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Biomedical subjects

A Remuzzi

Publications and source records attributed to A Remuzzi.

At least 37 records · Page 2Linked to original sources
PubMed1999

Glomerular size-selective dysfunction in NIDDM is not ameliorated by ACE inhibition or by calcium channel blockade.

BACKGROUND: In patients with insulin-dependent diabetes mellitus (IDDM) and overt nephropathy glomerular barrier size-selectivity progressively deteriorates with time and is effectively improved by angiotensin converting enzyme (ACE) inhibition. Whether similar glomerular functional changes develop in proteinuric patients with non-insulin-dependent diabetes mellitus (NIDDM), and whether antihypertensive agents can favorably affect glomerular filtration of macromolecules in these patients, has not been documented yet. METHODS: We investigated renal hemodynamics and fractional clearance of neutral dextrans of graded sizes, in nine proteinuric patients with NIDDM and renal biopsy findings of typical diabetic glomerulopathy. Six healthy volunteers served as controls. We also investigated the effects of an ACE inhibitor and of a calcium channel blocker, both given in doses targeted to achieve a comparable level of systemic blood pressure control, on glomerular hemodynamics and sieving function. Theoretical analysis of glomerular macromolecule transport was adopted to evaluate intrinsic glomerular membrane permeability properties. RESULTS: Fractional clearance of large macromolecules (42 to 66 A in radius) was significantly higher in diabetic patients than in controls, and the distribution of membrane pore radii was calculated to be shifted towards larger pore sizes in diabetics (mean radius increased from 55 to 60 A). Despite effective blood pressure control, neither antihypertensive affected glomerular hemodynamics to any significant extent. Fractional clearance of dextrans, as well as of albumin and IgG, and total urinary proteins were not modified by either treatments. CONCLUSIONS: These data indicate that patients with NIDDM and overt nephropathy develop abnormalities in size-selective function of the glomerular barrier and, at variance to IDDM, such changes were not ameliorated either by ACE inhibition or calcium channel blockade.

Adult↗
PubMed1999

ACE inhibition and ANG II receptor blockade improve glomerular size-selectivity in IgA nephropathy.

Protein trafficking across the glomerular capillary has a pathogenic role in subsequent renal damage. Despite evidence that angiotensin-converting enzyme (ACE) inhibitors improve glomerular size-selectivity, whether this effect is solely due to ANG II blocking or if other mediators also play a contributory role is not clear yet. We studied 20 proteinuric patients with IgA nephropathy, who received either enalapril (20 mg/day) or the ANG II receptor blocker irbesartan (100 mg/day) for 28 days in a randomized double-blind study. Measurements of blood pressure, renal hemodynamics, and fractional clearance of neutral dextran of graded sizes were performed before and after 28 days of treatment. Both enalapril and irbesartan significantly reduced blood pressure over baseline. This reduction reached the maximum effect 4-6 h after drug administration but did not last for the entire 24-h period. Despite transient antihypertensive effect, proteinuria was effectively reduced by both treatments to comparable extents. Neither enalapril nor irbesartan modified the sieving coefficients of small dextran molecules, but both effectively reduced transglomerular passage of large test macromolecules. Theoretical analysis of sieving coefficients showed that neither drug affected significantly the mean pore radius or the spread of the pore-size distribution, but both importantly and comparably reduced the importance of a nonselective shunt pathway. These data suggest that antagonism of ANG II is the key mechanism by which ACE inhibitors exert their beneficial effect on glomerular size-selective function and consequently on glomerular filtration and urinary output of plasma proteins.

Adult↗
PubMed1999

Xenogeneic serum promotes leukocyte-endothelium interaction under flow through two temporally distinct pathways: role of complement and nuclear factor-kappaB.

