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Biomedical subjects

P Zaoui

Publications and source records attributed to P Zaoui.

At least 19 recordsLinked to original sources
PubMed2002

Proteinuria and the expression of the podocyte slit diaphragm protein, nephrin, in diabetic nephropathy: effects of angiotensin converting enzyme inhibition.

AIMS/HYPOTHESIS: Proteinuria, reflecting increased glomerular permeability to macromolecules is a characteristic feature of diabetic nephropathy. Nephrin, a 1241-residue transmembrane protein is a key component of the podocyte slit pore membrane and a major contributor of the glomerular filtration barrier. We investigated the expression of nephrin in human kidney tissue from patients with diabetic nephropathy to elucidate its relationship with proteinuria and the effects of anti-proteinuric therapy with angiotensin converting enzyme inhibition. METHODS: Renal biopsies were examined from 14 patients with Type II (non-insulin-dependent) diabetes mellitus and proteinuria who had been randomised to receive treatment with the ACE inhibitor, perindopril (4 mg/day) or placebo for the preceding 2 years. These specimens were compared with control human tissue sections, obtained from areas of normal renal cortex following nephrectomy for malignancy. Proteinuria was measured, specimens were examined histologically for injury and the expression of nephrin messenger RNA was assessed by quantitative in situ hybridisation. RESULTS: Glomeruli from placebo-treated patients with diabetic nephropathy, showed a 62% reduction in nephrin expression compared with control subjects (p=0.0003). In contrast, nephrin RNA in glomeruli from perindopril treated patients was similar to that in the non-diabetic control group. In both placebo and perindopril treated patients, a close inverse correlation was noted between the magnitude of nephrin gene expression and the degree of proteinuria (placebo: r=0.86, p=0.013, perindopril: r=0.91, p=0.004). CONCLUSION/INTERPRETATION: Modulation in nephrin expression is related to the extent of proteinuria in diabetic nephropathy. These changes define, at a molecular level alterations in the glomerulus that occur in relation to proteinuria in diabetes and the effects of anti-proteinuric treatment with ACE inhibition.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed2001

Role of ACE inhibitors in patients with diabetes mellitus.

The adjective 'epidemic' is now attributed to the rapidly growing number of patients with diabetes mellitus, mainly type 2. and the specific complications linked to this disorder. Provided they are recognised early enough, these different complications can be treated; in some patients the evolutive course of these complications can be slowed or even stopped. Furthermore, some recent observations suggest that specific tissular lesions may be prevented or even reversed. Although glycaemic control is essential, other therapeutic measures that must also be taken include those to control blood pressure and to lower lipid levels. Of the agents available to control the complications of diabetes mellitus, cardiovascular drugs, and particularly ACE inhibitors, have a pre-eminent place. Experimental and epidemiological data suggest that activation of the renin-angiotensin-aldosterone system plays an important role in increasing in the micro- and macrovascular complications in patients with diabetes mellitus. Not only are ACE inhibitors potent antihypertensive agents but there is a growing body of data indicating that also they have a specific 'organ-protective' effect. For the same degree of blood pressure control, compared with other antihypertensive agents, ACE inhibitors demonstrate function and tissue protection of considered organs. ACE inhibitors have been reported to improve kidney, heart, and to a lesser extent, eye and peripheral nerve function of patients with diabetes mellitus. These favourable effects are the result of inhibition of both haemodynamic and tissular effects of angiotensin II. Finally, there are a growing number of arguments favouring the use of ACE inhibitors very early in patients with diabetes mellitus.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed2000

[Heterogeneity of nephropathies in type 2 diabetes].

