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Biomedical subjects

C E Alpers

Publications and source records attributed to C E Alpers.

At least 55 records · Page 3Linked to original sources
PubMed1997

Focal segmental glomerulosclerosis in primates infected with a simian immunodeficiency virus.

Focal and segmental glomerulosclerosis (FSG) with endothelial tubuloreticular inclusions (TRIs) is the typical lesion of human HIV-associated glomerulopathy. Autopsy studies showed the presence of FSG in 3 of 15 macaques dying 15-120 weeks after experimental infection with a simian immunodeficiency virus (SIVMne). Ultrastructural studies generally revealed numerous endothelial TRIs (also present in normals), mesangial expansion, and evidence of mesangial cell injury. One additional animal had a small-vessel polyarteritis with a proliferative and focally crescentic glomerulonephritis; seven animals had mild, multifocal interstitial nephritis. All animals had documented viremia after infection; 14 of 15 developed antibodies to SIV postinoculation. Additional postmortem findings included severe enterocolitis, encephalitis, and opportunistic infections. In contrast, autopsy studies of macaques infected with a type D simian retrovirus (SAIDS-D/Washington, SRV-2) for similar periods of time (n = 40) showed no evidence of FSG. One SRV-infected animal had a mild proliferative glomerulonephritis. These studies indicate SIV-infected primates may provide a relevant model for study of human HIV-associated nephropathy. They also indicate the variable pathology that can be seen in primate infections of distinct retrovirus types, each of which produces a simian immunodeficiency state that resembles human AIDS.

AIDS-Associated Nephropathy↗
PubMed1997

Localization of PDGF alpha-receptor in the developing and mature human kidney.

Using in situ hybridization and immunocytochemistry we describe the renal localization of the PDGF alpha-receptor. PDGF alpha-receptor mRNA was uniformly present in human metanephric kidney in interstitial cells and vascular arcades that course through the blastema. PDGF alpha-receptor mRNA was present in some mesangial structures in early glomeruli, but was largely lost as glomeruli matured. It was present in adventitial fibroblasts, but usually not in vascular smooth muscle cells or endothelial cells of the fetal vasculature. This pattern persisted in adult kidneys, with extensive expression of mRNA by interstitial cells and only occasional expression by mesangial cells. All in situ hybridization findings were corroborated by immunocytochemistry. Double immunolabeling confirmed the rare expression of the PDGF alpha-receptor protein by vascular smooth muscle cells and the absence of its expression by endothelial cells. Given that both PDGF A- and B-chain can promote smooth muscle cell and fibroblast migration and proliferation and that both signal through the PDGF alpha-receptor, these data suggest that PDGF alpha-receptor may play important roles in the early vasculogenesis of the fetal kidney as well as in the pathogenesis of renal interstitial fibrosis.

Adult↗
PubMed1997

Age-related glomerulosclerosis and interstitial fibrosis in Milan normotensive rats: a podocyte disease.

In Milan normotensive (MNS) rats glomerulosclerosis and interstitial fibrosis develop spontaneously in the absence of hypertension. Renal changes were sequentially assessed in these rats between 2 and 10 months of age. At 10 months, rats were characterized by heavy proteinuria, increased serum creatinine, focal or global glomerulosclerosis in 51 +/- 12% of the glomeruli as well as tubulointerstitial injury involving > 25% of the section area. Cell injury in podocytes (evidenced as increased expression of desmin and by electron microscopy) and interstitial fibroblasts (increased expression of alpha-smooth muscle actin) and mild glomerular hypertrophy were witnessed as early as three to four months of age and preceded glomerulosclerosis and interstitial fibrosis. Only minor evidence of mesangial cell activation (as assessed by glomerular (de novo alpha-smooth muscle actin or type I collagen expression or increased cell proliferation) was noted throughout the observation period. Later stages of the disease were characterized by glomerular and/or tubulointerstitial macrophage influx and osteopontin expression (a chemoattractant), mild accumulation of lymphocytes, platelets, fibrinogen, as well as by a progressive accumulation of various matrix proteins. Progressive renal disease in MNS rats is thus noteworthy for the relative lack of mesangial cell activation. Rather, early podocyte damage, induced by yet unknown mechanisms, may underlie the development of glomerulosclerosis and subsequent interstitial fibrosis.