Endothelial cell activation and mononuclear cell infiltration are consistent features of discordant xenograft rejection. This study evaluated whether xenogeneic serum--as a source of xenoreactive natural antibodies and complement--induced endothelial activation with consequent leukocyte adhesion and transmigration under flow conditions. Porcine aortic endothelial cells (PAEC) were incubated for 30 min, 1 h 30 min, or 5 h with 10% human serum or 10% porcine serum and then perfused with human leukocytes in a parallel plate flow chamber under flow (1.5 dynes/cm2). Adherent and transmigrated cells were counted by digital image analysis. Results showed that human serum significantly (P < 0.01) increased over time the number of adherent leukocytes compared with porcine serum. Stimulation of PAEC with human serum also promoted a progressive increase in leukocyte transmigration that reached statistical significance (P < 0.01) at 1 h 30 min and at 5 h compared with porcine serum. Studying the role of complement in leukocyte-endothelium interaction in xenogeneic conditions, a marked complement C3 deposition on PAEC exposed to human serum was shown by immunofluorescence, whereas cells incubated with porcine serum were negative. Next, it was documented that human serum decomplemented by heating and C3-deficient human serum failed to promote both leukocyte adhesion and transmigration, results that were comparable to porcine serum. To elucidate the intracellular mediators involved in endothelial cell activation by xenogeneic serum, this study focused on transcriptional factor nuclear factor-kappaB (NF-kappaB), a central regulator for the induction of different genes, including adhesive molecules and chemoattractants. Positive nuclear staining of NF-kappaB (p65 subunit) found by confocal fluorescence microscopy of PAEC exposed to human serum was taken to reflect NF-kappaB activation. NF-kappaB was instead strictly localized in the cell cytoplasm in PAEC incubated with the homologous serum. Heat-inactivated human serum failed to activate NF-kappaB. Electrophoretic mobility shift assay of nuclear extracts from PAEC exposed to human serum revealed an intense NF-kappaB activation that was inhibited by the NF-kappaB inhibitor pyrrolidinedithiocarbamate. The NF-kappaB inhibitors pyrrolidinedithiocarbamate and tosyl-phe-chloromethylketone did not affect the number of adherent and transmigrated leukocytes in PAEC exposed to human serum for 30 min and 1 h 30 min. Both inhibitors instead significantly reduced leukocyte adhesion and transmigration induced by human serum at 5 h. Confocal fluorescence microscopy studies showed that human serum induced an increase in the expression of vascular cell adhesion molecule-1 and intercellular adhesion molecule-1. Functional blocking of these adhesive molecules with the corresponding antibodies significantly inhibited xenogeneic serum-induced leukocyte adhesion. These data suggest that leukocyte adhesion and transmigration are directly dependent on complement deposited on PAEC in the early phase of cell activation (30 min and 1 h 30 min) induced by xenogeneic serum, whereas leukocyte adhesive events observed after 5 h of incubation of endothelial cells with xenogeneic serum are possibly regulated by transcription of NF-kappaB-dependent genes. The finding that xenogeneic serum promotes leukocyte-endothelial interaction depending on NF-kappaB activation might be relevant for designing future therapeutic strategies intended to prolong xenograft survival.

Animals↗
PubMed1999

Angiotensin-converting enzyme inhibition prevents loss of glomerular hydraulic permeability in passive heymann nephritis.

We used morphometric techniques and theoretical analysis to investigate structural and functional changes of the glomerular membrane that develop in passive Heymann nephritis (PHN), an experimental model of human membranous glomerulopathy The effect of angiotensin-converting enzyme (ACE) inhibition on the above parameters was also investigated to explore the mechanisms by which this treatment exerts functional and structural protection at the renal tissue level. Morphometric analysis of glomerular capillary by light and electron microscopy was performed in normal control rats and in rats injected with rabbit anti-Fx 1A antibody, 12 months after induction of PHN. A group of PHN rats treated with lisinopril during the observation period was also investigated. Glomerular capillary architecture was not significantly altered in PHN rats, thus glomerular volume and capillary lumen volume were comparable with normal controls; only mesangial volume was significantly elevated in PHN rats. Glomerular membrane structure was significantly affected by PHN: the thickness of the glomerular basement membrane (GBM) increased, and the frequency of epithelial filtration slits decreased. Electron-dense deposits in the subepithelial space of the GBM were estimated to occupy more than 20% of the GBM area. Theoretical analysis of glomerular hydraulic permeability allowed us to predict that, after these structural changes, the permeability of the GBM and the epithelial layer significantly decreased, with an average reduction in the ultrafiltration coefficient (Kf) of approximately 43%. ACE inhibition limited mesangial expansion and prevented changes of glomerular epithelial cells (filtration slit frequency) but not GBM thickening. Immune deposits within the GBM were only partially prevented by lisinopril. A selective effect on epithelial permeability was calculated in lisinopril-treated rats, and a partial preservation of Kf reduction was observed. These results suggest that structural changes of the GBM and epithelial cells that develop in PHN are responsible for the reduced filtration capacity observed in this model. ACE inhibition only partially prevented immune-deposits in the GBM and favorably affected epithelial cell structure. These selective effects on glomerular podocytes may contribute to preserve water and macromolecule permeability of the glomerular capillary wall in this immunologic model of kidney disease.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1998

