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1.
Kidney Int ; 69(5): 823-31, 2006 Mar.
Article in English | MEDLINE | ID: mdl-16518341

ABSTRACT

A morphometric study was performed on 22 renal biopsies from hypertensive patients with proteinuria and/or azotemia, with no evidence of other renal disease. These results were compared with our earlier study of normotensive aging kidneys. Afferent arterioles in hypertensive kidneys showed a significant increase in lumen diameter (15.7+/-4.9 vs 13.4+/-4.7 microm, P=0.0007) and wall area (1234+/-769 vs 998+/-445 microm(2), P=0.037), due primarily to shift in the distribution of arteriolar types, from predominantly normal toward predominantly hyaline arterioles in hypertension. Glomeruli were divided into four basic types: normal, hypertrophic, focal segmental glomerulosclerosis (FSGS) type, and sclerosing. Overall, glomeruli in hypertensive kidneys were much larger than in normotensive aging kidneys, for example, total capillary area (16 247+/-10 681 vs 11 624+/-5702 microm(2), P<0.00001). This increase was due primarily to an increase in size of each type, for example, for hypertrophic glomeruli: total capillary area (22 205+/-10 426 vs 15 349+/-4577 microm(2), P=0.0038). There was an excellent correlation between arteriolar lumen diameter and mean glomerular capillary area for hypertrophic/FSGS-type glomeruli (r=0.4778, P=0.0013), such that as arteriolar diameter increases the mean glomerular capillary area increases, consistent with loss of autoregulation. The morphologic correlates of loss of autoregulation, with afferent arteriolar dilatation and increase in glomerular capillary size, glomerular hypertrophy, and subsequent FSGS, are present on a focal basis in aging kidneys and, much more extensively, although still focally, in hypertensive kidneys.


Subject(s)
Hypertension/pathology , Hypertension/physiopathology , Kidney/pathology , Kidney/physiopathology , Adult , Aged , Aged, 80 and over , Aging/pathology , Aging/physiology , Arterioles/pathology , Capillaries/pathology , Female , Glomerulosclerosis, Focal Segmental/pathology , Glomerulosclerosis, Focal Segmental/physiopathology , Homeostasis , Humans , Hyalin/metabolism , Hypertrophy , Kidney/blood supply , Kidney Glomerulus/blood supply , Kidney Glomerulus/pathology , Male , Middle Aged , Renal Circulation
3.
Gene Ther ; 10(7): 569-79, 2003 Apr.
Article in English | MEDLINE | ID: mdl-12646862

ABSTRACT

Gene electrotranfer is an attractive physical method to deliver genes to target tissues. The aim of this study was to evaluate in vivo gene electrotransfer into spleen, one of the most important lymphoid organ, in order to create a new tool to modulate the immuno-inflammatory system. C57Bl/6 mice were submitted either to intramuscular electrotransfer (IME) as a reference method or to intrasplenic (ISE) gene electrotransfer. In the naked injected plasmids, the CMV promoter controlled the expression of luciferase, secreted alkaline phosphatase, EGFP, or IFNgamma. The ISE optimal electrotransfer conditions were first determined and ISE was found to be an efficient gene transfer method, which can be used to express secreted or intracellular proteins transiently. Although transfected cells were still present in the spleen 30 days after ISE, transfected spleen cells could recirculate since they were detected in extrasplenic locations. Using a T-lymphocyte-specific promoter controlling the expression of EGFP, splenic T cells could be targeted. Finally, it appeared that ISE procedure does not impair by itself the immune response and does not result in a significant production of antibodies directed to the transgenic proteins in C57Bl/6 mice. This strategy constitutes a new method to manipulate the immune response that can be used in various experimental designs.


Subject(s)
Electroporation/methods , Genetic Therapy/methods , T-Lymphocytes/metabolism , Alkaline Phosphatase/genetics , Animals , Enzyme-Linked Immunosorbent Assay/methods , Female , Gene Expression , Green Fluorescent Proteins , Interferon-gamma/genetics , Luciferases/genetics , Luminescent Proteins/genetics , Male , Mice , Mice, Inbred C57BL , Muscle, Skeletal/metabolism , Transgenes
4.
Kidney Int ; 60(5): 1893-903, 2001 Nov.
Article in English | MEDLINE | ID: mdl-11703608