DIVERSE KIDNEY DISORDERS: Patients with type 2 diabetes mellitus who develop nephropathy can have various types of disorders capable of progressively destroying the kidneys. It is now clear that the same type of diffuse or nodular glomerulosclerosis develops irrespective of the type of diabetes, i.e. the pathophysiology of hyperglycemia. HETEROGENEITY: There is however a certain degree of heterogeneity in terms of clinical presentation, clinical course and response to treatment. Heterogeneity is due to age, the number of different accumulated risk factors and disease states, genetic factors that are in the process of being identified, and finally, lesions to the urologic apparatus, the arteries, and the renal parenchyma itself that are not directly caused by diabetes. PRACTICAL IMPACT: Mixed lesions, due to both diabetic and non-diabetic causes, may therefore exist in the same kidney. These different possibilities should be systematically considered in order to adopt an individualized investigative and therapeutic attitude for each new patient.

Biopsy↗
PubMed2000

Adult Fanconi syndrome secondary to light chain gammopathy. Clinicopathologic heterogeneity and unusual features in 11 patients.

Fifty-seven cases of Ig light chain-associated Fanconi syndrome (FS) have been reported so far, mostly as isolated reports. The pioneering work by Maldonado and associates (35), who reviewed the first 17 cases in 1975, led to the unifying concept that patients with FS and Bence Jones proteinuria have a special form of plasma cell dyscrasia characterized by slow progression of the tumor and by prominent crystal formation in proximal tubule cells, in the absence of myeloma casts in the distal tubule. We carefully reappraised these characteristics in a series of 11 patients. Ten renal biopsy specimens were available for electron microscopy, adding to the 15 previously reported cases with ultrastructural studies. Moreover, 10 of the kappa light chains could be entirely or partially sequenced and tested for their resistance to cathepsin B, a lysosomal protease present in proximal tubule cells. Our series showed an unexpected clinicopathologic heterogeneity. Seven patients presented with the typical clinical and pathologic features of FS and low-mass myeloma or monoclonal gammopathy of undetermined significance (MGUS), in keeping with Maldonado et al's description. Crystals in bone marrow cells were detected in patients of this group, only. Three patients who presented with full-blown FS exhibited, however, the characteristic features of myeloma cast nephropathy in the setting of high-mass myeloma. One patient of this group also had numerous crystals in proximal tubule cells. The eleventh patient had complete FS with MGUS, but no crystals in proximal tubule cells even after electron microscopy. Contrasting with the clinicopathologic heterogeneity, genetic and biochemical analyses of the light chains showed a striking homogeneity. First, they all were of the kappa type. Second, 8 of 9 belonged to the V kappa I variability subgroup, which indicates that FS light chains are related by the sequence of their variable regions. Third, the 8 V kappa I light chain sequences most likely originated from only 2 germline genes, LCO2/012 and LCO8/018. Fourth, all 5 LCO2/012-derived sequences presented an unusual hydrophobic or nonpolar residue at position 30. These sequence peculiarities may account for unusual physicochemical properties of the light chains including the resistance of their variable domain V kappa to proteolysis by cathepsin B, observed in 7 of 9 patients in our series, while light chains isolated from patients with myeloma cast nephropathy are completely digested. Resistance of V kappa to proteolysis in FS patients can explain the accumulation of the light chain in the endocytotic compartment of the proximal tubule cells, leading to impairment of proximal tubule functions.

Adult↗
PubMed2000

Role of metalloproteases and inhibitors in the occurrence and progression of diabetic renal lesions.