Identification of a novel gene--SSK1--in human endothelial cells exposed to shear stress.

To identify transcriptionally regulated genes potentially involved in the effect of shear stress on endothelial gene expression, we performed a differential display analysis of mRNAs from human umbilical vein endothelial cell (HUVEC) exposed to laminar shear stress (12 dynes/cm2) in comparison to HUVEC maintained in static condition. We identified a cDNA fragment overexpressed by laminar shear stress. The full-length, SSK1, was 3653 long and encoded for a novel protein of 1050 amino acids. Northern blot demonstrates that SSK1 mRNA is expressed at high levels also in placenta, a weak transcript was present in heart, skeletal muscle, kidney and pancreas. Homology searches of the protein databases showed that SSK1 is related to numerous serine-threonine kinases. The highest homology was found with a very recently described gene, BUBR1, an analogue of BUB1, which is a kinase involved in the regulation of cell cycle. The most conserved residues in catalytic domains II, III, VIb, VII, VIII and IX of serine-threonine protein kinases were found in the C terminal region of SSK1 which further supports the kinase nature of the new protein. The putative serine-threonine kinase SSK1 may represent a tool by which mechanical forces regulates phosphorylation events within endothelial cells.

Amino Acid Sequence↗
PubMed1998

Leukocyte-endothelial interaction is augmented by high glucose concentrations and hyperglycemia in a NF-kB-dependent fashion.

We addressed the role of hyperglycemia in leukocyte-endothelium interaction under flow conditions by exposing human umbilical vein endothelial cells for 24 h to normal (5 mM), high concentration of glucose (30 mM), advanced glycosylation end product-albumin (100 microg/ml), or hyperglycemic (174-316 mg/dl) sera from patients with diabetes and abnormal hemoglobin A1c (8.1+/-1.4%). At the end of incubation endothelial cells were perfused with total leukocyte suspension in a parallel plate flow chamber under laminar flow (1.5 dyn/cm2). Rolling and adherent cells were evaluated by digital image processing. Results showed that 30 mM glucose significantly (P < 0. 01) increased the number of adherent leukocytes to endothelial cells in respect to control (5 mM glucose; 151+/-19 versus 33+/-8 cells/mm2). A similar response was induced by endothelial stimulation with IL-1beta, here used as positive control (195+/-20 cells/mm2). The number of rolling cells on endothelial surface was not affected by high glucose level. Stable adhesion of leukocytes to glucose-treated as well as to IL-1beta-stimulated endothelial cells was preceded by short interaction of leukocytes with the endothelial surface. The distance travelled by leukocytes before arrest on 30 mM glucose, or on IL-1beta-treated endothelial cells, was significantly (P < 0.01) higher than that observed for leukocytes adhering on control endothelium (30 mM glucose: 76.7+/-3.5; IL1beta: 69.7+/-4 versus 5 mM glucose: 21.5+/-5 microm). Functional blocking of E-selectin, intercellular cell adhesion molecule-1, and vascular cell adhesion molecule-1 on endothelial cells with the corresponding mouse mAb significantly inhibited glucose-induced increase in leukocyte adhesion (67+/-16, 83+/-12, 62+/-8 versus 144+/-21 cells/ mm2). Confocal fluorescence microscopy studies showed that 30 mM glucose induced an increase in endothelial surface expression of E-selectin, intercellular cell adhesion molecule-1, and vascular cell adhesion molecule-1. Electrophoretic mobility shift assay of nuclear extracts of human umbilical vein endothelial cells (HUVEC) exposed for 1 h to 30 mM glucose revealed an intense NF-kB activation. Treatment of HUVEC exposed to high glucose with the NF-kB inhibitors pyrrolidinedithiocarbamate (100 microM) and tosyl-phe-chloromethylketone (25 microM) significantly reduced (P < 0.05) leukocyte adhesion in respect to HUVEC treated with glucose alone. A significant (P < 0.01) inhibitory effect on glucose-induced leukocyte adhesion was observed after blocking protein kinase C activity with staurosporine (5 nM). When HUVEC were treated with specific antisense oligodesoxynucleotides against PKCalpha and PKCepsilon isoforms before the addition of 30 mM glucose, a significant (P < 0.05) reduction in the adhesion was also seen. Advanced glycosylation end product-albumin significantly increased the number of adhering leukocytes in respect to native albumin used as control (110+/-16 versus 66+/-7, P < 0.01). Sera from diabetic patients significantly (P < 0.01) enhanced leukocyte adhesion as compared with controls, despite normal levels of IL-1beta and TNFalpha in these sera. These data indicate that high glucose concentration and hyperglycemia promote leukocyte adhesion to the endothelium through upregulation of cell surface expression of adhesive proteins, possibly depending on NF-kB activation.

