
Adult↗
Kinesin is rapidly transported in the optic nerve as a membrane associated protein.
We have investigated the membrane vs. cytosolic distribution of newly synthesized and total kinesin in rabbit retinal ganglion cell axons which comprise the optic nerve. We find that kinesin is rapidly transported into the axon and that this newly synthesized protein is completely membrane-associated while approximately two third of the total kinesin in the optic nerve is membrane associated. Of this membrane associated kinesin about half is resistant to removal by treatment with 100 mM Na2CO3 (pH 11.3) and none can be stripped by 1 M NaCl. The newly synthesized axonal kinesin is completely resistant to removal by Na2CO3 treatment. By these criteria, at least one third of the total and essentially all of the rapidly transported axonal kinesin appears to exist as an integral membrane protein, consistent with it functioning as the anterograde motor for rapid vesicle transport from the cell body through the axon.
Animals↗
Membranoproliferative glomerulonephritis associated with hepatitis C virus infection.
BACKGROUND AND METHODS: Hepatitis C virus (HCV) infection causes both acute and chronic liver disease and is also associated with mixed cryoglobulinemia. Whether HCV is also associated with renal disease, as is the hepatitis B virus, is not known. We describe the clinical, pathologic, virologic, and immunologic features of eight patients with HCV infection who were referred to nephrologists for glomerulonephritis. Four patients were treated with interferon alfa. RESULTS: All eight patients had proteinuria, and seven had decreased renal function. Renal biopsy in all patients revealed membranoproliferative glomerulonephritis, characterized by the deposition of IgG, IgM, and C3 in glomeruli. Electron microscopy of the biopsy specimens showed cryoglobulin-like structures in three of four patients. All eight patients had HCV RNA detected in their serum, elevated serum aminotransferase concentrations, and hypocomplementemia, and the majority had cryoglobulins and circulating immune complexes in their serum. Cryoprecipitates from the three patients who were tested contained HCV RNA and IgG anti-HCV antibodies to the nucleocapsid core antigen (HCVc or c22-3). IgM rheumatoid factors, present in all patients, bound anti-HCV IgG in all six patients tested. Four patients received interferon alfa for 2 to 12 months; all had evidence of decreased HCV replication and improvement of their renal and liver disease. CONCLUSIONS: Chronic HCV infection is associated with cryoglobulinemia and membranoproliferative glomerulonephritis. The pathogenesis is unknown, but may relate to deposition within glomeruli of immune complexes containing HCV, anti-HCV IgG, and IgM rheumatoid factors.
Adult↗
Atypical pelvic lymphocele: sonographic appearance.
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Adult↗
Dynamic elongation behavior in the medial collateral and anterior cruciate ligaments during lateral impact loading.
The objectives of this experimental study were to determine (a) how quickly the medial collateral ligament (MCL) and the anterior cruciate ligament (ACL) elongate when a lateral impact force is imparted to the knee and if a person can react rapidly enough to provide protective muscle forces in the case of such an impact, (b) if the MCL and the ACL elongate simultaneously during a lateral impact, and (c) if resection of the ACL affects elongation of the MCL during a lateral impact. Eight whole-leg cadaver specimens were used. Each leg was mounted vertically in a testing-frame with the knee in 0 and 30 degrees of flexion. A submaximal impact was delivered from the lateral side by a pendulum instrumented with a force transducer. Elongation of the midsubstance of the MCL and the ACL was measured with Hall-effect displacement transducers. The ACL was resected and the entire test sequence was repeated. Following a lateral impact, elongation of the MCL and ACL reached peak values by 70 ms. This study indicated that contraction of the leg musculature would not protect the MCL and ACL from injury when a lateral impact load is applied to the knee. The MCL and the ACL never elongated simultaneously during a lateral impact. After lateral impact loading, the time required to reach maximum elongation (peak delay) averaged 52 ms in the anterior MCL fibers and 61 ms in the ACL when the knee was in 0 degrees of flexion. At 30 degrees of flexion, the peak delay averaged 38 ms in the anterior MCL fibers and 22 ms in the ACL.(ABSTRACT TRUNCATED AT 250 WORDS)
Aged↗
Morphometry of the semitendinosus and gracilis tendons with application to anterior cruciate ligament reconstruction.
The length and cross-sectional area of human semitendinosus and gracilis tendons were measured in both single- and multi-strand configurations for the purpose of anterior cruciate ligament graft preparation. The average lengths of the semitendinosus and the gracilis tendons were 235 +/- 20 mm (mean +/- SD) and 200 +/- 17 mm, respectively. The cross-sectional area of a doubled semi-tendinosus tendon (two strands) was significantly less than that of a 10-mm-wide patellar tendon graft (P < 0.001). The cross-sectional area of the tripled semitendinosus tendon (three strands) and the 10-mm-wide patellar tendon were similar. Doubling of the combined semitendinosus and gracilis tendons (four strands) and tripling of this combination (six strands) resulted in a significantly greater cross-sectional area in comparison to the 10-mm-wide patellar tendon (P < 0.05, four strands; P < 0.001 six strands). This investigation demonstrates that anterior cruciate ligament grafts fashioned using multiple-strand combinations of the semitendinosus and gracilis tendons result in a cross-sectional area that is comparable to the bone-patellar tendon-bone graft. This is an important finding since cross-sectional area reflects the intra-articular volume of collagenous tissue. This information should be helpful to surgeons considering using the hamstring tendons as an anterior cruciate ligament graft.
Aged↗
An in vivo comparison of anterior tibial translation and strain in the anteromedial band of the anterior cruciate ligament.
The objective of this in vivo study was to determine if strain in the anteromedial band (AMB) of the anterior cruciate ligament (ACL) may be predicted by an external measurement of anterior tibial-femoral translation. A Hall effect strain transducer was implanted on the AMB of five human subjects with normal intact ACLs. AMB strain was then measured during anterior shear loading of the tibia relative to the femur, with the knee flexed to 30 and 90 degrees, simulating the loads applied in the Lachman and anterior drawer tests, respectively. The Knee Signature System, a commercially available arthrometer, was used to simultaneously measure anterior tibial translation relative to the femur. The resulting AMB strains and translations during anterior shear loading of the tibia with respect to the femur at 30 and 90 degrees were compared using a regression analysis to determine if AMB strain could be predicted from a measure of anterior tibiofemoral translation at either flexion angle. AMB strain at 150 N anterior shear load at 30 degrees flexion (3.0%) was significantly greater than that at 150 N anterior shear load at 90 degrees flexion (0.9%). During anterior shear loading at 30 degrees flexion, AMB strain correlated with anterior tibial translation (r2 = 0.59). However, there was no significant correlation between AMB strain and anterior tibial translation for anterior shear loading at 90 degrees flexion (r2 = 0.002). Therefore, AMB strain was not accurately predicted from an external measurement of tibial displacement at 90 degrees in this experiment.
Adult↗