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Biomedical subjects

G Remuzzi

Publications and source records attributed to G Remuzzi.

At least 271 records · Page 15Linked to original sources
PubMed1993

A specific endothelin subtype A receptor antagonist protects against injury in renal disease progression.

We have recently reported that renal preproendothelin-1 gene is up-regulated in rats with renal mass reduction (RMR) and that time-dependent increase in urinary excretion of the corresponding peptide correlates with renal disease progression. Here we evaluated whether a specific endothelin subtype A (ETA) receptor antagonist, FR139317, reduced signs of disease activity in this model. Two groups of rats were given FR139317 or its vehicle (saline) from day 7 to day 60 after the surgical procedure. Sham-operated animals were the control group. Blood pressure, urinary protein excretion and serum creatinine were evaluated at days 0, 7 (before FR139317 or saline administration), 30, 45 and 60. At sacrifice, histological evaluation of renal tissue was performed. The results showed that ETA receptor blocker reduced the abnormal permeability to proteins, limited glomerular injury and prevented renal function deterioration thus confirming the working hypothesis. These findings suggest that this class of compounds may eventually prove useful in the treatment of human progressive nephropathies.

Animals↗
PubMed1993

Enhanced nitric oxide synthesis in uremia: implications for platelet dysfunction and dialysis hypotension.

Nitric oxide (NO), a potent vasodilator which also inhibits platelet adhesion and aggregation, is generated by endothelial cells and platelets from its precursor L-arginine. Since N-monomethyl-L-arginine (L-NMMA), an inhibitor of NO synthesis, normalizes the prolonged bleeding time of uremic rats, it has been suggested that bleeding associated with uremia was due to an excessive NO formation. With the present study we sought to evaluate whether in patients with chronic renal failure--like in uremic rats--defective platelet aggregation were associated with excessive formation of NO and whether uremic plasma promotes NO synthesis by cultured vascular endothelium. Data indicated that plasma L-arginine was higher in uremics than in controls, uremic platelets generated more NO than control platelets, and intraplatelet levels of cGMP (the NO second messenger) were also higher in uremic than in control platelets. Moreover, uremic plasma potently induced NO synthesis by cultured endothelial cells, a phenomenon which was further amplified by adding to uremic plasma endotoxin and interferon gamma. Increased NO biosynthesis may contribute to platelet dysfunction and possibly other manifestations of uremic syndrome, including hemodialysis hypotension.

Adult↗
PubMed1993

Defective glomerular [3H]lysoPAF metabolism in the autologous phase of rabbit nephrotoxic nephritis.

Glomerular infiltration of blood-derived mononuclear cells contributes to the glomerular injury in the autologous phase of nephrotoxic nephritis (NTN). LysoPAF has recently been shown to be chemotactic for human monocytes, thus its accumulation might account for monocyte recruitment. We investigated [3H]lysoPAF metabolism in isolated glomeruli from normal and NTN rabbits studied both in the heterologous and in the autologous phases of the disease. [3H]lysoPAF was converted to [3H]1-O-alkyl-glycerol and [3H]1-O-alkyl-2-acyl-GPC by phospholipase C and acyltransferase, respectively, both in normal and NTN glomeruli. Glomerular metabolism of [3H]lysoPAF was normal during the heterologous phase of NTN. By contrast, in isolated glomeruli from NTN rabbits studied in the autologous phase of the disease, a significantly lower [3H]lysoPAF degradation occurred with respect to normal ones. This defective degradation resulted in a significantly reduced formation of [3H]1-O-alkyl-glycerol. The apparent Km for enzymatic conversion of [3H]lysoPAF to [3H]1-O-alkyl-glycerol, determined at 15 minutes as a function of [3H]lysoPAF concentration, was doubled in glomeruli from rabbits studied in the autologous phase of NTN as compared to normal ones, while Vmax values were similar in the two groups. These results show a defective glomerular lysoPAF degradation in the autologous phase of NTN, likely due to a decreased affinity of phospholipase C to lysoPAF. Altered lysoPAF metabolism results in glomerular accumulation of lysoPAF in the autologous phase of NTN, as shown by significantly higher levels of lysoPAF measured in nephritic glomeruli as compared to normal ones.