ABSTRACT

BACKGROUND: Response of the renal tubules to proteinuria is implicated in progression of renal disease. Experimentally, proteinuria causes increased tubular synthesis of macrophagic and other chemokines, with increased tubular cellular proliferation and apoptosis, leading to interstitial inflammation and fibrosis. Clinically, diminution of proteinuria leads to the slowing of progression, but whether this leads to reduction in tubular lesions has not been directly demonstrated in humans. METHODS: Initial (Bx1) and systematic six-month biopsies (Bx2) from 71 patients with lupus nephritis were studied, with a subset of 34 biopsies also stained for proliferating cell nuclear antigen (PCNA), the macrophage marker PGM1, and cytokeratins (AE1/AE3), and morphometric cell and tubular profile counts performed. RESULTS: Positive correlations were found between increasing levels of proteinuria and the following light microscopic parameters: tubular epithelial pyknosis, tubular epithelial nuclear "activation," tubular lumenal macrophages, interstitial inflammation and fibrosis, but not with tubulointerstitial immunofluorescence. Significant positive correlations also were found with the following immunohistochemical parameters: PCNA in epithelial cells (r = 0.74) and tubular luminal cells (r = 0.47); tubular lumenal macrophages (r = 0.63) and tubular epithelial cells with acquired PGM1 staining (r = 0.36); and pyknotic tubular epithelial cells (r = 0.47). All showed strong correlations with serum creatinine (S(Cr)) as well. All were reduced at Bx2, generally in parallel to the reduction in proteinuria. Tubulointerstitial immune deposits appear to play only a minor role in the development of tubular epithelial lesions and the progression of renal disease in lupus. They show only limited correlation with SCr and no correlation with proteinuria. By multiple regression, they are not associated with tubular epithelial lesions, interstitial inflammation or interstitial fibrosis at either biopsy, whereas tubular epithelial lesions are strongly associated with interstitial inflammation at Bx1 and with interstitial fibrosis at Bx2. Cytokeratin correlated strongly with S(Cr) (r = 0.53, P = 0.002) but not with proteinuria (r = 0.27, NS), and was the sole immunohistochemical parameter to increase at Bx2. It appears to be a sensitive marker for tubular atrophy. CONCLUSIONS: In this study both proteinuria and SCr showed a hierarchy of correlations with morphologic variables: Tubular epithelial cell changes> tubular macrophages> interstitial inflammation> interstitial fibrosis, corresponding to current experimental models, but not previously demonstrated in humans.


Subject(s)
Kidney Tubules/pathology , Lupus Nephritis/pathology , Proteinuria/etiology , Creatinine/blood , Fibrosis , Humans , Immunohistochemistry , Keratins/analysis , Kidney Tubules/immunology , Lupus Nephritis/complications , Macrophages/pathology , Proliferating Cell Nuclear Antigen/analysis
6.
Nephrol Dial Transplant ; 16(8): 1598-606, 2001 Aug.
Article in English | MEDLINE | ID: mdl-11477161

ABSTRACT

BACKGROUND: We assessed whether a differential oxidizability of apolipoprotein B (apo B)-containing lipoproteins (LDL and VLDL) may explain the oxidative stress that we had observed at the onset of renal fibrosis in Zucker obese (ZO) rats (Nephrol Dial Transplant 2000, 15: 467--476). METHODS: Ex vivo copper-induced oxidation of lipoproteins was performed in 1-, 3-, and 9-month-old ZO and age-matched lean (ZL) rats. LDL/VLDL oxidizability was determined by spectrophotometry at 234 nm by monitoring the formation of conjugated diene hydroperoxides. RESULTS: A significant increase in lag time (reflecting the resistance to oxidation) was observed in ZO rats at 3 months while the maximal diene production (reflecting the amount of hydroperoxides formed during oxidation) was higher in ZO than in ZL rats as early as 1 month. Lipoproteins were larger in ZO than in ZL rats, as shown by their core to surface component ratio. Furthermore, ZO lipoproteins had increased vitamin E and polyunsaturated fatty acid (PUFA) content, with no change in vitamin E/PUFA ratio. CONCLUSIONS: Rather than oxidizability of apo B-containing lipoproteins, the ability of these molecules to produce high levels of conjugated dienes, which can act as toxic tissue messengers, appears to be a critical trait in the development of renal fibrosis in this rat model of obesity and renal fibrosis.