Cell Adhesion↗
PubMed1998

Xenogeneic human serum promotes leukocyte adhesion to porcine endothelium under flow conditions, possibly through the activation of the transcription factor NF-kappa B.

Endothelial cell activation and leukocyte infiltration are a consistent feature of discordant xenograft rejection. Here we evaluated whether xenogeneic serum, as a source of xenoreactive natural antibodies and complement, induced endothelial cell activation with consequent leukocyte adhesion under flow conditions. Porcine aortic endothelial cells (PAEC) were incubated for 1 hr 30 min or 5 hr with 10% homologous porcine serum (control) or 10% xenogeneic human serum and then perfused with total human leukocytes in a parallel plate flow chamber under laminar flow (1.5 dynes/cm2). Adherent cells were counted by digital image analysis. Xenogeneic human serum significantly (P < 0.01) increased the number of adherent leukocytes as compared with porcine serum. A similar adhesive response was elicited by TNF alpha (100 U/ml), one of the most potent inducers of endothelial cell adhesive properties, here used as positive control. In order to elucidate possible mechanisms underlying endothelial cell activation by xenogeneic serum, we focussed on transcription factor NF-kappa B, a central regulator for the induction of different genes, including adhesive molecules and chemoattractants. By confocal fluorescence microscopy, we observed a positive staining for NF-kappa B (p65 subunit) in the nuclei of PAEC exposed for 1 hr 30 min to human serum, which indicated NF-kappa B activation in this setting. At variance, in PAEC incubated with the homologous serum, NF-kappa B was strictly localized in the cell cytoplasm. Treatment of PAEC exposed to xenogeneic serum with the NF-kappa B inhibitors pyrrolidinedithiocarbamate (PDTC, 25 microM) and tosyl-phechloromethylketone (TPCK, 25 microM) significantly (P < 0.01) reduced leukocyte adhesion in respect to PAEC treated with human serum alone. Findings that xenogeneic serum promotes leukocyte-endothelium interaction possibly through NF-kappa B activation might be relevant for designing future therapeutic strategies aimed at prolonging xenograft survival.

Animals↗
PubMed1998

Numerical analysis of viscous flow through fibrous media: a model for glomerular basement membrane permeability.

Viscous flow through fibrous media is characterized macroscopically by the Darcy permeability (KD). The relationship between KD and the microscopic structure of the medium has been the subject of experimental and theoretical investigations. Calculations of KD based on the solution of the hydrodynamic flow at fiber scale exist in literature only for two-dimensional arrays of parallel fibers. We considered a fiber matrix consisting of a three-dimensional periodic array of cylindrical fibers with uniform radius (r) and length connected in a tetrahedral structure. According to recent ultrastructural studies, this array of fibers can represent a model for the glomerular basement membrane (GBM). The Stokes flow through the periodic array was simulated using a Galerkin finite element method. The dimensionless ratio K* = KD/r2 was determined for values of the fractional solid volume (phi) in the range 0.005 < or = phi < or = 0.7. We compared our numerical results, summarized by an interpolating formula relating K* to phi, with previous theoretical determinations of hydraulic permeability in fibrous media. We found a good agreement with the Carman-Kozeny equation only for phi > 0.4. Among the other theoretical analysis considered, only that of Spielman and Goren (Environ. Sci. Technol. 2: 279-287, 1968) gives satisfactory agreement in the whole range of phi considered. These results can be useful to model combined transport of water and macromolecules through the GBM for the estimation of the radius and length of extracellular protein fibrils.