Animals↗
PubMed1993

Renal endothelin gene expression is increased in remnant kidney and correlates with disease progression.

We previously demonstrated that urinary endothelin excretion is increased in rats with extensive renal mass reduction, a model of progressive renal disease. Here we explored whether the increased urinary endothelin in this model were due to induction of renal pre-pro-endothelin-1 gene and whether changes in endothelin synthetic pathway correlated with the development of glomerulosclerosis. Four groups of rats with renal mass reduction and four groups of sham-operated control rats were studied 7, 30, 60 and 120 days after the surgical procedure. Urinary protein excretion in renal mass ablation animals did not differ from controls at seven days, but was already significantly elevated (P < 0.01) 30 days after surgery. Then proteinuria progressively increased in rats with remnant kidney at values above 400 mg/day at day 120. Serum creatinine concentration also progressively increased with time in renal mass ablation rats, unlike sham-operated animals, and values were significantly different (P < 0.01) at each of the points considered. Rats with renal mass reduction, unlike sham-operated animals, developed focal glomerulosclerosis that affected 8% of glomeruli at day 30, and 24% of glomeruli at day 120. Seven days after renal mass reduction renal pre-pro-endothelin-1 (pre-pro ET) mRNA was comparable to that of sham-operated rats, while a 2.5-, 5- and fourfold increase in 2.3 Kb pre-proET-1 transcript was observed at 30, 60 and 120 days, respectively. Urinary excretion of endothelin was significantly elevated (P < 0.01) in rats with renal mass reduction with respect to sham-operated rats, starting from 30 days after surgery and increased further thereafter.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1993

Urinary excretion of platelet activating factor in patients with immune-mediated glomerulonephritis.

We have investigated whether human immune-mediated glomerulonephritis is associated with changes in platelet activating factor (PAF) biosynthesis. Urinary PAF, taken as a marker of its renal synthesis, was significantly higher in patients with membranous nephropathy (N = 9) than in healthy controls (N = 8). This was not due to a lower degradation of PAF since urinary acetylhydrolase activity was comparable in patients and controls. A significant positive correlation between urinary excretion of PAF and proteinuria was observed. PAF generation was comparable in polymorphonuclear cells isolated from patients with membranous nephropathy and controls. PAF levels in blood from patients with membranous nephropathy were significantly lower than in controls, suggesting that the excessive generation of PAF is confined to the kidney. The results document that signs of renal disease activity in human membranous nephropathy are associated with an excessive renal synthesis of PAF.

1-Alkyl-2-acetylglycerophosphocholine Esterase↗
PubMed1993

Thymic recognition of class II major histocompatibility complex allopeptides induces donor-specific unresponsiveness to renal allografts.

Recent data show that intrathymic injection of allogeneic cells induces donor-specific unresponsiveness to allografts. There is also evidence to suggest that, in addition to recognizing intact MHC molecules, T cells can recognize processed MHC peptides, although the role of this indirect mode of allo-recognition in allograft rejection is unknown. We report that a single intrathymic injection of 100 micrograms of a mixture of eight 25-mer synthetic polymorphic class II MHC allopeptides, representing the full-length sequence of RT1.Bu beta and RT1.Du beta (WF) into incompatible (RT1l) LEW recipients, induced a state of long-term unresponsiveness to subsequent engraftment 2 days later of WF, but not third party (RT1n) BN renal allografts. Intrathymic injection of 100 micrograms of either RT1.Bu beta or RT1.Du beta peptide mixtures alone were insufficient to prolong renal allograft survival. Intravenous or intrasplenic injection of the allopeptide mixture did not affect renal allograft survival, establishing the role of thymic recognition of class II MHC allopeptides in inducing systemic unresponsiveness. The induction of intrathymic donor-specific unresponsiveness was abrogated if thymectomy was performed on the day of renal transplantation or 5 days later. PBLs from long-term surviving animals exhibited marked reduction of proliferation to WF, but not third party BN stimulator lymphocytes in the standard mixed lymphocyte response assay in vitro. These observations emphasize the role of recognition of processed MHC molecules in vascularized allograft rejection and confirm the role of the thymus in acquired systemic tolerance to alloantigens.