Subject(s)
Alkenes/metabolism , Kidney Diseases/metabolism , Lipoproteins/metabolism , Animals , Apolipoproteins B/metabolism , Fatty Acids, Unsaturated/metabolism , Fibrosis , Kidney/pathology , Lipoproteins/chemistry , Male , Obesity/genetics , Obesity/metabolism , Oxidation-Reduction , Rats , Rats, Zucker , Thinness , Vitamin E/metabolism
7.
Circulation ; 104(2): 197-202, 2001 Jul 10.
Article in English | MEDLINE | ID: mdl-11447086

ABSTRACT

BACKGROUND: A chronic immune response involving proinflammatory T helper cell 1 (Th1) lymphocyte activation occurs in the atherosclerotic lesion, but whether this activation is protective or deleterious remains unclear. Methods and Results-- We modulated the immune response of the atherosclerosis-prone apolipoprotein E-deficient (apoE(-/-)) mouse. Eight-week-old apoE(-/-) mice were treated daily with pentoxifylline (PTX), a known inhibitor of the Th1 differentiation pathway, or PBS (control) for 4 weeks or 12 weeks. Twelve-week PTX treatment reduced atherosclerotic lesion size by 60% (P<0.01). PTX-treated mice developed lesions that were limited to the degree of fatty streaks. In contrast, control mice developed mature fibrofatty atherosclerotic lesions. In parallel, the proportion of interferon (IFN)-gamma-producing Th1 splenic lymphocytes was significantly reduced by PTX, and lesion size was correlated to the proportion of IFN-gamma(+) T cells. In vitro addition of PTX to cultured spleen cells did not modify the production of IFN-gamma but increased the production of IL-10 by T cells, indicating that PTX does not suppress IFN-gamma production but rather blocks Th1 polarization while promoting Th2 polarization. CONCLUSIONS: Thus, PTX protected mice from atherosclerosis by reducing the Th1 polarization of T helper lymphocytes. This study demonstrates that the Th1 immune response associated with atherosclerosis is deleterious and that a modulation of the Th1 differentiation pathway may provide a new pharmacological tool to treat this disease.


Subject(s)
Apolipoproteins E/deficiency , Arteriosclerosis/immunology , Down-Regulation/immunology , Th1 Cells/immunology , Animals , Apolipoproteins E/genetics , Arteriosclerosis/blood , Body Weight/drug effects , Cell Count , Cell Differentiation/drug effects , Cell Differentiation/immunology , Cells, Cultured , Cholesterol, HDL/blood , Disease Models, Animal , Disease Progression , Interferon-gamma/biosynthesis , Interleukin-10/biosynthesis , Lymphocyte Activation/genetics , Lymphocyte Activation/immunology , Male , Mice , Mice, Knockout , Pentoxifylline/pharmacology , Phosphodiesterase Inhibitors/pharmacology , Spleen/cytology , Spleen/drug effects , Spleen/immunology , Spleen/metabolism , Th1 Cells/drug effects , Th1 Cells/metabolism , Th2 Cells/immunology , Triglycerides/blood
8.
Am J Physiol Renal Physiol ; 280(4): F683-94, 2001 Apr.
Article in English | MEDLINE | ID: mdl-11249860

ABSTRACT

We examined the role of inflammation in the development of renal interstitial fibrosis in Zucker obese rats, which rapidly present kidney lesions in the absence of hypertension and hyperglycemia. Type I and III collagens were quantified using a polarized light and computer-assisted image analyzer. The expression of mRNA encoding matrix components, adhesion molecules, chemokines, and growth factors was followed by RT-PCR. The presence of synthesized proteins as well as lymphocytes and macrophages was determined by immunohistochemistry. Interstitial fibrosis developed in two phases. The first phase occurred as early as 3 mo and resulted from a neosynthesis of type III collagen and fibronectin and a reduction of extracellular matrix catabolism, in parallel with an overexpression of transforming growth factor-beta(1) and in the absence of any lymphocyte or macrophage infiltration. After 6 mo, interstitial fibrosis worsened with a large accumulation of type I collagen, concomitantly with a large macrophage infiltration. Thus inflammation cannot explain the onset of interstitial fibrosis that developed in young, insulinoresistant, normoglycemic, obese Zucker rats but aggravated this process afterward.