Animals↗
PubMed1998

Pharmacological and clinical profile of valsartan.

The development of angiotensin II (Ang II) receptor antagonists is one of the latest advances in the pharmacological treatment of hypertension and other related diseases. Since the antagonism of angiotensin biological activity has been shown to represent a potent way to favorably affect systemic hypertension, its use is becoming more and more widespread among clinical practice. Besides the originally developed inhibitors of angiotensin II converting enzyme, today molecules that are effective in selectively blocking the type I angiotensin II receptor are available. In this report we describe the main characteristics of one of these compounds, the angiotensin receptor antagonist valsartan, in terms of pharmacological profile as well as efficacy and tolerability. The main purpose is to provide a comprehensive description of the knowledge gained during several years of experimental and clinical studies that can be useful for guidance during the choice for treatment of hypertension, as well as to obtain other potential beneficial effects of this drug on progressive organ damage related to hypertension.

Journal Article↗
PubMed1998

The antiproteinuric effect of angiotensin antagonism in human IgA nephropathy is potentiated by indomethacin.

Evidence is available from animal and human studies that protein traffic through the glomerular capillary has a pathogenetic role in subsequent renal damage and that angiotensin-converting enzyme (ACE) inhibitors appear superior to other drugs in lowering proteinuria and the rate of renal function decline. This study compares the effect of ACE inhibition or angiotensin II (AngII) receptor blockade on urinary protein excretion and renal hemodynamics in 20 patients with IgA glomerulonephritis randomized to receive enalapril (20 mg/d) or irbesartan (100 mg/d) for 28 d in a double-blind study with two parallel groups. This study also evaluated whether addition of indomethacin (75 mg twice a day) to each of the two treatments resulted in a more potent antiproteinuric effect. Enalapril alone reduced total protein excretion (61% change from baseline) and fractional clearance of albumin without changes in GFR and minor elevation in renal plasma flow. Also, patients randomized to receive the AngII receptor antagonist irbesartan for 28 d had lower proteinuria (55% change from baseline) and fractional clearance of albumin at the end of the treatment period with similar renal hemodynamic changes. When indomethacin was added to enalapril treatment, a further significant reduction in urinary proteins and fractional albumin clearance was observed. In patients given irbesartan, the addition of indomethacin further reduced proteinuria and fractional clearance of albumin. The combined therapy with enalapril or irbesartan and indomethacin did not significantly affect GFR and renal plasma flow compared with baseline. These findings indicate that in patients with IgA glomerulonephritis the antiproteinuric effect of blocking AngII activity by either ACE inhibitors or AngII receptor antagonists is potentiated by indomethacin, an effect that occurred without impairment of renal function.

Adult↗
PubMed1998

Progressive glomerular injury in the MWF rat is predicted by inborn nephron deficit.

It has been suggested that a reduced number of nephrons may predispose to systemic hypertension and glomerular injury. Compensatory hemodynamic changes, due to a low number of glomeruli, might be responsible for glomerular functional and structural changes. It is difficult to evaluate this hypothesis in humans because of limitations in estimating the number of nephrons in the living kidney. The aim of the present study was to estimate nephron number, single glomerular hemodynamics, and glomerular volume in male and female MWF rats, a strain that spontaneously develops systemic hypertension, proteinuria, and glomerulosclerosis. Male and female Wistar rats were used as controls. At 12 to 14 wk of age, male MWF rats developed proteinuria, whereas female MWF and Wistar rats showed normal urinary protein excretion rate. Glomerular number was significantly reduced in male and female MWF rats (13,690+/-1,489 and 12,855+/-1,781 gl/ kidney, respectively) compared with Wistar rats (26,955+/-2,171 and 27,166+/-1,754 gl/kidney, respectively). The mean number of nephrons per unit of body weight was also lower in MWF males (88+/-10) compared with MWF females (139+/-20) and compared with male and female Wistar animals (142+/-14 and 221+/-22 gl/g body wt). Whole-kidney hemodynamic parameters and the number of nephrons were used to calculate single-nephron filtration rate and plasma flow. Both measures were markedly elevated in male MWF rats relative to values obtained in the other three groups. Similarly, glomerular volume was significantly greater in MWF males than in other animals. These results suggest that an inborn deficit of nephrons may be responsible for spontaneous development of later-in-life hypertension and renal dysfunction. The data also indicate the need to investigate the role of this potential pathogenetic factor for human hypertension and kidney disease in humans.

