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G Remuzzi

Publications and source records attributed to G Remuzzi.

At least 55 records · Page 3Linked to original sources
PubMed1991

Angiotensin converting enzyme inhibition improves glomerular size-selectivity in IgA nephropathy.

Clearances of uncharged dextrans of broad size distribution were used to evaluate the effects of a 30 day course of enalapril on glomerular barrier function in 10 patients with IgA nephropathy and proteinuria (from 1.4 to 5.6 g/day). Dextran clearance experiments were repeated three times: before enalapril therapy, after 30 days of enalapril and again 30 days after enalapril withdrawal. GFR, but not RPF, was significantly reduced by enalapril (basal 38.3 +/- 11.9, enalapril 30.2 +/- 12.6 ml/min/1.73 m2) and returned to basal values after enalapril withdrawal. Urinary protein excretion and fractional clearance of albumin were both significantly reduced by enalapril (basal 2.3 +/- 1.1 g/day and 102 +/- 90 x 10(-5), enalapril 1.2 +/- 0.6 g/day and 51 +/- 23 x 10(-5), respectively) and returned to basal values after enalapril withdrawal. Transglomerular passage of large dextrans (radii 54 to 62 A), but not of lower size (26 to 42 A) were significantly lowered by enalapril. When enalapril was withdrawn the dextran-sieving profile returned comparable to the baseline levels. A theoretical analysis of dextran-sieving profiles indicated that enalapril lowered the radius of largest membrane pores. This effect was independent from glomerular hemodynamic changes. We conclude that angiotensin converting enzyme inhibitors (CEI) in humans with IgA nephropathy reduces urinary protein excretion by a primary action on the intrinsic glomerular membrane properties enhancing barrier size-selective function. The hypofiltration associated with enalapril therapy in these patients, which was eliminated by its withdrawal, has to be taken into account as a possible undesired effect of CEI in long-term treatment.

Adult↗
PubMed1991

Renoprotective effect of low iron diet and its consequence on glomerular hemodynamics.

It has been reported that anemia limits renal injury in rats with reduced renal mass. We studied the effect of a low iron diet, given to reduce hematocrit, on urinary protein excretion and glomerular function in male MWF/Ztm rats, which spontaneously develop proteinuria and glomerular sclerosis. At 20 weeks of age, micropuncture and glomerular volume measurements were performed in untreated rats fed standard chow and in rats fed an isocaloric diet with low iron (5 mg/kg) content. Two additional groups of rats were used for total kidney function and glomerular volume evaluation at 35 weeks of age. At 20 weeks of age animals on low iron diet showed significantly (P less than 0.01) reduced hematocrit (46 +/- 5% vs. 54 +/- 2%) and proteinuria (60 +/- 15 vs. 225 +/- 34 mg/24 hr) than control animals, and no statistically significant differences were observed in single nephron hemodynamics. At 35 weeks of age rats on low iron diet had significantly lower proteinuria than age matched controls (222 +/- 68 vs. 411 +/- 71 mg/24 hr, P less than 0.01) and developed less glomerular sclerosis (mean percentage of sclerotic glomeruli was respectively 14 +/- 7% and 31 +/- 17%, P less than 0.05). Glomerular volume was comparable in animals on the low iron diet and in controls both at 20 and 35 weeks of age. These data indicate that low iron diet protected male MWF/Ztm rats against glomerular injury without significant effects on glomerular hemodynamics and on glomerular volume.

Anemia, Hypochromic↗
PubMed1991

Co-participation of thromboxane A2 and leukotriene C4 and D4 in mediating cyclosporine-induced acute renal failure.

The relative role of thromboxane (TxA2) and sulfidopeptide leukotrienes C4 (LTC4) and D4 (LTD4) in the acute renal failure induced by cyclosporine was studied in the rats. Bolus i.v. administration of 20 mg/kg of CsA but not vehicle to adult male Sprague-Dawley rats resulted in a significant fall in glomerular filtration rate from 0.85 +/- 0.10 and renal plasma flow (RPF) 2.45 +/- 0.14 ml/min/100 g body wt to values at 20 min of 0.47 +/- 0.03 and 1.01 +/- 0.12 ml/min/100 g body wt (P less than 0.01), respectively, without a fall in mean arterial pressure. This hemodynamic effect was maintained for the following 40-min period. Pretreatment of rats with the TxA2 receptor antagonist GR32191 (3 mg/kg i.v.) allowed a partial but significant preservation of GFR (0.60 +/- 0.05 ml/min/100 g body wt) and RPF (1.55 +/- 0.12 ml/min/100 g body wt). In addition, the antagonism of endogenously produced LTC4 and LTD4 with the putative receptor antagonist L-649,923 (1 mg/kg i.v.) partially prevented the fall in GFR (0.65 +/- 0.07 ml/min/100 g body wt) and RPF (1.80 +/- 0.18 ml/min/100 g body wt) at 20 min after CsA injection. The combined administration of GR32191 and L-649,923 completely abolished the CsA-induced decline in GFR (0.80 +/- 0.09 ml/min/100 g body wt) and RPF (2.40 +/- 0.12 ml/min/100 g body wt). These findings suggest that TxA2 and LTC4/LTD4 participate in mediating renal function deterioration induced by acute CsA administration in the rat.