Actins↗
PubMed1997

A new model of renal microvascular endothelial injury.

Although the importance of injury with consequent activation of endothelium is well-recognized in diseases affecting the glomerular endothelial cell (GEN), research on GEN injury in vivo has been hampered by the lack of adequate animal models. Here we report the establishment and characterization of a new GEN injury model in rats. This model was induced by selective renal artery perfusion with anti-GEN IgG and resulted in the severe acute renal failure with marked platelet deposition and development of a thrombotic microangiopathy involving glomeruli. Peritubular capillary endothelial cells were also damaged that was associated with severe tubular necrosis. Although the glomerular changes were severe, half of the glomeruli recovered by day 10, while interstitial changes remained throughout our observation time course. Proliferation of GEN was observed during the recovery phase. An increased expression of endothelial nitric oxide synthase in GEN was also observed, and may be an adaptive mechanism to counteract the thrombosis and ischemia. This model should be useful to investigate the pathophysiology of renal microvascular diseases and the mechanisms of GEN injury, activation and recovery in vivo.

Acute Kidney Injury↗
PubMed1997

Renal microvascular injury induced by antibody to glomerular endothelial cells is mediated by C5b-9.

We have recently developed a model of thrombotic microangiopathy with injury to the glomerular endothelial cell (GEN) induced by heterologous antibody to rat GEN. In addition to GEN injury rats developed glomerular platelet aggregation and fibrin deposition, acute renal failure, and acute tubular necrosis with interstitial inflammation. To study the role of complement in mediating this lesion, we induced the disease in normal complement PVG rats and measured the effects of generalized complement depletion with cobra venom factor (CVF) and of selective C6 deficiency using genetically C6 deficient PVG animals. Complement sufficient rats developed severe endothelial injury accompanied by platelet aggregation, fibrin deposition, decrease in endothelial cells assessed by antibody staining in the glomerulus, and macrophage infiltration. These changes were associated with marked reduction in renal function. These features were either absent or markedly diminished in complement depleted or C6 deficient rats. This demonstrates that C5b-9, the terminal product of activation of the complement cascade, plays an important role in the pathogenesis of this immune renal microvascular endothelial injury model. Thus, the complement system may play a pathogenic role in renal microvascular diseases such as thrombotic microangiopathy.

Acute Kidney Injury↗
PubMed1997

High-density lipoprotein-binding protein (HBP)/vigilin is expressed in human atherosclerotic lesions and colocalizes with apolipoprotein E.

Accumulation of cholesteryl esters within cells of the arterial intima is a hallmark of atherosclerosis. A small number of proteins have been shown in vitro to be upregulated by cellular cholesterol loading, including apolipoprotein E (apoE) and the recently cloned HDL-binding protein (HBP), but only apoE has been shown to be upregulated in cholesterol-loaded cells in atherosclerosis. To determine whether HBP (also called vigilin) might be expressed in human atherosclerosis, immunohistochemistry and in situ hybridization were performed on coronary arteries of 18 patients. HBP/vigilin was detected on all endothelial cells. HBP/vigilin mRNA and protein also were detected on a subset of macrophages and occasionally on smooth muscle cells (SMC) in atherosclerotic plaques but were not detected on these cell types in nondiseased coronary intima. The majority of HBP/vigilin-expressing macrophages were foam cells, but HBP/vigilin expression also was detected rarely in nonfoam cell macrophages. Foam cell macrophage HBP/vigilin expression was present in 100% of atherosclerotic quadrants, and nonfoam cell macrophage HBP/vigilin expression was present in 6% of atherosclerotic quadrants. HBP/vigilin-expressing human plaque cells also expressed apoE. However, HBP/vigilin was detected in cardiac myocyte foam cells of an apoE-deficient mouse, demonstrating that HBP/vigilin expression can occur independently of apoE. These results suggest that in vivo HBP/vigilin expression is upregulated by intracellular cholesterol loading but also that other factors present in atherosclerotic plaques may upregulate HBP/vigilin. Although the exact function of HBP/vigilin is unknown, its expression in plaque macrophages suggests a role for this molecule in atherogenesis.

Amino Acid Sequence↗
PubMed1997

A role for P-selectin in neutrophil and platelet infiltration in immune complex glomerulonephritis.