Subject(s)
Glomerulosclerosis, Focal Segmental/immunology , Glomerulosclerosis, Focal Segmental/pathology , Obesity/immunology , Obesity/pathology , Transforming Growth Factor beta/genetics , Animals , Blood Glucose , Collagen/analysis , Collagen/genetics , Creatinine/blood , Fibronectins/genetics , Fibrosis , Gene Expression/physiology , Hyperinsulinism/immunology , Hyperinsulinism/pathology , Hyperlipidemias/immunology , Hyperlipidemias/pathology , Image Processing, Computer-Assisted , Immunohistochemistry , Lymphocytes/immunology , Macrophages/immunology , Male , RNA, Messenger/analysis , Rats , Rats, Zucker , Reverse Transcriptase Polymerase Chain Reaction , Tissue Inhibitor of Metalloproteinase-1/genetics , Transforming Growth Factor beta1
9.
Kidney Int ; 59(1): 304-16, 2001 Jan.
Article in English | MEDLINE | ID: mdl-11135084

ABSTRACT

BACKGROUND: A new Biopsy Index containing the Glomerular Activity (GAI), Tubulointerstitial Activity (TIAI), Chronic Lesion (CLI), and Immunofluorescence (IFI) indices was developed, showing better correlations with clinical and outcome parameters than the National Institutes of Health Activity and Chronicity Indices (AI and CI) in lupus nephritis. This report examines the ability of these indices and individual morphologic variables to predict doubling of serum creatinine (SCr; CRX2). METHODS: Renal biopsies from 71 patients with lupus nephritis with an initial biopsy (Bx1) and systematic control biopsy (Bx2) after six months of therapy were studied. Kaplan-Meier survival curves were developed for each index and morphologic variable at each biopsy. A subset of 30 biopsies was stained with the macrophage marker PGM1. RESULTS: At Bx1, only the TIAI and the quantity of C3 and vascular staining on IF were predictive of CRX2. At Bx2, particularly predictive of CRX2 were the GAI, IFI, Biopsy Index, and BxInfl, a composite variable comprised of all of the inflammatory variables. Among individual variables, glomerular and tubular macrophages correlated the best with clinical and outcome parameters. Crescents and karyorrhexis/fibrinoid necrosis also correlated with outcome. Neither the NIH CI or our CLI, nor the TIAI correlated with outcome. In 30 biopsies stained with PGM1, PGM1+ cells correlated well with glomerular and tubular macrophages identified on routine stains and showed even better correlations with SCr, proteinuria, and progression to renal insufficiency than the latter. A diffuse membranoproliferative (MPGN) pattern was seen in seven patients at Bx1. In four of the seven patients, MPGN disappeared with therapy, and all finished with normal renal function. However, among the three patients in whom MPGN persisted and eight patients in whom MPGN, focal or diffuse, appeared under therapy, six reached end-stage renal disease, and a seventh died with marked renal insufficiency. CONCLUSIONS: The biopsy index and its components correlate modestly with CRX2 at Bx1, but strongly at Bx2, particularly IFI, BxInfl, and glomerular and tubular macrophages. Stains for macrophage markers form a valuable adjunct in interpretation of renal biopsies in systemic lupus erythematosus (SLE). MPGN features do not have an ominous significance at Bx1, but their persistence or appearance under therapy are associated with poor outcome.


Subject(s)
Kidney/pathology , Lupus Nephritis/pathology , Macrophages/pathology , Adult , Biopsy , Creatinine/blood , Female , Glomerulonephritis, Membranoproliferative/blood , Glomerulonephritis, Membranoproliferative/pathology , Humans , Immunohistochemistry , Kidney Glomerulus/pathology , Male , Middle Aged , Monocytes/pathology , Predictive Value of Tests , Reoperation
11.
Kidney Int ; 58(5): 1851-8, 2000 Nov.
Article in English | MEDLINE | ID: mdl-11044204

ABSTRACT

BACKGROUND: The nonspecific lesion of focal segmental glomerulosclerosis (FSGS) can occur as a primary disease or in a variety of secondary settings. In mitochondrial cytopathies (MCs), the phenotypic expression of the disease depends on the degree of cellular dysfunction, and this correlates with the proportion of abnormal mitochondrial DNA in the cells and the dependence of tissues on oxidative metabolism. The most common renal manifestation in MCs is tubular dysfunction; little has been reported about glomerular diseases. METHODS: Cases of four adult patients with FSGS and MC are reported. Routine histology and mitochondrial DNA analysis were carried out on renal biopsies. RESULTS: Family history and clinical manifestations in the four patients with FSGS suggested a diagnosis of MC. An A3243G transition in the mitochondrial DNA tRNA(leu(UUR)) was found in lymphocytes and kidney. Glomerular lesions of FSGS were associated with unusual hyaline lesions, which appeared to represent individual myocyte necrosis in afferent arterioles and small arteries. CONCLUSION: FSGS is a renal manifestation of MCs. The renal lesion can precede other manifestations of the genetic disease by many years. The striking arteriolar lesions in these cases may have resulted in glomerular hypertension and hyperperfusion, leading to secondary epithelial cell abnormalities and, ultimately, FSGS. However, primary epithelial cell dysfunction caused by mitochondrial defects could not be ruled out on morphological grounds. MCs should be considered in cases of so-called primary FSGS, particularly if there is a familial history of diabetes, neuromuscular disorders, or deafness.