Animals↗
PubMed1997

Fluid shear stress modulates von Willebrand factor release from human vascular endothelium.

Fluid shear stress generated by blood flow on arterial wall may play a role in the process of atherosclerosis, not only affecting the mass transport phenomena that take place in blood, but also by modulation of synthesis and secretion of humoral factors released by vascular endothelium that mediate platelet-vessel wall interactions. The present study was designed to investigate whether shear stress, induced by laminar flow, modulates von Willebrand factor (vWF) release from cultured human umbilical vein endothelial cells (HUVEC) and whether this physical stimulation can affect vWF synthesis. Monolayers of HUVEC were exposed to laminar flow of varying magnitude (from 2 to 12 dynes/cm2) using a cone-and-plate device. The release of vWF in cell supernatant and in extracellular matrix by cells exposed to flow or maintained in static conditions was evaluated by enzyme-linked immunosorbent assay. HUVEC exposed to laminar flow released higher amounts of vWF into the cell supernatant within few hours of exposure and vWF secretion was dependent on shear stress magnitude. vWF released in extracellular matrix was also higher in cell monolayers exposed to shear than in static controls. vWF mRNA expression in HUVEC was not affected by exposure of cells to laminar flow, indicating that shear-induced vWF release reflected enhanced secretion without de novo protein synthesis. Immunofluorescence studies showed that the release of vWF is due to exocytosis from Weibel-Palade bodies, the storage organelles of vWF. These data indicate a novel mechanism by which local hemodynamic shear forces modulate endothelial cell function and may play a role in development of arterial thrombotic events.

Cells, Cultured↗
PubMed1996

Cyclosporine enhances leukocyte adhesion to vascular endothelium under physiologic flow conditions.

We investigated the effect of cyclosporine (CyA) on leukocyte adhesion to endothelium under flow conditions. Confluent human umbilical vein endothelial cells (HUVECs) were incubated for 24 hours with CyA (1, 5, and 10 micromol/L) and then exposed to a total human leukocyte suspension in a parallel plate flow chamber under laminar flow (1.5 dynes/cm2. Human umbilical vein endothelial cells stimulated with interleukin-1beta (20 U/mL) were used as a positive control. Adherent cells were measured by digital image analysis. Results showed that CyA dose-dependently increased the number of leukocytes adhering to HUVECs compared with control cells. Leukocyte adhesion markedly increased on HUVECs incubated with interleukin-lbeta, one of the most potent inducers of endothelial cell adhesiveness. Exposure of endothelial cells to CyA did not affect the number of rolling leukocytes, which was similar to control values. To examine the role of adhesion molecules in CyA-induced leukocyte adhesion, HUVECs were incubated with monoclonal antibodies against intercellular adhesion molecule-1 (ICAM-1), vascular adhesion molecule-1 (VCAM-1), and E-selectin before adhesion assay. Functional blocking of ICAM-1, VCAM-1, and E-selectin on endothelial cells significantly inhibited CyA (10 micromol/L)-induced leukocyte adhesion. Confocal fluorescence microscopy studies showed that CyA induced an increase in the endothelial surface expression of ICAM-1, VCAM-1, and E-selectin. Pretreatment of leukocytes with the platelet activating factor receptor antagonist L659,989 significantly reduced the number of leukocytes adhering to CyA-treated HUVECs. We suggest that CyA enhances leukocyte adhesion to endothelium by upregulating adhesive proteins on endothelial surface membrane. Blocking leukocyte receptor for platelet-activating factor partially prevents adhesion, suggesting a role for endothelial cell-associated platelet-activating factor in the interaction between leukocytes and CyA-treated endothelium.