Renal remodelling in hyperinsulinic/insulinopenic states is mediated by glucotoxicity, endothelial dysfunction and vascular and nephron collagen turnover. Hypertensive and renal links are renewed by renoprotective interventions of renin-angiotensin. Vasoactive peptide processing and vascular collagen deposition are under the tight control of two zinc metalloproteinase families that regulate vascular tone and trophicity: gluzincins (or vasopeptidases) are convertases of angiotensins, endothelins or atrial natriuretic factors; and metzincins or matrix metalloproteases (MMP, matrixins)] regulate vascular type IV collagen basement membrane proteolysis. Association of natural tissue inhibitors of MMPs, pharmacological inhibitors of vasopeptidases [either conventional (angiotensin-converting enzyme inhibitors) or innovative (omapatrilat)], together with synthetic MMP inhibitors, are currently screened to counteract vascular remodelling and renal scarring. Our studies focused on the 72 kDa (MMP-2) and 92 kDa (MMP-9) matrixin gelatinases and tissue inhibitors involved in basement membrane degradation and rebuilding. Three complementary settings were developed, allowing evaluations from basic to clinical stages. A leucocyte-endothelial transmigration model was designed for transcription and addressing of enzymes and inhibitors, in situ matrix degradation, and blockading by metalloprotease inhibitors (captopril). Insulin-resistant fructose-fed rats showed heavy proteinuria and glomerulosclerosis involving angiotensin II-dependent changes in renal gelatinases and inhibitors. Urinary gelatinolytic profiles from Type 2 diabetic patients with overt nephropathy were compared with those of normal first-degree relatives and age-matched healthy controls. Physiologically, MMP-9 was the primary urinary gelatinolytic enzyme. In Type 2 diabetic proteinuric patients, MMP-9 and MMP-2 releases were significantly increased in the absence of renin-angiotensin blockade, while first-degree relatives showed reduced gelatinase levels suggestive of a genetic control of renal matrix regulation prior to potential glycaemic dysregulation. These preliminary data suggest that local MMP/TIMP imbalance is involved in diabetic renal remodelling. Further studies are needed to define the redundancies and specificities of vasopeptidase and MMP inhibitors, differentiate the antihypertensive effect from target-organ protection, screen for innovative pharmacological compounds, and validate simple, efficient biological markers of renal fibrosis progression and the effect of anti-fibrotic therapeutic interventions.

Animals↗
PubMed1999

Expansion of cortical interstitium is limited by converting enzyme inhibition in type 2 diabetic patients with glomerulosclerosis. The Diabiopsies Group.

Renal interstitial expansion is now considered a useful marker of progression of several nephropathies. This study describes a multicenter, prospective, double-blind, placebo-controlled, randomized trial of the effects of Perindopril (4 mg/d) on kidney structure and function over 2 yr in 26 type 2 diabetic patients with proteinuria ranging from 70 to 4210 mg/d and relatively preserved GFR (creatinine clearance >60 ml/min). All patients underwent baseline renal biopsy, but four (15%) were not randomized because of the presence of nondiabetic nephropathy. The remaining 22 were randomized ( 11 to Perindopril [PE], 11 to placebo [PO]), and 19 (9 PE, 10 PO) underwent follow-up biopsy at 2 yr. BP was controlled equally in both groups throughout. Proteinuria increased in PO patients (+1562 mg/d) but declined in PE patients (-156 mg/d) (P < 0.05). Morphometric analysis was performed by light microscopy using a Biocom computer. Over the 2 yr, mean cortical interstitial fractional volume identical at baseline increased significantly in PO patients (31.7 +/- 5.3 versus 40.2 +/- 11.1%; P = 0.001) but was unchanged in PE patients (33.8 +/- 4.9 versus 34.7 +/- 6.6%; P = 0.50). It is concluded that: (1) nondiabetic nephropathy is present in approximately 15% of albuminuric type 2 diabetic patients; and (2) Perindopril prevents interstitial expansion in hypertensive patients with biopsy-proven diabetic glomerulopathy. These results support a role of angiotensin II in the progression of interstitial changes in type 2 diabetic patients with nephropathy.

Adult↗
PubMed1999

Huge progression of diabetes prevalence and incidence among dialysed patients in mainland France and overseas French territories. A second national survey six years apart. (UREMIDIAB 2 study).