Subject(s)
Glomerulosclerosis, Focal Segmental/etiology , Kearns-Sayre Syndrome/complications , Adolescent , Adult , DNA, Mitochondrial/genetics , DNA, Mitochondrial/metabolism , Female , Glomerulosclerosis, Focal Segmental/pathology , Humans , Kearns-Sayre Syndrome/genetics , Kearns-Sayre Syndrome/pathology , Kidney/metabolism , Kidney Glomerulus/blood supply , Kidney Glomerulus/pathology , Lymphocytes/metabolism , Male , Muscle, Smooth, Vascular/pathology , Pedigree , RNA, Transfer, Leu/genetics
12.
Diabetes ; 49(3): 466-75, 2000 Mar.
Article in English | MEDLINE | ID: mdl-10868970

ABSTRACT

Diabetic glomerulosclerosis is defined by increased glomerular extracellular matrix (ECM) that is mainly synthesized by mesangial cells that underwent an activation mediated by cytokines and growth factors from various cellular origins. In this study, we tested whether macrophages could infiltrate the glomeruli and influence ECM synthesis in experimental diabetes. To test our hypothesis, we initially studied the dynamics of glomerular macrophage recruitment in streptozotocin-induced diabetic rats at days 1, 2, 4, 8, 15, and 30 by using quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) on isolated glomeruli and immunohistochemistry and morphometry. We then assessed the role of macrophages on the basis of the pharmacological modulation of their recruitment by insulin or ACE inhibitor treatments and by X-irradiation-induced macrophage depletion at days 8 and 30. Macrophages were recruited within the glomeruli at the very early phase of hyperglycemia by using RT-PCR CD14 detection from day 2 and by using ED1 immunohistochemistry from day 8. This glomerular macrophage infiltration was associated with an increase in alpha1-chain type IV collagen mRNA. In parallel, the diabetic glomeruli became hypertrophic with an increase in the mesangial area. Macrophage recruitment was preceded by or associated with an increased glomerular expression of vascular cell adhesion molecule 1, intracellular adhesion molecule 1, and monocyte chemoattractant protein 1, which contributes to monocyte diapedesis. Glomerular interleukin-1beta mRNA synthesis was also enhanced as early as day 1 and could be involved in the increase in ECM and adhesion molecule gene expressions. Insulin treatment and irradiation-induced macrophage depletion completely prevented the glomerular macrophage recruitment and decreased alpha1-chain type IV collagen mRNA and mesangial area in diabetic rats, whereas ACE inhibitor treatment had an incomplete effect. It can be concluded that in the streptozotocin model, hyperglycemia is followed by an early macrophage recruitment that contributes to the molecular and structural events that could lead to glomerulosclerosis. Therefore, besides direct stimulation of mesangial cells by hyperglycemia, macrophages recruited in the glomeruli during the early phase of hyperglycemia could secondarily act on mesangial cells.


Subject(s)
Diabetes Mellitus, Experimental/physiopathology , Kidney Glomerulus/physiopathology , Macrophages/physiology , Animals , Blood Glucose/analysis , Body Weight , Cell Adhesion Molecules/biosynthesis , Cell Movement , Chemokine CCL2/metabolism , Collagen/genetics , Diabetes Mellitus, Experimental/pathology , Glomerular Mesangium/pathology , Hypertrophy , Interleukin-1/genetics , Kidney Glomerulus/pathology , Macrophages/pathology , Male , RNA, Messenger/metabolism , Rats , Rats, Sprague-Dawley , Reference Values
13.
Nephrol Dial Transplant ; 15(4): 467-76, 2000 Apr.
Article in English | MEDLINE | ID: mdl-10727540

