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Biomedical subjects

C E Alpers

Publications and source records attributed to C E Alpers.

At least 91 records · Page 5Linked to original sources
PubMed1995

Pathogenesis of cyclosporine nephropathy: roles of angiotensin II and osteopontin.

Low-salt-diet, cyclosporine (CsA; 15 mg/kg per day)-treated rats develop striped interstitial fibrosis, arteriolar hyalinosis, and azotemia similar to the chronic nephropathy observed in humans. To examine the role of angiotensin II in this model, rats on a low-salt diet were given CsA, CsA and the angiotensin II receptor Type I antagonist Losartan (10 mg/kg per day), CsA and hydralazine/furosemide, or vehicle. At Day 35, CsA-treated rats had tubular injury, arteriolopathy of the afferent arteriole, increased expression of the monocyte-macrophage adhesive protein osteopontin, interstitial macrophage infiltration, increased interstitial transforming growth factor-beta expression, and interstitial fibrosis. This study provides new insight in both pathogenic and therapeutic aspects of CsA nephropathy. The pathogenesis of CsA nephropathy involves the expression of osteopontin by tubular epithelial cells, the level of which closely correlates with the degree of macrophage infiltration and interstitial fibrosis in all groups (r = 0.79 and 0.74, respectively; P < 0.001). Therapeutic conclusions can be drawn from the observation that both losartan and hydralazine/furosemide reduced osteopontin expression, macrophage infiltration, transforming growth factor-beta expression, and interstitial fibrosis, but did not prevent the decrease in GFR. Treatment with losartan, but not with hydralazine and furosemide, markedly reduced arteriolopathy. It was concluded that angiotensin II contributes to the vasculopathy (hyalinosis) induced by CsA. In contrast, the interstitial fibrosis mediated by CsA can be partially prevented by both an angiotensin II Type I receptor antagonist or by hydralazine and furosemide. This suggests that the interstitial fibrosis can be dissociated from the vascular effects of CsA. The beneficial effects of lowering blood pressure or vasodilation per se may be difficult to distinguish from the specific effects of angiotensin II receptor blockade.

Angiotensin II↗
PubMed1995

Participation of glomerular endothelial cells in the capillary repair of glomerulonephritis.

In many glomerular diseases severe injury to the mesangium may occur, leading to matrix dissolution and damage to the glomerular capillaries. Although the destruction of glomerular architecture may lead to permanent injury, in some cases spontaneous recovery occurs. The mechanisms that mediate this recovery are unknown. In this study we provide evidence for glomerular capillary repair (angiogenesis) in the adult injured glomerulus. Injection of anti-Thy 1 antibody into rats results in severe mesangiolysis with capillary ballooning, microaneurysm formation, and loss of endothelial cells in addition to mesangial cells. Although mesangial proliferation is a major response to injury, proliferation of endothelial cells also can be documented from days 2 to 14 in association with repair of the capillaries. The endothelial cell proliferation peaks on days 2 and 7, when it is seven- to ninefold greater than normal. Many of the endothelial cells display morphological features of angiogenesis. The initial wave of endothelial cell proliferation can be reduced by 40% with neutralizing anti-basic fibroblast growth factor antibodies (P < 0.001). The later glomerular endothelial cell proliferation is associated with upregulated expression of vascular permeability factor/endothelial cell growth factor (VPF/VEGF) and an increase of flk, a VPF/VEGF receptor. Although PDGF is expressed in this model, anti-PDGF antibody treatment did not affect the endothelial cell proliferative response. In summary, glomerular endothelial cells have an active role in the glomerular response to injury. Glomeruli are capable of healing microaneurysms, and the mechanism involves basic fibroblast growth factor- and VPF/VEGF-mediated endothelial proliferative responses.

Animals↗
PubMed1995

The pathogenesis of tubulointerstitial disease associated with glomerulonephritis: the glomerular cytokine theory.

Numerous studies have suggested that tubulointerstitial disease has a major impact on the overall function and prognosis of glomerular disease. The mechanism by which tubulointerstitial disease develops in patients with glomerular and other diseases is unknown. In this review, we discuss the hypothesis that factors released from injured glomeruli act on tubules and interstitial cells to induce expression of chemotactic and adhesive factors that attract mononuclear cells into the interstitium. Evidence is provided that osteopontin is one candidate leukocyte adhesive factor involved in this process, but others are likely involved. The recruited leukocytes (primarily macrophages) then release inflammatory mediators that injure tubular cells and activate interstitial fibroblasts, resulting in tubulointerstitial injury with eventual fibrosis.