Cell Adhesion↗
PubMed1996

Angiotensin II modulates glomerular capillary permselectivity in rat isolated perfused kidney.

Studies in experimental animals and humans have documented that inhibition of the renin-angiotensin system by angiotensin-converting enzyme inhibitors reduces urinary protein excretion rate and retards the development of renal injury. Here we sought to investigate whether angiotensin II (All) modified the size-selective properties to macromolecules of the glomerular capillary barrier in isolated perfused rat kidney preparation. Compared with basal values, continuous All infusion into the renal artery at the rate of 3 or 8 ng/min, but not at 0.6 ng/min, induced a progressive and significant increase in urinary protein excretion rate. Evaluation of the sieving properties of the glomerular barrier by fractional clearance of polydisperse Ficoll showed that All significantly enhanced the filtration of tracer molecules of radil > or = 34A. All-induced changes in urinary protein excretion rate and in Ficoll fractional clearance were completely prevented by pretreatment with the specific All Type 1 receptor antagonist SR 47436.

Angiotensin II↗
PubMed1996

Impact of renin-angiotensin system blockade on structure and function of glomerular membrane components in animal models of kidney disease.

The most promising therapeutic intervention to slow the progression of renal diseases is the inhibition of the renin-angiotensin system, either using angiotensin-converting enzyme inhibitors or angiotensin II (Ang II) receptor antagonists. In this article, we review the experimental evidences that are available on the effects of these treatments on glomerular capillary wall (GCW) function. Besides the well-known hemodynamic effects, Ang II antagonism exert specific actions on glomerular permeability to water and macromolecules, consisting in the elevation of hydraulic permeability and amelioration of membrane-sieving function. Experimental investigations of functional and structural properties of the glomerular membrane have been performed to discover the mechanisms responsible for the protective effects of these treatments. On the basis of these observations, we illustrate how Ang II antagonism interfere with the complex nature of the glomerular capillary affecting its hemodynamics, modulate its cellular components and result in the preservation of GCW function.

Angiotensin II↗
PubMed1995

Verotoxin-1 promotes leukocyte adhesion to cultured endothelial cells under physiologic flow conditions.

Hemolytic uremic syndrome (HUS), which is the most common cause of acute renal failure in infants and small children, is caused by verotoxin (VT)-producing Escherichia coli infection. Endothelial injury determines microvascular thrombosis and evidence is available from recent studies that suggests that leukocyte activation participates in endothelial damage. We studied here the effect of VT-1 on leukocyte adhesion to vascular endothelium under physiologic flow conditions. Human umbilical vein endothelial cells (HUVECs) were incubated for 24 hours with VT-1 (0.1, 1, and 10 pmol/L) and then exposed to a total leukocyte suspension in a parallel plate flow chamber under laminar flow conditions (1.5 dynes/cm2). Adherent cells were counted by digital image processing. Results showed that VT-1 dose-dependently increased the number of adhering leukocytes to HUVECs as compared with unstimulated cells. The adhesive response elicited by VT-1 was comparable to that of interleukin-1 beta (IL-1 beta), one of the most potent inducers of endothelial cell adhesiveness. Exposure of HUVECs to VT-1 did not affect the number of rolling leukocytes, which was similar to that of control values. To examine the role of adhesion molecules in VT-1-induced leukocyte adhesion, HUVECs were incubated with mouse monoclonal antibodies against E-selectin, intercellular adhesion molecule-1 (ICAM-1), and vascular cell adhesion molecule-1 (VCAM-1) before adhesion assay. Functional blocking of E-selectin, ICAM-1, and VCAM-1 on endothelial cells significantly inhibited VT-1-induced increase in leukocyte adhesion. In some experiments, before VT-1 incubation, HUVECs were pretreated for 24 hours with tumor necrosis factor alpha (TNF alpha; 100 U/mL), which is known to increase VT receptor expression on HUVECs. The number of adhering leukocytes on HUVECs exposed to TNF alpha and VT-1 significantly increased as compared with HUVECs incubated with VT-1 and TNF alpha alone. These results suggest that VT-1 modulates leukocyte-endothelium interaction, thus increasing leukocyte adhesion and upregulating adhesive proteins on endothelial surface membrane.

Animals↗