ABSTRACT

BACKGROUND: Several factors favour the development of kidney lesions. We examined the role of oxidative stress in the onset of renal alterations that occur in Zucker obese (ZO) fa/fa rats. METHODS: Kidney structure, biological data, glycation parameters, advanced glycation end products (AGE), thiobarbituric acid-reactive substances (TBARS), circulating antibodies anti-malondialdehyde (MDA)-modified low-density lipoprotein (LDL), antioxidant defenses (Cu/Zn and Mn superoxide dismutase (SOD), catalase, glutathione peroxidase (GPx) activities, glutathione level), were determined in plasma and/or kidney of young and old ZO rats and lean (ZL) Fa/fa littermates. RESULTS: Renal lesions and functional decline appeared at 3 months in hyperlipidaemic, hyperinsulinaemic, normotensive ZO rats, independently of any macrophage-ED(1)(+)-cell infiltration. At 6 months and thereafter, kidney lesions and functional impairment worsened while numerous ED(1)(+)-cells invaded the interstitium. At 3 and 9 months, TBARS level in the LDL/very low-density lipoprotein fraction and in the kidney was higher in ZO than in ZL rats. Anti-MDA-LDL antibodies were increased in ZO rats. At 3 months, renal activity of Cu/Zn SOD was higher, and activities of catalase and GPx lower in ZO than in ZL rats, leading to an accumulation of hydrogen peroxide (H(2)O(2)). At 9 months, a decrease in Cu/Zn SOD activity and an increase in glutathione level were observed. Blood glucose and glycated proteins, as well as AGE in kidney, remained similar in both ZL and ZO rats, whatever their age. CONCLUSION: These data suggest that oxidative stress triggers, at an early age, the onset of kidney lesions and functional impairment in ZO rats, in absence of hyperglycaemia, hypertension and inflammation.


Subject(s)
Blood Pressure/physiology , Glomerulosclerosis, Focal Segmental/metabolism , Hyperglycemia/blood , Oxidative Stress/physiology , Animals , Blood Glucose/metabolism , Cholesterol/blood , Disease Models, Animal , Fibrosis , Glomerulosclerosis, Focal Segmental/pathology , Glomerulosclerosis, Focal Segmental/physiopathology , Glycated Hemoglobin/metabolism , Glycation End Products, Advanced/metabolism , Glycosylation , Inflammation , Kidney Tubules/metabolism , Kidney Tubules/pathology , Lipid Peroxidation/physiology , Male , Rats , Rats, Zucker , Thiobarbituric Acid Reactive Substances/metabolism , Triglycerides/blood , Urodynamics
14.
J Am Soc Nephrol ; 10(3): 507-18, 1999 Mar.
Article in English | MEDLINE | ID: mdl-10073601

ABSTRACT

Even 10 yr after the identification of the antiphospholipid syndrome (APS), renal involvement in the course of APS is still relatively unrecognized, and is probably underestimated. The association of anticardiolipin antibodies and/or lupus anticoagulant with the development of a vaso-occlusive process involving numerous organs is now confirmed. In a multicenter study, 16 cases of "primary" APS (PAPS) were found and followed for 5 yr or more, all with renal biopsy. In all 16 cases of PAPS, there was a vascular nephropathy characterized by small vessel vaso-occlusive lesions associated with fibrous intimal hyperplasia of interlobular arteries (12 patients), recanalizing thrombi in arteries and arterioles (six patients), and focal cortical atrophy (10 patients). In combination, these led to progressive destruction of the kidney, accelerated by acute glomerular and arteriolar microangiopathy in five patients. Focal cortical atrophy is a distinctive lesion, present in 10 biopsies, and likely represents the histologic and functional renal analogue to the multiple cerebral infarcts detected on imaging studies. The clinical hallmark of this vascular nephropathy in PAPS is systemic hypertension, only variably associated with renal insufficiency, proteinuria, or hematuria. The ensemble of histologic renal lesions defined in this study should aid in the separation of the lesions found in cases of secondary APS, especially systemic lupus erythematosus, into those lesions related to APS and those related to the underlying disease.


Subject(s)
Antibodies, Antiphospholipid/analysis , Antiphospholipid Syndrome/pathology , Kidney Diseases/pathology , Renal Artery Obstruction/pathology , Thrombosis/pathology , Adult , Antiphospholipid Syndrome/complications , Biopsy, Needle , Female , Humans , Kidney/blood supply , Kidney/pathology , Kidney Diseases/etiology , Kidney Diseases/immunology , Male , Middle Aged , Prognosis , Renal Artery Obstruction/etiology , Retrospective Studies , Severity of Illness Index , Thrombophlebitis/etiology , Thrombophlebitis/pathology , Thrombosis/etiology
15.
Am J Physiol ; 275(3): F379-86, 1998 09.
Article in English | MEDLINE | ID: mdl-9729510