Animals↗
PubMed1995

Hepatitis C virus associated membranous glomerulonephritis.

Hepatitis C virus infection has been associated with a variety of extrahepatic disorders. We report four patients with membranous glomerulonephritis and hepatitis C virus infection. In contrast to patients previously reported with HCV infection and membranoproliferative glomerulonephritis, these patients have normal or minimally reduced complement levels and no evidence of rheumatoid factor or cryoglobulinemia. A liver biopsy in one patient was consistent with chronic active hepatitis although liver enzymes were only minimally elevated and coagulation studies normal. Three patients were treated with alpha-interferon with some success. Treatment with alpha-interferon may have a beneficial effect in reducing proteinuria and improving liver function and may be related to the ability of interferon to suppress viremia. Future studies need to focus on clarifying the role of the virus in causing glomerular disease and improving dosing strategies for alpha-interferon. Randomized, controlled studies need to be performed to determine whether the beneficial effect of alpha interferon is significant, and if so, if it is superior to conventional therapies.

Adult↗
PubMed1994

Hepatitis C virus-associated glomerulonephritis. Effect of alpha-interferon therapy.

Hepatitis C virus (HCV) infection may present as a primary glomerular disease. We report 34 adult patients who presented with proteinuria and had circulating anti-HCV antibodies. Primary risk factors included a history of intravenous drug abuse (56%) or blood transfusion (18%). Patients presented with nephrotic syndrome (71%) or with non-nephrotic proteinuria (29%) and had membranoproliferative or acute proliferative glomerulonephritis on renal biopsy. Signs of clinical liver disease were infrequent (18%), though elevated liver function tests were common (66%) and liver biopsy in 16 of 18 patients showed chronic active hepatitis. Cryoglobulinemia was frequent (59%), but only 44% had extrarenal manifestations. In 100% of cases tested, HCV RNA could be found in the serum or cryoprecipitates. Fourteen patients received interferon alpha for 6 to 12 months with a significant reduction in proteinuria but no improvement in renal function. A good clinical response correlated with disappearance of HCV RNA from the serum during treatment; however, relapse of viremia and renal disease was common after completing therapy. Evidence for HCV infection should be sought in all patients with primary glomerular disease. The optimal treatment strategy, however, remains to be defined.

Adult↗
PubMed1994

Osteopontin expression in angiotensin II-induced tubulointerstitial nephritis.

Osteopontin is an arginine-glycine-aspartate (RGD) containing secreted phosphoprotein recently shown to stimulate a local macrophage influx when injected subcutaneously in mice. We examined the effect of angiotensin II infusion on renal injury and osteopontin expression in the rat kidney by in situ hybridization and immunohistochemistry. Preceding pathologic changes in tubular and interstitial cells, a dramatic increase in renal osteopontin protein and mRNA levels was observed primarily in epithelial cells of the distal tubules, collecting ducts and Bowman's capsule. Although both cortex and medulla showed increased osteopontin levels, the effect was most pronounced in the renal cortex which normally showed very little constitutive osteopontin expression. Interestingly, regions of the kidney expressing high osteopontin levels correlated with sites of monocyte/macrophage accumulation. These observations, coupled with recent findings that osteopontin may be a pro-inflammatory protein, suggests that osteopontin over-expression may facilitate monocyte/macrophage accumulation at the sites of renal tubulointerstitial injury.

Angiotensin II↗
PubMed1994

Renal proliferative and phenotypic changes in rats with two-kidney, one-clip Goldblatt hypertension.

Angiotensin II (AII) is a vasoconstrictive peptide with hypertrophic and mitogenic effects on many cell types. Previous studies have shown that in vivo administration of AII in rats results in proliferation of, and phenotypic changes in, many renal cell populations, but in doses also causing hypertension. Thus, it was not possible to differentiate nonhemodynamic from hypertensive effects of AII. Therefore, we studied rats with renin-dependent, AII-mediated hypertension (the two-kidney, one-clip Goldblatt model; mean systolic blood pressure 238 +/- 48 v 140 +/- 6 mm Hg in sham-operated controls). The unclipped kidneys, which were exposed to high blood pressure, developed significant glomerular and tubulointerstitial injury, tubulointerstitial cell proliferation, dense focal interstitial monocyte-macrophage influx, increased deposition of types I and IV collagen, as well as increased cellular expression of desmin and actin, in tubulointerstitial areas when examined at 11 weeks. In contrast, clipped kidneys, protected from hypertension but with high local renin expression, had minimal abnormalities. These studies suggest that in this model increased renin, and presumably AII, does not mediate significant proliferative or phenotypic changes in the kidney in the absence of hypertension at 11 weeks.