In 1989, we conducted a survey (UREMIDIAB) on the prevalence of diabetes among the population on Renal Replacement Therapy (RRT) in Mainland France (MF), the lowest of the developed countries (6.9%) with a North-South gradient (higher prevalence in the North). This highlighted a possible (genetical or nutritional) "new french paradox" in mainland France populations. In 1992 we conducted a similar study in the french (mainly non caucasian) overseas territories (OT) hosting 3.2% of the total french population, and observed a prevalence of diabetes in RRT of 22.9%. The frequency of diabetes mellitus as a cause of ESRD increasing worldwide, we conducted a second survey in year 1995, in MF and the OT. This study, UREMIDIAB 2, included all of the 244 french dialysis centers. A "Center file" allowed us to determine the prevalence and incidence of diabetes in the french RRT population, (response rate 73%). Then a "Patient medical file" (response rate 64.8% for MF and 91% for the OT) provided detailed informations: type of diabetes (type 1 or 2), etiology of nephropathy, status of diabetic complications, family's geographic origin of the patient. In MF the prevalence of diabetics in RRT doubled within 6 years: 13.04% vs 6.9%, the incidence reached 15.7%. In the OT the prevalence and the incidence reached 25.7% and 35.6%, respectively. Type 2 diabetes represented 87% and 93% of the RRT diabetics in MF and the OT, respectively. Diabetic nephropathy was considered as the cause of renal failure in 91.3% of type 1 and 57.5% of type 2 diabetics under dialysis. We found: 14.7% of myocardial infarction, 12.7% of cerebral strokes, 17.6% of amputations (extreme 37% in some OT centers) among this diabetic RRT population. A North-East (higher prevalence) South-West (lower) gradient was confirmed. We conclude that, while an unusual low prevalence (< or = 13%) of diabetics under dialysis persists in some parts of Mainland France, the total prevalence has been doubled within 6 years (1989/95) and that in Overseas Territories, hosting similar mixed blood populations than USA (afro-caribbeans, asians, indians, micronesians and metis), the high incidence of diabetes in RRT has reached the US levels during the same period.

Diabetes Mellitus, Type 1↗
PubMed1998

Human B lymphocytes synthesize the 92-kDa gelatinase, matrix metalloproteinase-9.

Matrix metalloproteinases (MMPs) are involved in the remodeling of connective tissue as well as in disease states associated with acute and chronic inflammation or tumoral metastatic processes. Despite detailed and extensive studies of the mechanisms of lymphocyte extravasation, remarkably little is known about the expression and regulation of metalloproteinases involved in the migratory process. By using zymography and reverse transcription-polymerase chain reaction experiments, we have demonstrated that Epstein-Barr virus-immortalized B lymphocytes are able to secrete a 92-kDa metalloproteinase with gelatinolytic activity which has been purified and identified as being MMP-9. Moreover, the tissue inhibitor of metalloproteinase was shown to be constitutively expressed by the B cells. The expression of 92-kDa gelatinase is mediated by cytokines, growth factors, lipopolysaccharide, concanavalin A, and the tumor promotor phorbol 12-myristate 13-acetate. Time dependence activity increased rapidly up to 24 h of incubation with lipopolysaccharide or concanavalin A stimulation while it requires a delay and more time to have an optimum effect when cytokines were the stimulating agents; transforming growth factor-beta abolished 92-kDa gelatinase production. Both staurosporine and wortmannin are inductive stimuli, and the level of MMP-9 secreted into the media is greater than that observed with other agents except concanavalin A. Elicitation of the chemotactic migration of B cells through a model basement membrane by lipopolysaccharide was shown to be correlated with gelatinase expression and inhibited by 7 mM captopril. Our study indicates that Epstein-Barr virus-B lymphocytes express 92-kDa gelatinase, the production of which can be modified by a variety of physiological and pharmacological signals which have been shown to differ according to the cell type.

Androstadienes↗
PubMed1998

Matrix metalloproteinase expression in rat pancreatic islets.

