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Biomedical subjects

G Remuzzi

Publications and source records attributed to G Remuzzi.

At least 217 records · Page 12Linked to original sources
PubMed1995

New insights into circulating cell-endothelium interactions and their significance for glomerular pathophysiology.

Neutrophil and monocyte infiltration of kidney glomeruli is a striking pathologic finding in the early stages of most forms of glomerulonephritis and appears to be an important determinant of glomerular injury. Recent research has permitted to clarify the mechanisms of leukocyte trafficking to inflamed glomeruli, which appear to involve several coordinated steps: chemotaxis along a concentration gradient of chemoattractants, adhesion to endothelial cells, diapedesis between endothelial cells, and interaction with resident renal cells. In glomerulonephritis, the deposition of immune complexes within glomerular capillaries triggers the local synthesis of chemotactic factors, including complement fragments, platelet-activating factor, leukotrienes, interleukin-8, and monocyte chemotactic protein-1, which promote attraction of neutrophils and monocytes within the glomerular tuft. Adhesion to resident glomerular cells, a critical step in the process of leukocyte infiltration, is a dynamic process that results from opposite factors: (1) shear forces generated by the movement of blood within the glomerular microcirculation that tend to detach inflammatory cells from the vascular wall and (2) adhesion glycoproteins expressed on the surface of leukocytes and endothelial cells, which are upregulated in human and experimental glomerulonephritis. It has been proposed that P-selectin, which is rapidly expressed on the surface of endothelial cells exposed to various stimuli, is a principal mediator of initial low-affinity binding of leukocytes (rolling). The tethering component mediated by P-selectin facilitates interaction of leukocytes with platelet-activating factor, a biologically active phospholipid that is rapidly synthesized by activated endothelial cells and is coexpressed with P-selectin on the endothelial cell plasma membrane.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1995

Direct podocyte damage in the single nephron leads to albuminuria in vivo.

The hypothesis that detachment of podocytes leads to albuminuria was tested by studying the single nephron albuminuria in vivo after injecting a saponin solution (0.6 mg/ml) in Bowman's space of superficial glomeruli, which produces selective damage of the podocytes, in female Munich-Wistar-Frömter rats. Animals were subsequently installed under a fluorescence microscope, a purified fluoresceinated rat albumin solution was intravenously injected and the passage of the fluorescent albumin was followed through the microscope. Of the 47 glomeruli injected with the saponin solution (in 6 animals) 46 became fluorescent within seconds with the fluorescence progressing from Bowman's space into the proximal tubule and then in the rest of the tubule. In superficial non-injected and control-injected glomeruli weak fluorescence could be detected only in the glomerular tuft and the peritubular capillaries. Tubuli injected with the saponin solution remained indistinguishable from non-injected tubuli. Electron microscopic study of the saponin-injected glomeruli confirmed the selective removal of podocytes. Immunogold electron microscopy confirmed that the intact albumin molecule effectively passed the glomerular capillary wall at the site where podocyte detachment had occurred. It is concluded that selective removal of podocytes at the single nephron level leads to albuminuria in vivo, and therefore podocytes play a crucial role in regulating the permeability of the glomerular capillary wall.

Albumins↗
PubMed1995

ACE inhibition prevents renal failure and death in uninephrectomized MWF/Ztm rats.