Animals↗
PubMed1993

Glomerulonephritis.

Advances in cell and molecular biology have generated fresh insights into the mechanisms of glomerular injury, a field with very few substantial advances in the past 20 years. Currently, the nature of renal antigens involved in the immune reaction is being identified, as in the case of Goodpasture antigen. Many recent studies focus on T-cell and macrophage functions in glomerulonephritis that initiate acute inflammatory events and determine glomerular disease progression. Recent data established that after inflammatory cell migration to the glomerulus, subsequent damage depends on cell adhesion to cytokine-activated endothelial cells, a process mediated by a variety of specialized molecules. It seems easy to predict that within the next few years these studies will have a major impact on the way these diseases are treated. Already, evidence indicates that, in experimental animals, monoclonal antibodies blocking adhesive molecules prevent or reduce glomerular damage. Cytokines and growth factors, by promoting resident cell proliferation and modulating extracellular matrix synthesis and metabolism, modulate acute glomerular injury and subsequent scarring. Recent studies have established that glomerular injury is related to urinary protein excretion, an issue that has been approached in humans by combining studies on barrier size selectivity with morphometry. An emerging concept suggests that leaking of proteins through the glomerular capillary has an intrinsic renal toxicity that is likely due to proximal tubular over-reabsorption of the abnormally filtered macromolecules. Data are also accumulating that may soon link the degree of tubulointerstitial injury with glomerular damage and subsequent development of renal scarring.

Animals↗
PubMed1993

Supernatant of endothelial cells exposed to laminar flow inhibits mesangial cell proliferation.

We investigated the effects of culture medium conditioned with endothelial cells exposed to hemodynamic shear forces on modulation of mesangial cell (MC) growth. Confluent monolayers of bovine aortic endothelial cells, grown in medium containing 10% fetal calf serum, were exposed to static or to laminar flow conditions for 24 h using a cone-and-plate device. Endothelial cell-conditioned medium was used to study the growth of bovine MC by [3H]thymidine uptake. The proliferative response of MC to fresh medium (containing 10% fetal calf serum) and to culture medium from endothelial cells under static flow [66.7 +/- 34.1 vs. 73.9 +/- 30.0 counts/min (cpm) x 10(-3)] was comparable. In contrast, medium conditioned with endothelial cells exposed to laminar shear stress of 8 dyn/cm2 almost completely abolished MC proliferation (5.8 +/- 6.9 cpm x 10(-3), P < 0.01). To establish whether this effect is due to endothelial cell production of a substance that inhibits MC proliferation or simply to metabolization of serum growth factors in the culture medium, we performed shear stress experiments using serum free medium and we added 10% fetal calf serum after shear exposure just before the proliferation assay. In this condition a significant antiproliferative effect of endothelial cell supernatant under laminar flow was obtained (27.7 +/- 23.4 vs. 68.8 +/- 45.8 cpm x 10(-3), laminar vs. static, P < 0.05), suggesting that endothelial cells under shear stress effectively produce a factor that inhibits MC proliferation. These results would suggest that local glomerular capillary blood flow could play a role in the regulation of MC mitogenesis.

Animals↗
PubMed1993

Renal handling of sodium in the nephrotic syndrome.