Acute Kidney Injury↗
PubMed1991

Increased renal endothelin production in rats with reduced renal mass.

Renal endothelin (ET) production was investigated in rats after renal mass ablation, a model of progressive renal disease characterized by glomerular hemodynamic alterations and capillary thrombosis, and in sham-operated animals. Thrombin stimulation of renal cortical tissue from rats with renal mass reduction, 45 but not 7 days after surgery, generated significantly (P less than 0.01) more ET than tissue from sham-operated animals. Exposure to thrombin of isolated glomeruli from remnant but not sham kidneys also significantly (P less than 0.01) increased ET production compared with unstimulated glomeruli. At day 45, in rats with renal mass ablation ET plasma levels were numerically lower, whereas urinary excretion rate of ET was significantly (P less than 0.01) increased compared with sham-operated animals. After a 50-min intravenous infusion of 125I-ET to normal rats and animals with renal mass ablation, less than 0.3% and 0.03%, respectively, of total infused radioactivity was recovered in urine. These results indicate that thrombin-stimulated ET production by renal cortical tissues is increased in rats with renal mass reduction. Despite normal or low-normal plasma ET levels, urinary excretion of the peptide is markedly increased in this model. The exogenously labeled ET added to circulation is not excreted by the kidney, suggesting that enhanced urinary excretion rate would reflect an increased renal production of the peptide in rats with remnant kidney.

Animals↗
PubMed1991

Platelet-activating factor alters glomerular barrier size selectivity for macromolecules in rats.

The effect of platelet-activating factor (PAF) on glomerular permeability to macromolecules was investigated in the isolated kidneys from normal male Sprague-Dawley rats perfused at constant pressure. Compared with basal values, infusion of PAF (10 nM final concentration) into the isolated kidneys induced a progressive and significant increase in protein excretion (6.7 +/- 2.7 vs. 40.7 +/- 10.4 micrograms/min, P less than 0.01), completely reversible 20 min after PAF infusion was discontinued (8.5 +/- 1.3 micrograms/min). In additional experiments, during PAF infusion the fractional clearance of small neutral dextrans (radius 24-48 A), defined as the ratio of the clearance of neutral dextrans to the clearance of creatinine, was comparable to preinfusion values, whereas fractional clearance of large dextrans (greater than 50 A) was significantly elevated (P less than 0.005) above preinfusion values. The specific PAF receptor antagonist L 652731 completely prevented the increased fractional clearance of large dextrans induced by PAF. Finally, lowering Ca2+ concentration in the perfusion medium from 2.5 to less than 0.1 mM markedly reduced proteinuria in isolated kidneys exposed to PAF (80.0 +/- 10.3, 42.8 +/- 3.1, and 22.0 +/- 7.6 micrograms/min, respectively, for 2.5, 1.25, and less than 0.1 mM). These results indicate that in isolated perfused kidneys 1) PAF-induced proteinuria is a functional phenomenon reversible on discontinuing PAF infusion, 2) PAF modifies glomerular size-selective properties by increasing transmural passage of large dextran molecules, and 3) PAF-induced change in glomerular permselective properties is dependent on Ca2+ concentration in the extracellular medium.

Animals↗
PubMed1991

Endothelin induces diuresis and natriuresis in the rat by acting on proximal tubular cells through a mechanism mediated by lipoxygenase products.

Besides being a potent renal vasoconstrictor, endothelin causes diuresis and natriuresis. At which site along the nephron and how endothelin alters water and sodium handling in the tubule remain to be clarified. It was found that endothelin (75 pmol) given as an i.v. infusion in vivo to rats caused diuresis and urinary sodium excretion to double but did not affect glomerular filtration rate and renal plasma flow. On raising the dose of endothelin to 150 pmol, a further increase in diuresis and natriuresis was found, whereas glomerular filtration rate fell 33% and renal plasma flow fell 36%; 300 pmol of endothelin reduced glomerular filtration rate by 73% and renal plasma flow by 77% but did not significantly affect diuresis and absolute sodium excretion. It did, however, increase fractional sodium excretion eightfold. Lithium clearance studies of changes in tubular handling of water and sodium indicated that infusion of 150 pmol of endothelin to rats caused a reduction in absolute (pre, 84.7 +/- 5.9; post, 47.9 +/- 6.1 microEq/min/100 g) and fractional (pre, 85.7 +/- 3.0; post, 64.7 +/- 6.4%) proximal reabsorption of sodium. Endothelin infusion (150 pmol) was not associated with any significant change in plasma atrial natriuretic peptide levels, which on average remained comparable to those in rats given the vehicle alone (49.7 +/- 8.4 versus 46.3 +/- 5.6 pg/mL). In the isolated perfused rat kidney preparation, exposure to 150 pmol of endothelin significantly increased fractional sodium excretion over preinjection values (pre, 2.2 +/- 0.2; post, 7.3 +/- 1.0%) despite a marked decrease in glomerular filtration rate and renal perfusate flow. Additional in vivo experiments showed that oral administration of the specific 5-lipoxygenase inhibitor L-651,392 to rats prevented the increase in urine flow rate (pre, 5.7 +/- 0.1; post, 6.6 +/- 0.8 microL/min), and in absolute (pre, 0.33 +/- 0.04; post, 0.37 +/- 0.05 microEq/min) and fractional (pre, 0.10 +/- 0.02; post, 0.11 +/- 0.03%) sodium excretion caused by bolus i.v. infusion of endothelin (150 pmol). Similarly, a specific leukotriene C4/D4 receptor antagonist, L-649,923, also prevented the diuretic and natriuretic effect of 150 pmol of endothelin i.v. infusion. These findings show that (1) endothelin has a diuretic and natriuretic effect that is independent of its action on renal hemodynamics; (2) this effect depends on a direct action on the proximal tubules; (3) atrial natriuretic peptide does not appear to be involved in this effect; and (4) the diuretic and natriuretic responses to endothelin are mediated by 5-lipoxygenase products.