ABSTRACT

Four Na+/H+ exchangers (NHE1 to NHE4) have been detected in the kidney. Renal NHE2 expression sites have not been fully established. We have raised rabbit antisera against an oligopeptide related to the amino acids 652 to 661 of rat NHE2. Western blot analysis of plasma membrane fractions isolated from rat renal cortex showed that affinity-purified anti-NHE2 antibody detected an 85-kDa protein in apical but not in basolateral membranes. The labeling of this 85-kDa protein was specifically blocked by preincubation of the antibody with its monomeric peptide, indicating specific recognition. Indirect immunolabeling was performed on sections of paraformaldehyde-fixed rat kidney embedded in paraffin. Strong staining was seen in the apical membrane of cortical thick ascending limbs, distal convoluted tubules, and connecting tubules. Much weaker apical staining was found in medullary thick ascending limbs of Henle. In the inner medulla, some thin limbs were intensively labeled by the anti-NHE2 antibody. No staining could be detected in any segments of the proximal tubule and collecting duct.


Subject(s)
Kidney/chemistry , Sodium-Hydrogen Exchangers/analysis , Animals , Blotting, Western , Cell Membrane/chemistry , Immunoblotting , Immunohistochemistry , Kidney Cortex/chemistry , Kidney Tubules/chemistry , Male , Nephrons/chemistry , Rats , Rats, Sprague-Dawley , Tissue Distribution
16.
J Clin Invest ; 102(5): 910-8, 1998 Sep 01.
Article in English | MEDLINE | ID: mdl-9727059

ABSTRACT

Atherosclerosis is associated with immune activation. T cells and macrophages infiltrate atherosclerotic plaques and disease progression is associated with formation of autoantibodies to oxidized lipoproteins. In the apo E knockout mouse, a genetic model of cholesterol-induced atherosclerosis, congenital deficiency of macrophages, lymphocytes, or interferon-gamma receptors result in reduced lesion formation. We have now evaluated whether immune modulation in the adult animal affects disease development. Injections of 7-wk-old male apo E knockout mice with polyclonal immunoglobulin preparations (ivIg) during a 5-d period reduced fatty streak formation over a 2-mo period on cholesterol diet by 35%. Fibrofatty lesions induced by diet treatment for 4 mo were reduced by 50% in mice receiving ivIg after 2 mo on the diet. ivIg treatment also reduced IgM antibodies to oxidized LDL and led to inactivation of spleen and lymph node T cells. These data indicate that ivIg inhibits atherosclerosis, that it is effective both during the fatty streak and plaque phases, and that it may act by modulating T cell activity and/or antibody production. Therefore, immunomodulation may be an effective way to prevent and/or treat atherosclerosis.


Subject(s)
Adjuvants, Immunologic/therapeutic use , Apolipoproteins E/deficiency , Arteriosclerosis/therapy , Immunoglobulin G/pharmacology , Animals , Aorta/pathology , Arteriosclerosis/immunology , Arteriosclerosis/pathology , Cell Division/immunology , Diet , Histocytochemistry , Immunoglobulin M/immunology , Inflammation/immunology , Lipoproteins, LDL/immunology , Mice , Mice, Knockout , T-Lymphocytes/metabolism
17.
Kidney Int ; 53(4): 918-25, 1998 Apr.
Article in English | MEDLINE | ID: mdl-9551398

ABSTRACT

Collapsing glomerulopathy (CG), a severe form of focal segmental glomerulosclerosis (FSG), is characterized by tuft retraction and consolidation in numerous glomeruli and changes in podocyte morphology and topography. Other glomeruli are less affected. Collapsing glomerulopathy is also characterized by tubulointerstitial atrophy and fibrosis. The pathophysiology of the glomerular and tubulointerstitial lesions is poorly understood. We studied renal tissue of five Black and three White patients, all human immuno-deficiency virus (HIV) negative, with nephrotic syndrome, renal failure, and histological evidence of CG. Immunohistochemistry identified normal podocyte phenotypes by podocalyxin, vimentin and complement receptor 1 (CR1) labeling. Three monoclonal antibodies were used to further characterize podocyte epitopes: anti-CD68 clone KP1, anti-CD68 clone PG-M1 and anti-M130 clone M18 (Ber-MAC3). Light microscopy of collapsed glomeruli showed podocyte swelling, vacuolization, multinucleation, "cobblestone-like" alignment around the glomerular tuft, and pseudo-crescent formation in Bowman's space. In collapsed glomeruli, podocalyxin, vimentin and CR1 labeling tagged both normal and vacuolated podocytes still attached to the GBM, but labeling was not found in cobblestone-like podocytes or in podocytes detached from the GBM. Conversely, numerous podocytes undergoing detachment and shedding into Bowman's space expressed macrophagic-associated epitopes. Cells with macrophagic-associated epitopes clumped in cystically dilated tubules and were aligned in tubules of smaller caliber. Their appearance was that of viable cells. There was no morphologic indication that these cells expressing macrophage-associated antigens originated from outside the glomeruli or outside the tubules. We conclude that in CG podocytes detach from the GBM, lose their normal podocytic phenotype and acquire macrophage differentiation antigens. The presence of cells with such antigens in tubular lumens suggests that detached metaplastic podocytes progress along the tubule or, alternatively, that CG tubular cells also undergo metaplastic changes into macrophage-like cells.