In the nephrotic syndrome abnormal sodium and water retention occurs at the kidney level that ultimately causes expansion of interstitial volume and edema. The mechanisms and factors involved remain ill defined. The traditional view has considered hypovolemia, due to urinary protein losses and decreased oncotic pressure, as the afferent stimulus of a complex pathway of responses that come together to enhance reabsorption of sodium and water along the nephron. However, given the fact that only a minority of nephrotic patients have low plasma volume, it has been hypothesized that sodium retention by the kidney is a primary phenomenon occurring in response to intrarenal rather than systemic mechanisms. Experimental evidence is available to support this possibility, and indicates that distal nephron sites are involved in avid sodium retention in the nephrotic syndrome. Several studies have been designed to establish the role of neurohumoral mediators, including the renin-angiotensin-aldosterone axis and sympathetic nervous system. These data suggest that although activation of these systems may contribute to salt retention, they may be minor factors in this process. Recently, attention has focused on atrial natriuretic peptides (ANP), which increase sodium and water excretion in experimental animals and humans. A markedly blunted natriuretic and diuretic response to the systemic infusion of ANP has been reported in the nephrotic syndrome. A defect in the number and affinity of receptor binding sites for the peptide as well as in the level of intracellular cyclic guanosine monophosphate, the second messenger of ANP, has recently been investigated.(ABSTRACT TRUNCATED AT 250 WORDS)

Atrial Natriuretic Factor↗
PubMed1993

Renal cyclophilin-like protein gene expression parallels changes in sodium excretion in experimental nephrosis and is positively modulated by atrial natriuretic peptide.

Experimental evidence is available to indicate that intrarenal mechanisms play a role in the impaired salt excretion of nephrotic syndrome by multiple and still incompletely defined mediators. It is documented herein that the gene encoding for cyclophilin-like protein (Cy-LP) is up-regulated in renal medulla from adriamycin (ADR)-treated rats as compared with control animals. In the cortex of rats with ADR nephrosis, no change in Cy-LP as compared with that in controls was found for the entire observation period. By contrast, in the medulla of nephrotic rats, Cy-LP gene expression was significantly higher than in controls. Values of urinary Na excretion were inversely correlated to Cy-LP mRNA expression levels. Because in ADR nephrosis a blunted natriuretic response to ANP has been previously reported, it was investigated whether ANP infusion modulated Cy-LP mRNA in the renal medulla. ADR-treated rats, but not control rats, infused for 1 h with ANP (1 microgram/kg.min) had a significant (P < 0.05) increase in medullary Cy-LP mRNA as compared with nephrotic animals receiving the vehicle alone. These findings might be taken to suggest that renal Cy-LP gene expression is positively modulated in nephrotic syndrome and parallels changes in sodium excretion.

Animals↗
PubMed1993

Heterogeneous nature of renal lesions in type II diabetes.

The nature of renal damage in patients with type II diabetes remains unclear. This study was directed to evaluate pathologic changes in 52 patients affected by type II diabetes with overt clinical nephropathy by conventional and morphometric techniques. The duration of diabetes ranged from 6 to 384 months, urinary protein excretion ranged from 0.9 to 9.2 g/24 h, and serum creatinine ranged from 0.9 to 9 mg/dL. Specimens were examined semiquantitatively by light microscopy, immunofluorescence, and electron microscopy. Glomerular tuft cross-sectional area was measured by a versatile computer system. Pathologic examination revealed three distinct patterns arbitrarily defined as Classes 1, 2, and 3. Class 1 included 19 patients with typical changes of diabetic nephropathy characterized by a high score of glomerulosclerosis (mean score, 2.1), marked glomerular hypertrophy (23,632 microns2), and arteriolar hyalinosis (mean score, 2). There was a positive correlation between glomerulosclerosis and arteriolar hyalinosis scores (P < 0.05). Class 2 included 16 patients showing chronic and aspecific changes. As compared with Class 1 patients, these patients had less glomerulosclerosis (mean score, 1.3) and less arteriolar hyalinosis (mean score, 0.8) but more severe ischemic glomerular lesions (mean score, 1.4) and arteriosclerosis (mean score, 2). Class 3 included 17 patients showing glomerular disease superimposed on diabetic glomerulosclerosis. There were no differences in age, mean duration of diabetes, renal function, urinary protein excretion, and mean arterial pressure among the three classes of patients. This study indicates that renal lesions in patients with type II diabetes manifest in a quite heterogeneous fashion.(ABSTRACT TRUNCATED AT 250 WORDS)

Aged↗
PubMed1993

Short- and long-term effect of angiotensin II receptor blockade in rats with experimental diabetes.