P-selectin is one of the key early mediators of leukocyte adhesion in inflammatory conditions. This report examines the role of P-selectin in a neutrophil- and platelet-mediated model of glomerulonephritis (the concanavalin A [con A] model). The administration of neutralizing anti-P-selectin antibody (PB 1.3) reduced the platelet influx at 10 min (P < 0.05) and was associated with a 60% reduction in the neutrophil infiltrate and a 50% reduction in the number of oxidant-producing cells at 3 h within glomeruli. No effect on glomerular monocyte-macrophage accumulation was observed, and proteinuria was reduced by 20% but did not reach significance. It is concluded that P-selectin plays an important role in mediating the neutrophil and platelet accumulation in this model and likely has a role in mediating the glomerular injury.

Animals↗
PubMed1996

Oxidation-specific epitopes in human coronary atherosclerosis are not limited to oxidized low-density lipoprotein.

BACKGROUND: Previous small studies have demonstrated positive immunohistochemical staining in rabbit and human atherosclerotic plaques by antibodies that recognize oxidized low-density lipoprotein (OxLDL), but none have examined a large number of human coronary arteries or evaluated whether epitopes recognized by these antibodies might be present on plaque proteins other than OxLDL. METHODS AND RESULTS: Immunohistochemistry was performed on atherosclerotic (n = 87) and nonatherosclerotic (n = 51) coronary arterial segments from 20 patients by use of monoclonal antibodies that recognize epitopes on macrophages, smooth muscle cells, apolipoprotein (apo) B, and OxLDL. Staining with the OxLDL antibody (Ox5) was much more prevalent in atherosclerotic than in control segments. Extracellular Ox5 staining colocalized with apo B, but cell-associated Ox5 staining occurred in the absence of cell-associated apo B staining, which suggests that cell-associated epitopes for Ox5 were on proteins other than LDL. Epitopes for Ox5 formed in vitro on two readily available non-apo B proteins, human serum albumin and apo A-I, when these proteins were incubated under conditions of oxidant stress with polyunsaturated but not monounsaturated fatty acids; furthermore, an antioxidant inhibited Ox5 epitope formation. Thus, epitopes for Ox5 can form on proteins other than apo B. Also, phorbol ester-treated macrophages cultured in apo B-free medium developed epitopes for Ox5. CONCLUSIONS: These findings are consistent with the hypothesis that atherosclerosis is associated with oxidative modification of proteins in addition to LDL, particularly cell-associated proteins, and that the antiatherosclerotic effects of antioxidants seen in some studies may not be solely due to prevention of LDL oxidation.

Adult↗
PubMed1996

Platelet-derived growth factor-A mRNA expression in fetal, normal adult, and atherosclerotic human aortas. Analysis by competitive polymerase chain reaction.

BACKGROUND: To understand which growth factors are important for growth of atherosclerotic plaques, it is necessary to know the factor's relative abundance and how its gene is regulated in relation to cell proliferation. We tested whether platelet-derived growth factor-A (PDGF-A) mRNA levels correlated with cell proliferation in developing aorta, normal adult aorta, and atherosclerotic plaques. METHODS AND RESULTS: We developed a competitive reverse transcription-polymerase chain reaction (RT-PCR) assay to measure human PDGF-A mRNA levels in small tissue samples. A mutated PDGF-A synthetic RNA was used as an internal standard to compete with endogenous PDGF-A mRNA for amplification. The assay is highly sensitive and much more precise than routine RT-PCR. Correction for heteroduplex pairing between the endogenous and mutant PCR products correlates precisely with synthetic RNA standards and quantitative Northern blotting. Immunostaining with the proliferation marker (proliferating cell nuclear antigen) showed the following rank order of proliferation: fetal aorta >> atherosclerotic plaque > normal aortic media. PDGF-A mRNA levels, however, did not correlate with proliferation. Normal adult aorta contained the most PDGF-A mRNa (34.0+/-7.6 amol/microgram total RNA). Fetal aortas were intermediate (10.2+/-1.6 amol/microgram total RNA); advanced atherosclerotic plaques contained the least PDGF-A mRNA (0.3+/-0.1 amol/microgram total RNA). PDGF-A protein was readily detectable in normal media by immunostaining. Advanced plaques generally had less cell-associated PDGF-A protein, although A-chain was also detected in plaque matrix. CONCLUSIONS: PDGF-A mRNA and protein do not correlate with proliferation among these three groups. The significance of high levels of PDGF-A mRNA in the "quiescent" aortic media is unknown but it clearly does not promote cell replication.