Many studies have consistently documented that angiotensin converting enzyme (ACE) inhibitors prevent proteinuria and glomerulosclerosis in progressive renal disease, but very few data are available on whether they also prevent renal failure and death. The mechanisms of the beneficial effect of ACE inhibition are only partially understood. Recent data suggest that angiotensin II modulates renal synthesis of endothelin-1, a vasoactive peptide implicated in the process of renal injury. Here we investigated in a long-term study whether ACE inhibition ameliorated renal function in uninephrectomized (UNx) male MWF/Ztm rats. Three groups of rats at nine weeks of age underwent UNx or sham-operation. Nephrectomized animals were left untreated or treated with the ACE inhibitor lisinopril in drinking water. In untreated UNx animals systolic blood pressure, serum creatinine, urinary protein and renal synthesis of endothelin-1, evaluated by its urinary excretion, were significantly increased, as compared with control animals with two kidneys. End-stage renal failure developed in all untreated UNx rats that died within 9 to 14 months from UNx. ACE inhibitor significantly reduced systolic blood pressure, completely prevented proteinuria and renal function deterioration, and reduced endothelin-1 excretion. All UNx rats treated with lisinopril were alive 14 months after UNx. These results show that ACE inhibition prevents end-stage renal failure induced by UNx in male MWF/Ztm, and that the beneficial effects of angiotensin II inhibition in this model are related to modulation of renal synthesis of endothelin-1.

Aging↗
PubMed1995

Three-dimensional analysis of glomerular morphology in patients with subtotal nephrectomy.

Previous studies documented that single section examination of kidney tissue underestimates glomerulosclerosis and that three-dimensional examination of glomerular morphology improves recognition of the incidence and distribution of sclerotic changes within the glomerular capillary tuft. We have adopted this technique to evaluate the true frequency and the spatial extent of glomerulosclerosis in patients who were subjected to extensive renal mass reduction. We re-evaluated four kidney biopsies of patients with a solitary kidney who had undergone partial nephrectomy for renal-cell carcinoma. Histopathological examination aimed at detection of glomerular sclerotic lesions was performed on serial sections (from 75 to 93 serial sections for each biopsy, 3 microns thick) together with three-dimensional morphometric analysis of glomerular tuft and sclerotic areas using a computer-based image processing system. Results were compared with observations based on more conventional single section evaluation of the same biopsies. Among 65 glomeruli examined by three-dimensional morphometric analysis, only 8% were normal, 42% revealed segmental sclerosis and 51% global sclerosis. These results confirmed that single section evaluation grossly overestimates the number of normal glomeruli (37% vs. 8%, respectively), since the majority of glomeruli classified as normal are indeed affected by sclerotic changes in areas typically out of the section plane. The three-dimensional distribution of sclerosis is characterized by the appearance of multi-focal areas affecting a small capillary tuft volume (< 10%) which ultimately propagate to the entire capillary tuft. Despite the maintenance of renal function, at the time of biopsy in patients with extensive ablation of renal mass, the incidence of glomerulosclerosis affects almost the entire glomerular population.(ABSTRACT TRUNCATED AT 250 WORDS)

Biopsy↗
PubMed1995

Toward novel antirejection strategies: in vivo immunosuppressive properties of CTLA4Ig.

Allograft rejection is a process that depends on T cell receptor-ligand interaction and costimulatory signals generated when accessory molecules binds to their ligands, such as CD28 to the B7 molecules. We investigated the possibility that B7 blockade in vivo by the soluble CD28 receptor homolog CTLA4Ig modulates rejection process in a rat model of kidney allograft. Lewis rats orthotopically transplanted with MHC incompatible kidney from Brown-Norway rats were given an intraperitoneal injection of CTLA4Ig (0.2 or 0.5 mg/day) or a nonspecific immunoglobulin for seven days, starting the day of transplant. While control rats rejected the graft within 10 days, all animals given CTLA4Ig had a prolonged kidney allograft survival, independently from the dose of the fusion protein employed. Actually, at the dose of 0.2 mg/day kidney grafts survived 36 to 50 days (median 44 days), while with the highest dose graft survival was 40 to 60 days (median 50 days). In all CTLA4Ig-treated rats renal grafts were well functioning as documented by serum creatinine concentrations comparable to age- and sex-matched control rats 30 days after transplant. At this time in vitro mixed lymphocyte culture (MLR) experiments showed a significant reduction of proliferation of peripheral blood lymphocytes from CTLA4Ig-treated rats when challenged with BN but not third party Wistar Furth lymphocytes. We have also shown that combining a short course of CTLA4Ig (0.2 mg/day) with a dose of cyclosporine (CsA) low enough to fail to inhibit graft rejection allowed indefinite engraftment of kidney allograft without the need of continuous immunosuppression.(ABSTRACT TRUNCATED AT 250 WORDS)

Abatacept↗
PubMed1995

PAF mediates neutrophil adhesion to thrombin or TNF-stimulated endothelial cells under shear stress.