The short- and long-term effects of specific angiotensin II (AII) receptor blockade on the evaluation of glomerular injury in moderately hyperglycemic diabetic rats were studied. Three groups of animals were used, a control group, a group of diabetic rats treated with insulin, and a group of insulin-treated diabetic rats receiving the AII receptor antagonist losartan in drinking water. After 4 to 6 wk of observation, diabetic rats showed higher systolic blood pressure and GFR than normal controls. Losartan treatment prevented both systolic blood pressure and GFR rise. Three other groups of rats, similarly treated for a 1-yr period, were used for renal functional and morphologic evaluation. Diabetic animals had higher urinary protein excretion and glomerulosclerosis incidence than did normal controls. Losartan significantly prevented proteinuria and glomerulosclerosis. Evaluation of the sieving properties of the glomerular membrane by Ficoll fractional clearance showed an important increase in the filtration of this marker in diabetic animals, as compared with that in controls, and almost complete prevention of this change in losartan-treated animals. Theoretical analysis of fractional clearance data with a heteroporous model of glomerular size-selectivity showed that in diabetic animals the size of membrane pores was increased uniformly, as compared with that in controls. These changes were completely prevented by the AII receptor antagonist. The results presented here strongly indicate that reduction of AII activity plays a crucial role in the preservation of glomerular structure and function and suggest that the favorable effects previously observed with angiotensin-converting enzyme inhibition in this model depend directly on the reduction of AII activity.

Angiotensin Receptor Antagonists↗
PubMed1993

Colchicine allows prolonged survival of highly reactive renal allograft in the rat.

Colchicine, with its immunosuppressive properties, has been used with beneficial effects in autoimmune diseases. Whether colchicine, by virtue of the above properties, could attenuate the process of kidney allograft rejection in the rat is investigated in this report. Untreated Lewis rats (N = 6) given an incompatible kidney allograft from Brown-Norway rats rejected the graft within 12 days. Colchicine at a daily ip dose of 40 (N = 6) or 10 (N = 4) micrograms/kg promoted long-term survival (> 170 days) of major histocompatibility complex-incompatible kidney grafts. Animals (N = 4) given 4 micrograms of colchicine per kilogram had a graft failure within 10 days. Experiments have also been performed to evaluate the effect of colchicine withdrawal at different time intervals from transplantation on subsequent allograft survival. Colchicine (40 micrograms/kg per day ip) was given for 12, 6, or 1 mo or for 15 days to an additional four groups of six animals each without any other immunosuppressants. The withdrawal of colchicine did confer long-term inhibition of the immune system in animals treated for at least 1 mo, as documented by a graft survival of more than 80 days. By contrast, those animals who discontinued colchicine after only 15 days of treatment had graft rejection within the next 8 days. Mixed lymphocyte culture experiments showed a significant (P < 0.01) reduction of the proliferation of peripheral blood lymphocytes taken from all groups of animals 30 days after colchicine withdrawal when challenged with Brown-Norway lymphocytes.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1992

Renal protective effect of angiotensin-converting enzyme inhibition in aging rats.

Aging in rats with intact kidneys is associated with changes in selective glomerular permeability to macromolecules resulting in proteinuria and progressive glomerular sclerosis. We have previously reported that angiotensin-converting enzyme (ACE) inhibition in Munich Wistar Fromter/Ztm (MWF/Ztm) rats resulted in a significant reduction of proteinuria, in respect to untreated animals, and that treated animals were protected against the development of glomerular sclerotic lesions. The present study was designed to establish whether ACE inhibition protects against glomerular injury in male Sprague-Dawley rats, which develop spontaneous proteinuria and glomerulosclerosis with age. The effect of ACE inhibition was tested when proteinuria was already present. Four-month treatment with the ACE inhibitor perindopril prevented the increase in systolic blood pressure, compared with vehicle-treated animals, and significantly decreased urinary protein excretion of aging rats. Partial protection of the development of glomerular sclerosis was also observed.

Aging↗