Subject(s)
Glomerular Mesangium/pathology , Glomerulosclerosis, Focal Segmental/immunology , Glomerulosclerosis, Focal Segmental/pathology , Macrophages/chemistry , Adult , Antibodies, Monoclonal , Antigen-Presenting Cells/cytology , Antigens, CD/analysis , Antigens, Differentiation, Myelomonocytic/analysis , Biomarkers , Cell Differentiation/immunology , Epitopes/analysis , Female , Fluorescent Antibody Technique , Humans , Immunophenotyping , Macrophages/cytology , Male , Middle Aged , Sialoglycoproteins/analysis
18.
Virchows Arch ; 432(3): 267-77, 1998 Mar.
Article in English | MEDLINE | ID: mdl-9532007

ABSTRACT

In the first 6 days of hypertension, infiltrated mononuclear cells were colocalized with collagen (I) mRNA-overexpressing fibroblasts in the adventitial area of unclipped kidney. The number of adventitial infiltrated mononuclear cells was correlated with adventitial collagen (I) surface expansion. After 22 days of hypertension no collagen (I) mRNA-overexpressing fibroblasts or any increase in collagen area or mononuclear cell infiltration was observed. In the interstitium of unclipped kidney, collagen (I) mRNA overexpression, collagen (I) expansion and mononuclear cell infiltration began later, from the 7th day of hypertension, and kept increasing. In the clipped kidney, after expansion in the first 6 days of hypertension, the adventitial collagen remained stable. These results suggest that in the unclipped kidney fibroblastic activation begins within the first 6 days of hypertension in the adventitial area, but is transient, and fibrosis then spreads in the interstitium. Mononuclear cell infiltration is colocalized and correlated with adventitial and interstitial fibrosis. In the first 6 days, hypertension is not the only cause of fibrosis; the same level of adventitial fibrosis is detected in the nonhypertensive clipped kidney. All observed pathological phenomena could be detected within the first 3 days of hypertension.


Subject(s)
Cell Movement , Collagen/biosynthesis , Hypertension/metabolism , Hypertension/pathology , Nephritis, Interstitial/metabolism , Nephritis, Interstitial/pathology , Animals , Disease Models, Animal , Fibrosis , In Situ Hybridization , Leukocytes, Mononuclear/pathology , Male , Nephritis, Interstitial/physiopathology , RNA, Messenger/metabolism , Rats , Rats, Wistar
20.
Presse Med ; 26(26): 1236-7, 1997 Sep 13.
Article in French | MEDLINE | ID: mdl-9380624

ABSTRACT

BACKGROUND: Cholesterol crystal embolism is often an iatrogenic complication in ulcerated atherosclerosis of the aorta. CASE REPORTS: Two cases of multi-organ embolism of cholesterol crystals were histologically proven in patients treated with low-molecular-weight heparin. Both patients had acute renal failure, hypertension with acute pulmonary edema, skin necrosis and ischemia of the digestive tract. Outcome was favorable after discontinuing anticoagulants, symptomatic treatment, definitive hemodialysis and low-dose corticosteroids. DISCUSSION: These two cases are the first reported in the literature of cholesterol crystal embolism occurring during prophylactic treatment with low-molecular-weight heparin. They demonstrate that there is a risk of severe cholesterol embolism in high-risk patients after administration of low-molecular-weight heparin as for non-fractionated heparin, fibrinolytics, arteriography and cardiovascular surgery. Low-molecular-weight heparin thus should not be used in patients with a diagnosis of cholesterol crystal embolism.


Subject(s)
Anticoagulants/adverse effects , Embolism, Cholesterol/chemically induced , Heparin, Low-Molecular-Weight/adverse effects , Aged , Embolism, Cholesterol/etiology , Female , Humans , Male , Risk Factors
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