Adult↗
PubMed1996

Monocyte chemoattractant protein-1 mRNA expression in hemangiomas and vascular malformations.

Hemangiomas are vascular tumors that appear at or shortly after birth and undergo a rapid growth before involuting. During the proliferative phase, hemangiomas are infiltrated by macrophages, cells that are capable of initiating angiogenesis. Vascular malformations grow slowly, commensurate with the child, and do not regress or become infiltrated by macrophages. We demonstrate by in situ hybridization increased monocyte chemoattractant protein-1 (MCP-1) mRNA expression during hemangioma and vascular malformation growth. We found markedly upregulated expression of MCP-1 mRNA in all proliferative hemangioma specimens, expressed by alpha-actin perivascular smooth muscle cells and interstitial HAM 56+ macrophages. In contrast, 9 of 10 clinically involuting hemangiomas displayed no expression of MCP-1 mRNA. We found no expression of MCP-1 mRNA in vascular malformations, which correlates with the minimal monocytic infiltration of these lesions. We also showed that dexamethasone and interferon-alpha downregulate MCP-1 mRNA in cultured human vascular smooth muscle cells. Glucocorticoids can be efficacious in 30-50% of cases when given in the proliferative phase of hemangioma growth, but have no beneficial effect on vascular malformations. Interferon-alpha has been used to dramatically induce regression of steroid-refractory hemangiomas. Both of these agents' beneficial action on proliferative hemangiomas may, in part, result from reduced MCP-1 production and reduced influx of angiogenic macrophages.

Blood Vessels↗
PubMed1996

Neovascular expression of E-selectin, intercellular adhesion molecule-1, and vascular cell adhesion molecule-1 in human atherosclerosis and their relation to intimal leukocyte content.

BACKGROUND: Leukocyte recruitment is an early event in atherogenesis, and the leukocyte adhesion molecules E-selectin, intercellular adhesion molecule-1 (ICAM-1), and vascular cell adhesion molecule-1 (VCAM-1) recently have been detected in human atherosclerosis. However, no previous study has evaluated either the distribution of these three molecules at different sites within the arterial intima or their relation to plaque leukocyte content. METHODS AND RESULTS: Immunohistochemistry was performed on 99 coronary artery segments (34 controls and 65 with atherosclerotic plaque) to identify E-selectin, ICAM-1, VCAM-1, macrophages, smooth muscle cells, and T lymphocytes. For each segment, the presence or absence of adhesion molecule was determined at the arterial lumen, on intimal neovasculature, and on intimal nonendothelial cells. Each segment was scored for intimal macrophage and T-lymphocyte densities on a semiquantitative scale of 0 to 3. In atherosclerotic plaques, the prevalences of E-selectin, ICAM-1, and VCAM-1 on plaque neovasculature were twofold higher than their prevalences on arterial luminal endothelium. E-selectin was the only adhesion molecule for which expression on arterial luminal endothelial cells was more prevalent in plaques than in control segments. Increased plaque intimal macrophage density was associated with expression of VCAM-1 on neovasculature (P < .01) and on nonendothelial cells (P < .01). Increased plaque intimal T-lymphocyte density was associated with the presence of both ICAM-1 and VCAM-1 on neovasculature (both P < .01) and on nonendothelial cells (both P < .01). CONCLUSIONS: In atherosclerotic plaques, the expression of all three leukocyte adhesion molecules was more prevalent on intimal neovasculature than on arterial luminal endothelium. Further, the presence on neovasculature and nonendothelial cells of VCAM-1 and ICAM-1 was strongly associated with increased intimal leukocyte accumulation. These findings suggest that leukocyte recruitment through and/or activation of intimal neovasculature may play important roles in the pathogenesis of human atherosclerosis.

Adult↗
PubMed1996

Cyclosporine-associated thrombotic microangiopathy/hemolytic uremic syndrome following kidney and kidney-pancreas transplantation.