Matrix metalloproteinases (MMPs) are involved in the regulation of extracellular matrix turnover and tissue remodeling, through which they can influence the infiltration of a graft by immune-competent cells. Little is known about their role in islet allograft rejection. Therefore we investigated the expression of several MMPs and of two of their tissue inhibitors (TIMPs) in rat pancreatic islets. MMP and TIMP expression in isolated rat pancreatic islets was assessed by reverse transcriptase-polymerase chain reaction (RT-PCR) from total RNA. Several MMPs of different substrate specificities were found to be expressed in rat pancreatic islets, either shortly after islet isolation and in all conditions tested (MMP-9, TIMP-1) or after a lag time (MMP-2, MMP-3, MMP-14, TIMP-2). Fetal calf serum induced MMP-7 expression. The inflammatory cytokine interleukin-1 beta (IL-1 beta) did not induce MMP or TIMP expression. We showed that rat pancreatic islets are well equipped with MMPs and TIMPs, but the functional meaning of this expression remains to be elucidated. On the basis of the known effects on tissue remodeling and cytokine processing, we anticipate that they can influence islet engraftment and viability and participate to islet graft rejection.

Animals↗
PubMed1998

Inter-regulated balance between gelatinases and tissue inhibitor (TIMP-1) in isolated human glomeruli.

Leukocyte infiltration inside glomeruli necessitates basement membrane collagen i.v. breakdown and leads to mesangiolysis, cell proliferation and extracellular matrix synthesis during the repair process as observed in the course of acute glomerulonephritis, vasculitis and acute graft rejection. Two matrix metalloproteinases, MMP-2 and MMP-9 gelatinases, are expressed and co-secreted in balance with the tissue inhibitor of metalloproteinases-1 (TIMP-1) by activated neutrophils as well as by glomerular cells and are aimed to control basement membrane collage i.v. deposition. Using a conventional double mesh sieving method, pure populations of glomeruli were isolated from fresh human cortex specimen and maintained in short-term cultures. ELISA, zymography and immunoblotting of conditioned serum-free media revealed glomerular MMP-2, MMP-9 and TIMP-1 secretion and activity while reverse transcription-polymerase chain reaction amplification of cellular RNA demonstrated glomerular transcripts coding for these enzymes and their inhibitor. When purified neutrophils were allowed to adhere onto Transwell apparatus in contact with glomerular suspensions, neutrophil 92 kDa gelatinase seemed apparently inhibited mainly because the production of TIMP-1 was enhanced on both sides of the insert. Glomerular 72 kDa and 92 kDa gelatinases were activated shortly (1 to 6 h) after neutrophils had interacted with glomeruli and furthermore upon activation by inflammatory or vasoactive mediators such as phorbol. Decreased neutrophil MMP-9 activity together with reduced MMP-9 mRNA levels and protracted TIMP-1 transcription and secretion during cell-cell interaction could participate to cell detachment from degraded basement membranes and to increased collagen i.v. deposition leading to glomerulosclerosis after initial glomerular injury by inflammatory cells.

Cells, Cultured↗
PubMed1997

Proteolytic potential of human neutrophil membranes.

A synergistic role for proteases in the degradation of extracellular matrix proteins has been proposed. Plasma membrane was isolated from a neutrophil homogenate, on a sucrose gradient, and shown to activate gelatinolysis when purified 92 kDa gelatinase was added to the medium. This stimulatory activity was enhanced by the addition of phorbol 12-myristate 13-acetate (PMA), in a dose-dependent manner, and was partially sensitive to phenylmethylsulfonyl fluoride treatment. The effect was abolished by the addition of 1 M KCl or 0.05% Brij 35 extraction. Both elastase and urinary type plasminogen activator were shown to be involved in the process. Moreover, upon neutrophil stimulation by PMA, 92 kDa gelatinase, as elastase, became associated with the plasma membrane, as shown by a subcellular fractionation experiment. These in vitro observations suggest that human neutrophils may be able, in vivo, to recruit endogenous or exogenous proteinases to mediate proteolysis associated with diapedesis and chemotactism during the inflammation process.

Alkaline Phosphatase↗
PubMed1996

Differential expression and secretion of gelatinases and tissue inhibitor of metalloproteinase-1 during neutrophil adhesion.