Platelet-activating factor (PAF) is known to modulate polymorphonuclear leukocyte (PMN) adhesion to endothelial cells cultured under static conditions and activated by thrombin. In contrast, there are no data on the role of PAF in PMN adhesion to cells exposed to flow conditions and activated by stimuli other than thrombin. Here we used the PAF receptor antagonist L-659,989 to evaluate PMN adhesion to human umbilical vein endothelial cells (HUVEC) in basal conditions or upon challenge with thrombin or tumor necrosis factor-alpha (TNF-alpha). Experiments were performed under dynamic flow using a parallel-plate flow chamber and a computer-based image analysis system. Rolling and adhesion of PMNs to endothelial cells significantly increased upon stimulation with thrombin. Thrombin-stimulated HUVEC also synthesized higher amounts of PAF than untreated cells. Pretreatment of PMNs with L-659,989 significantly reduced their rolling and adhesion to thrombin-activated HUVEC. Stimulation of HUVEC with TNF-alpha significantly increased the number of rolling and adherent PMNs as compared with untreated cells. Adhesion of PMNs to and migration across TNF-alpha-stimulated HUVEC were reduced by L-659,989, whereas cell rolling was unchanged. We conclude that PAF mediates leukocyte interaction under flow conditions with HUVEC activated by inflammatory stimuli.

Cell Adhesion↗
PubMed1995

Nitric oxide synthesis by cultured endothelial cells is modulated by flow conditions.

In the present study, we examined the hypothesis that dynamic characteristics of flow modulate the production of vasoactive mediators, namely nitric oxide (NO) and endothelin-1 (ET-1), by human umbilical vein endothelial cells (HUVECs). Cells were exposed for 6 hours in a cone-and-plate apparatus to different types of flow: steady laminar, with shear stresses of 2, 8, and 12 dyne/cm2, pulsatile laminar, with shear stress from 8.2 to 16.6 dyne/cm2 and a frequency of 2 Hz; periodic laminar, with square wave cycles of 15 minutes and shear stress from 2 to 8 dyne/cm2, and turbulent, with shear stress of 8 dyne/cm2 on average. A second culture dish was kept in a normal incubator as a static control for each experiment. Laminar flow induced synthesis of NO by HUVECs that was dependent on shear-stress magnitude. Laminar shear stress at 8 dyne/cm2 also upregulated the level of NO synthase mRNA. As observed with steady laminar flow, pulsatile flow also induced an increase in NO release by endothelial cells. When HUVECs were subjected to step-change increases of laminar shear, a further increase of NO synthesis was observed, compared with steady laminar shear of the same magnitude. Turbulent flow did not upregulate NO synthase mRNA or increase NO release. Both laminar and turbulent shear stress reduced, although not significantly, ET-1 mRNA and ET-1 production compared with the static condition. These results indicate that local blood flow conditions modulate the production of vasoactive substances by endothelial cells. This may affect vascular cell functions such as nonthrombogenicity, regulation of blood flow, and vascular tone.

Amino Acid Oxidoreductases↗
PubMed1995

Blocking cell microtubule assembly inhibits the alloimmune response in vitro and prolongs renal allograft survival by inhibition of Th1 and sparing of Th2 cell function in vivo.