Cyclosporine-associated thrombotic microangiopathy (CsA-TMA) is characterized by anemia, acute renal failure, and renal TMA. We report a case-control study of 13 patients (seven kidney-alone transplant recipients and six kidney-pancreas transplant recipients) who developed TMA (12 CsA, 1 FK506). Once CsA-TMA was identified, CsA or FK506 was discontinued and isradipine, aspirin, and pentoxifylline were started. Cyclosporine was reinstituted in all patients once serum creatinine reached the previous baseline value. Patients developing further decreases in renal function on rechallenge with CsA were converted to FK506 (n = 3). Rechallenge with CsA was successful in nine of the 13 patients (69%), with three (23%) converted to FK506 for a total salvage rate of 92%. The creatinine clearance at 6 months, 1 year, and 2 years following transplantation was 73.2 +/- 25.7 mL/min, 54.7 +/- 18.8 mL/min, and 57.0 +/- 32.0 mL/min, respectively, for patients successfully rechallenged with CsA compared with 67 +/- 17 mg/min, 71.8 +/- 21.2 mL/min, and 69 +/- 19 mg/min, respectively, for controls (P = NS). The average creatine clearance for patients converted to FK506 was 44.7 +/- 31.2 mL/min at 6 months following transplantation (n = 3) and 27.0 +/- 11.3 mL/min at 1 year. In this case-controlled retrospective series of renal transplant patients with documented CsA-TMA, the triple-drug combination of isradipine, aspirin, and pentoxifylline allowed for the successful reinstitution of CsA or conversion to FK506 in the setting of TMA, and resulted in increased transplant survival compared with previous reports.

Adolescent↗
PubMed1996

Role of the complement membrane attack complex (C5b-9) in mediating experimental mesangioproliferative glomerulonephritis.

Previous studies have demonstrated that most pathologic changes in the antithymocyte serum (ATS) model of mesangioproliferative glomerulonephritis are complement-dependent. These include mesangiolysis, glomerular platelet infiltration, mesangial cell proliferation, mesangial cell production of growth factors and phenotypic change to express alpha-actin, glomerular macrophage infiltrate, mesangial matrix expansion, and proteinuria. The mechanism by which complement mediates these effects has not been defined. Because neutrophils do not participate in the ATS model, we hypothesized that the complement effects observed are consequent to glomerular cell insertion of the C5b-9 membrane attack complex of complement. This hypothesis was tested utilizing PVG rats which exhibit an absence of C6 inherited in an autosomal recessive pattern. C6 deficient (C-) PVG rat serum activated by zymosan produced normal amounts of C5a compared to normocomplementemic (C+) PVG rat controls but no C5b-9. When ATS was induced, C- PVG rats had a significant and marked reduction in mesangiolysis, platelet infiltration, mesangial cell proliferation, alpha-actin expression, macrophage infiltration, collagen IV deposition, and proteinuria compared to C+ controls. The reduction in each of these parameters was comparable to that achieved by systemic complement depletion of C+ PVG rats with cobra venom factor. These findings establish the role of C5b-9 in mediating each of the complement-dependent features of the ATS model and indicate that C5b-9 accounts for all of the complement-mediated effects observed. This study provides the first documentation of a functional role for C5b-9 in mediating a non-membranous inflammatory type of glomerular injury in vivo.

Animals↗
PubMed1996

SPARC is expressed in renal interstitial fibrosis and in renal vascular injury.

Tubulointerstitial inflammation and fibrosis are critical determinants for renal function and prognosis in a variety of human nephropathies. Yet, the pathophysiology of the injury remains obscure. We investigated the expression of SPARC (secreted protein acidic and rich in cysteine) by immunohistochemistry and in situ hybridization in experimental models characterized by tubulointerstitial fibrosis and matrix expansion in rats. SPARC is a secreted glycoprotein that has been demonstrated to affect cellular interaction with matrix proteins, modulate cell proliferation, bind to and/or inhibit growth factors such as PDGF and bFGF, and regulate angiogenesis. Interstitial expression of SPARC was most prominent in passive Heyman nephritis (PHN), chronic cyclosporine A (CsA) nephropathy, and the remnant kidney model and, to a lesser extent, in angiotensin II (Ang II)-infused animals. SPARC protein and mRNA were substantially increased at sites of tubulointerstitial fibrosis/matrix expansion. In the PHN model, SPARC protein was expressed by interstitial fibroblasts that also produced alpha-smooth muscle actin ("myofibroblasts") and correlated both temporally (r = 0.97) and spatially with sites of type I collagen deposition. Interstitial cell proliferation preceded the development of interstitial fibrosis, and maximal SPARC expression (d15) coincided with the initial decline in interstitial proliferation. In the Ang II-infusion model, which is characterized by arteriolopathy and tubulointerstitial injury, an increase in SPARC protein and mRNA was also seen in injured blood vessels. SPARC was shown to be expressed by vascular smooth muscle cells and also by cells in the adventitia of hypertrophied arteries. In summary, SPARC was transiently expressed by interstitial fibroblasts at sites of tubulointerstitial injury and fibrosis, and by smooth muscle cells and cells in the adventitia of injured arteries in the Ang II-model. In addition to its proposed role in extracellular matrix deposition. the antiproliferative properties of SPARC might contribute to the resolution of interstitial fibroblast proliferation in the PHN model.