Transmigrating neutrophils secrete a 92 kDa gelatinase (MMP-9) in order to degrade type IV endothelial basement membrane collagen. A model system for neutrophil adhesion combining a short pre-adhesion time (30 min) in plastic or endothelium-coated wells, medium removal and addition of soluble stimuli (fMLP, TNF alpha), enabled us to induce the release of a basal level of gelatinase activity (> 12% total cell content) from tertiary granules, while the release of vitamin B12 binding protein from specific granules was limited to 4% total cell content. Neutrophil gelatinase activity in unfractionated supernatants from endothelium-coated wells was significantly reduced (P < 0.01) compared to levels obtained on plastic supports, even after TNF alpha treatment or when cell populations were physically separated by trans-well inserts. In contrast, gelatin zymograms of supernatants from plastic and endothelium-coated wells remained similar. These findings suggest that MMP-9 is equally secreted but differentially inhibited by the tissue inhibitor of metalloproteinase-1 originating from the neutrophils. MMP-9 RT-PCR from neutrophils, assessed after up to one hour adhesion on plastic, yielded a single 270 bp fragment which was almost undetectable in the endothelial RT-PCR counterpart, whereas the TIMP-1 PCR product was apparent in both cell types. Furthermore, neutrophil adhesion on endothelial cells and TNF alpha activation for one hour induced the disappearance of MMP-9 cDNA without changes in TIMP-1 and beta-actin PCR products. These results suggest the existence of a dual down-regulation during neutrophil-endothelial interaction, both at the level of secreted MMP-9 activity and of MMP-9 gene transcription.

Cell Adhesion↗
PubMed1996

[TGF-beta: usage in nephrology].

TGF beta is a ubiquitous multifunctional cytokine produced by a wide variety of cells; its amino acid sequence indicates a marked conservation across species. Five isoforms have been identified, three of which, TGF beta 1, 2, 3, in mammals. It is secreted in a biologically latent form and is then activated by physiological mechanisms which are still poorly characterized. TGF beta is known as a regulator of cell growth, differentiation and proliferation, but exerts also a tight control over extracellular matrix synthesis. Although TGF beta has been found to have a beneficial role in connective tissue and bone repair processes, its overexpression could lead to fibrosis and fibroproliferative diseases. TGF beta is also involved in kidney fibrogenesis and new pathways aimed at preventing glomerulosclerosis and interstitial fibrosis using TGF beta-inhibitors are new topics of research.

Humans↗
PubMed1995

Beneficial effect of one HLA haplo- or semi-identical transfusion versus three untyped blood units on alloimmunization and acute rejection episodes in first renal allograft recipients.

Acute allograft rejection is the major risk factor of renal function decline and graft loss. Beside histocompatibility matches and pharmacological immunosuppression, blood transfusion is empirically used to detect responder subjects and to induce immune tolerance. Alloimmunization associated with blood transfusions readily detected by anti-HLA antibodies could induce acute vascular rejection episodes during the early period after grafting. Our open prospective study was aimed at analyzing the 1 year follow-up of 105 successive first cadaver renal transplant recipients according to the transfusion protocol as assessed by anti-HLA antibody production, acute rejection episodes, and graft survival. Our conventional transfusion protocol involved 3 nonphenotyped blood transfusions set up at least 20 days before grafting in a control cohort (group A) and was compared with a single pretransplant HLA haplo- or semi-identical blood transfusion in a successive group of patients (group B). Our results suggest that both protocols were associated with similar 1-year graft survivals (> 96% in both groups) and number of patients experiencing rejection episodes (20.7% in group A; 9.6% in group B; P NS). HLA haplo- or semi-identical transfusion was significantly beneficial in naive patients without previous alloantigen contact by pregnancy or blood transfusions during dialysis. Naive patients in group B did not develop post-transfusion anti-HLA antibodies compared to naive patients in group A (16.6%; P < 0.001), and they experienced significantly less acute rejection episodes (2.7%) compared to group A naive patients (20.8%; P = 0.02).

Blood Transfusion↗