Colchicine inhibits cell microtubule assembly by binding to and preventing the polymerization of tubulin monomers. Although there are data to indicate that colchicine inhibits a variety of cell-mediated immune responses, the effects and mechanisms of inhibiting cell microtubule assembly on the alloimmune response have not been thoroughly investigated. It has recently been shown that colchicine prevents acute rejection and promotes the long-term survival of rat renal allografts. In this study, the effects and mechanisms of inhibiting cell microtubule assembly by colchicine on the alloimmune response in vitro and in vivo were examined. First, the effects of colchicine on T lymphocyte response to alloantigen in vitro were tested. In the standard one-way mixed lymphocyte response (MLR), responder Lewis rat lymph node cells were cultured with irradiated Brown-Norway stimulators. Colchicine inhibited the MLR in a dose-dependent manner, with 100% inhibition at a concentration of 25 ng/mL (6.25 x 10(-8) M) and 50% inhibition at a concentration of approximately 5 to 10 ng/mL. Colchicine also inhibited the generation of cytotoxic T lymphocytes as well as cytotoxic T cell effector function in vitro in a dose-dependent fashion. Second, detailed immunohistologic studies of renal allografts harvested from unmodified control (acutely rejecting) and colchicine-treated rats (Day 15 or 30) were performed. These studies showed that grafts from colchicine-treated animals had significantly fewer mononuclear cell infiltrates and less edema, and moderately decreased deposition of immunoglobulin M, C3, and fibrin, as compared with acutely rejecting control grafts.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1995

Immunosuppressive therapy abrogates unresponsiveness to renal allograft induced by thymic recognition of donor antigens.

This laboratory and others have previously shown that the intrathymic injection of donor cells or major histocompatibility complex allopeptides induced indefinite survival of a subsequent graft without immunosuppression. This approach may open interesting new perspectives for transplant medicine. Studies to explore the feasibility of the technique in humans can only be designed with some form of concomitant immunosuppression to avoid the risk of irreversible rejection in the case that the thymus approach fails. Thus, one of the first issue to address is whether conventional immunosuppression interfered with the process of thymus tolerance. This study was designed to investigate the above issue. In transplanted Lewis control rats, cyclosporin A (CsA) (10 mg/kg per day) and methylprednisolone (MP) (10 mg/kg twice daily) for 3 days were invariably followed by kidney graft rejection within 10 days. In subsequent experiments, five groups of Lewis rats were injected with medium alone or Brown-Norway (BN) leukocytes into the thymus, and 24 h later, they were orthotopically transplanted with major histocompatibility complex-incompatible kidneys from BN rats. At the time of transplantation, Lewis rats received MP (10 mg/kg twice daily) CsA (10 mg/kg per day), or the combination of the two (MP+CsA at the same dose) for 3 days. Lewis rats injected intrathymically with BN leukocytes but not receiving immunosuppressants had indefinite survival of their kidney graft. The effect of the intrathymic injection of donor cells of inducing unresponsiveness to a subsequent kidney graft was abolished by concomitant immunosuppression. All animals given immunosuppressants rejected their graft within 12 days after surgery.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1995

The thymic way to transplantation tolerance.

Within the past three decades, extensive research has been carried out with the aim to prevent graft rejection by minimizing the side effects related to the use of immunosuppressants. The major goal in transplantation research remains the development of strategies that would allow one to achieve a state of donor-specific unresponsiveness in order to promote a condition of true tolerance without the need of immunosuppressants. Recent evidence has been provided that this is a pursuing goal, at least in experimental animals. The thymus plays the major role in the development of self-tolerance, and initial work in the late 1960s indicated that the thymus also plays a critical role in the induction of acquired tolerance to exogenous antigens. Recently, the interest in acquired thymic tolerance has been renewed by the observation that, in the rat, the thymus is an immunologically privileged site in which isolated pancreatic islets can be engrafted and survive indefinitely. Moreover, intrathymic injection of the islets induced donor-specific unresponsiveness, which allowed survival of a second donor-strain islet cell allograft transplanted into an extrathymic site. These findings on cellular allografts have been extended to vascularized organ allografts.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1995

Plasma clearance of nonradioactive iohexol as a measure of glomerular filtration rate.