Angiotensin II↗
PubMed1994

Glomerulopathies of dysproteinemias, abnormal immunoglobulin deposition, and lymphoproliferative disorders.

The glomerulopathies associated with dysproteinemias and lymphoproliferative disorders exhibit diversity in their morphologic appearance and underlying pathophysiology. Some entities, such as amyloidosis, light-chain nephropathy, and monoclonal immunoglobulin deposition disease, are now well-recognized clinical entities. The disease processes of fibrillary glomerulonephritis and immunotactoid glomerulopathy, which may be associated with these disorders, are becoming increasingly recognized and established entities as reports on significant series of patients continue to be published. Most new information about the pathogenesis of these entities comes from structural, biochemical, and synthetic studies of individual pathogenic paraproteins. The ability to use individual pathogenic human paraproteins to recreate disease in experimental animals is a development that may allow better understanding of disease pathophysiology. The determination of effective therapeutic strategies for the management of these disorders continues to be elusive.

Animals↗
PubMed1994

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↗
PubMed1994

Apolipoprotein E localization in human coronary atherosclerotic plaques by in situ hybridization and immunohistochemistry and comparison with lipoprotein lipase.

Apolipoprotein E (apo E) mediates both lipid accumulation by and removal from cells and may be secreted by both macrophages and smooth muscle cells in vitro, but its cellular source in atherosclerotic plaques is not known. Lipoprotein lipase (LPL) also enhances cell lipid accumulation and is synthesized by macrophage foam cells in atherosclerotic plaques. To determine the cellular source of apo E in human coronary atherosclerotic lesions and its relationship to LPL synthesis, in situ hybridization and immunohistochemistry were performed on 12 atherosclerotic plaques and six nondiseased coronary artery segments from 10 cardiac transplant recipients. Apo E messenger RNA was localized to both non-foam cell and foam cell macrophages in plaques, but not to other cell types, and was not detected in nonatherosclerotic arteries. Half of the regions with non-foam cell macrophages expressed neither apo E nor LPL messenger RNA, whereas 86% of macrophage foam cell-containing regions contained both messenger RNAs. Polyclonal antisera raised against human apo E localized apo E protein to the surface of macrophages and surrounding matrix in plaques but not in control coronary segments. An LPL-specific monoclonal antibody demonstrated that, similar to apo E, LPL protein on foam cell and non-foam cell macrophages was detected in atherosclerotic lesions, but LPL was also localized to intimal muscle smooth muscle cells and was not distributed as widely in association with matrix as was apo E. The expression of both apo E and LPL in atherosclerotic lesions but not in normal intima suggest that these molecules play a role in lipid metabolism in atherosclerosis.

Apolipoproteins E↗
PubMed1994

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↗
PubMed1993

Antigens of varying size persist longer in subepithelial than in subendothelial immune deposits in murine glomeruli.

The kinetics of removal of immune deposits from the subendothelial and subepithelial areas of glomeruli were analyzed in mice. Radiolabeled, cationized Ag of different molecular size, including human serum albumin, bovine thyroglobulin, and human IgM, were used to form the immune deposits in mouse glomeruli with specific, purified rabbit antibodies to these proteins. The disappearance curves of the radiolabeled Ag from glomeruli consisted of two exponential components. The immune deposits and their location in glomeruli were identified by immunofluorescence and electron microscopy. The t1/2 of disappearance of immune deposits were assigned to subendothelial or subepithelial deposits on the basis of ultrastructural observations. The t1/2 of subendothelial immune deposits ranged from 0.6 to 1.9 days with the three different Ag-antibody systems. In contrast, the t1/2 of the subepithelial immune deposits ranged from 9.32 to 231 days. The cationized human serum albumin in subepithelial areas had the longest t1/2, and this was not altered by the endogenous immune response to the injected materials, as determined in studies with nude mice. The results constitute formal documentation of the prolonged t1/2 of an exogenous Ag in glomerular immune deposits. The described approach can serve to examine variables that alter this prolonged presence of subepithelial immune deposits in glomeruli.

Animals↗
PubMed1993

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↗