Actins↗
PubMed1996

Beneficial effects of systemic immunoglobulin in experimental membranous nephropathy.

To test the hypothesis that systemic administration of immunoglobulin might reduce glomerular injury in membranous nephropathy through mechanisms involving inhibition of complement activation, we studied the passive Heymann nephritis (PHN) model of membranous nephropathy in rats. The daily administration of immunoglobulin goat IgG (600 mg/kg i.p.) reduced proteinuria by 52%. Quantitative immunohistochemical analysis showed that the glomerular deposition of C3c, an indicator of ongoing complement attack, and of C5b-9 was significantly decreased in the immunoglobulin treated group, while deposition of anti-Fx1A was not affected. Electron microscopic analysis demonstrated that the extent of subepithelial immune complexes did not appreciably differ between treated and control animals. Systemic complement levels were not altered by immunoglobulin treatment. These data suggest that the reduction in proteinuria that resulted from systemic immunoglobulin administration was mediated by modifying the effect of complement induced glomerular injury. This interpretation was further supported by in vitro data that documented a significant reduction in C5b-9 induced glomerular epithelial cell lysis in the presence of both goat and rat IgG. These results indicate that systemic administration of immunoglobulin can substantially reduce ongoing complement activation in the glomerulus in PHN rats and that this effect is associated with a significant reduction in glomerular injury.

Animals↗
PubMed1996

Mechanisms involved in the pathogenesis of tubulointerstitial fibrosis in 5/6-nephrectomized rats.

The 5/6 nephrectomy model is used to study pathogenetic mechanisms underlying chronic renal failure. We previously demonstrated that increased mesangial cell proliferation and glomerular PDGF B-chain expression precede glomerulosclerosis in this model. In the present study we have assessed the concomitant changes in the cortical tubulointerstitium. A wave of tubular and interstitial cell proliferation (as determined by immunostaining for PCNA) occurred at week 1 after 5/6 nephrectomy. This wave preceded the peak glomerular cell proliferation by one week. Tubulointerstitial cell proliferation decreased thereafter and reached control values by week 10. In situ hybridization and immunostaining for PDGF B-chain and beta-receptor in sham-operated controls showed labeling of distal tubules and collecting ducts, while no signal was present in the interstitium. PDGF B-chain mRNA and protein expression was markedly increased in tubules at weeks 2 and 4 after 5/6 nephrectomy and in the interstitium (particularly in areas of inflammatory infiltrates) at weeks 2 to 10. Similar changes occurred with PDGF receptor beta-subunit immunostaining. Interstitial expression of desmin and alpha-smooth muscle actin (markers of myofibroblasts) progressively increased after week 1. Interstitial influx of monocytes/macrophages with focal accentuation started at week 2. Counts of lymphocytes, neutrophils and platelets showed only minor changes. In parallel to the monocyte/macrophage influx, progressive interstitial accumulation of collagens I and IV, laminin, and fibronectin occurred. All of these changes were correlated with the increase in serum creatinine, proteinuria and an index of tubulointerstitial damage. We conclude that tubulointerstitial changes after 5/6 nephrectomy show similarities with those observed in the glomeruli. Tubular and interstitial overexpression of PDGF B-chain and its receptor may play a role in mediating fibroblast migration and/or proliferation in areas of tubulointerstitial injury.

Actins↗