Renal clearance of inulin is the best available indicator of GFR but cannot be used routinely for clinical purposes and is also difficult to perform for clinical investigation when repeated measurements are required. The aim of this study was to find a reliable alternative to inulin clearance that would allow one to avoid the use of radioactivity and problems related to the continuous infusion of the marker. The plasma clearance of unlabeled iohexol, a nonionic contrast agent, was used. Forty-one patients (creatinine clearance 6 to 160 mL/min per 1.73 m2) underwent simultaneous measurements of renal clearance of inulin and plasma clearance of iohexol. Iohexol was given as a single iv dose, and blood samples were drawn up to 600 min after the administration. Iohexol concentrations (by HPLC) were analyzed by a two-compartment, open-model system. A highly significant correlation between the plasma clearance of iohexol and the renal clearance of inulin over a wide range of GFR values was found. By analyzing the data with a simplified method that uses a one-compartment model corrected with the Bröchner-Mortensen formula, an excellent correlation with the inulin clearance was also observed. When only patients with moderate to severe renal failure were considered, a significant correlation between the two methods was found. A further comparison between GFR determined with iohexol and iopromide, a new low-osmolarity, low-viscosity contrast medium, was also performed in a subgroup of patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1995

Preliminary results of intrathymic injection of donor cells to prevent acute rejection in human heart transplantation.

In rodents, the intrathymic injection of donor cells or major histocompatibility complex peptides induces indefinite survival of a subsequent allograft with little or no immunosuppression. Here, experiments have been performed in two patients with cardiac transplantation to establish (1) the safety and tolerability of the intrathymic injection of donor leukocytes at the time of transplant surgery and (2) whether conventional immunosuppression interfered with the process of the thymic recognition of alloantigens. It was shown that the intrathymic inoculation of donor cells is safe and can be done without undesired effects. However, the procedure, as performed, did not protect from acute graft rejection. There are data enough to attribute the failure of the thymus technique in these two patients to the concomitant use of immunosuppressants. The results of this study are relevant for future trials aimed at finding the appropriate experimental conditions for the use of the thymic approach in human organ transplantation.

Acute Disease↗
PubMed1995

Glomerulonephritis: from new knowledge on the mechanisms of tissue damage to novel therapies.

Remarkable progress has been made in the past two years in the investigation of immunological events and effector mechanisms which lead to glomerular inflammation and tissue damage, suggesting a number of areas in which therapeutic modulation is possible. We review recent advances in the two major areas of investigation in this field: the nephritogenic response to glomerulonephritis and local inflammatory reaction, and the novel therapeutic perspectives that have emerged from insights into the biology and pathology of the immune and inflammatory response.

Animals↗
PubMed1995

Endothelin in the progressive renal disease of glomerulopathies.

Endothelin (ET) isopeptides are synthetized in the kidney and act as local hormones with an impressive number of diverse autocrine and paracrine functions. A variety of proinflammatory and vasoactive agents including thrombin, transforming growth factor beta, angiotensin II as well as mechanical forces enhance the renal synthesis of ET. Two receptor subtypes, ETA and ETB, are widely expressed in the kidney, coupled to multiple intracellular signal transduction pathways that mediate distinct activities. Renal vessels are peculiarly sensitive to the vasoconstrictive effect of ET, which, infused in the kidney, decreases renal blood flow and glomerular filtration rate. This effect, together with the capability of ET to induce contraction and proliferation of mesangial cells, as well as accumulation of mesangial matrix proteins, have suggested that ET may participate in the renal events that lead to renal disease progression. Evidence is now available that renal ET does play a role in the process of progressive renal injury in chronic models of renal disease to the extent that the selective pharmacological manipulation of ET pathway has a major positive impact on the progression of the disease. By contrast, more work is necessary to define the role of ET in the pathophysiology of human glomerulopathy. The recent availability of orally active compounds with potential human use, may hopefully speed progress in the area.

Animals↗