Animals↗
PubMed1991

Thymus-mediated immune tolerance to renal allograft is donor but not tissue specific.

Studies were conducted in Lewis (RT1l) rats to determine whether the process of unresponsiveness to kidney graft induced by the intrathymic glomerular transplantation were donor-strain specific as suggested by previous studies (Remuzzi et al., Lancet 1991;337:750-752). When glomeruli from Sprague-Dawley rats were injected in the thymus of Lewis rats, the subsequent kidney graft from a "third party" Brown-Norway (RT1n) rejected within 9 to 14 days. Moreover, an alternative site for glomerular antigen inoculation, such as i.p. administration, failed to induce a state of unresponsiveness to renal allograft. Whether tolerance was tissue specific was investigated by intrathymic injection of a preparation of donor blood cells that only included white cells. Such a maneuver, followed 10 days later by a kidney transplant, allowed indefinite renal graft survival in all animals, whereas all rats injected intrathymically with blood cell medium alone rejected the kidney graft in 8 to 11 days. Shortening the time interval between intrathymic injection of blood cells and kidney transplantation still allowed the graft to survive indefinitely. Finally, Lewis (RT1l) rats with chronic renal failure injected intrathymically with blood cells from Brown-Norway (RT1n) rats tolerated indefinitely a subsequent kidney graft from the same donor. These findings indicate that (1) the induction of immune tolerance to renal allograft induced by intrathymic injection of antigens is donor but not tissue specific; (2) the time interval between intrathymic injection of donor cells and the subsequent kidney transplantation can be reduced to 24 h; and (3) uremia does not preclude the possibility of renal allograft tolerance after the thymus procedure.

Animals↗
PubMed1991

Platelet-activating factor receptor blocking reduces proteinuria and improves survival in lupus autoimmune mice.

Platelet-activating factor (PAF) has been suggested recently to play an important role in immune glomerulonephritis, favoring the formation of immune deposits in glomeruli and contributing to the local inflammatory reaction. Here we sought to investigate whether urinary PAF excretion was modified in New Zealand Black x New Zealand White mice a model of genetically determined immune complex disease which mimics systemic lupus in humans and whether changes in PAF urinary excretion values correlated with the extent of proteinuria. To clarify the possible "in vivo" relevance of these findings we evaluated whether PAF receptor antagonist has any influence on the evolution of renal disease and survival of these mice. Our results showed that: 1) in lupus mice urinary PAF excretion increased progressively with age in New Zealand Black x White; 2) the increase in PAF excretion correlated with the severity of proteinuria; and 3) the chronic administration of a PAF receptor antagonist [L-659,989 [(+/- )-trans-2-(3-methoxy-5-methylsulfonyl-4-propoxyphenyl)-5- (3,4,5-trimethoxyphenyl)tetrahydrofuran]] starting from 26 weeks of age significantly delayed the onset of proteinuria and prolonged survival.

Animals↗
PubMed1991

L-arginine, the precursor of nitric oxide, abolishes the effect of estrogens on bleeding time in experimental uremia.

We have reported previously that conjugated estrogens that are effective in shortening the prolonged bleeding time in uremic patients are also effective on bleeding time in a rat model of uremia. Using such a rat model we have recently demonstrated that nitric oxide (NO), an endothelium-derived vasodilator, is involved in mediating the bleeding tendency of uremia. With the present study we wanted to investigate whether conjugated estrogen mixture or its active component, 17 beta-estradiol, reduce uremic bleeding by interfering with the NO pathway. Our results showed that the shortening effect of conjugated estrogen and 17 beta-estradiol on bleeding time of uremic rats was completely reversed by giving the animals the NO precursor L-arginine, but not D-arginine, which is not a precursor of NO. Dexamethasone which at variance to progesterone inhibits the process of induction of NO-forming enzyme, shortened the prolonged bleeding time of uremic rats within 4 hours from injection. This effect was eliminated by L-arginine but not D-arginine administration. The glucocorticoid receptor antagonist cortexolone prevented the shortening of bleeding time induced by dexamethasone, suggesting that a receptor-mediated mechanism is involved in the hemostatic effect of dexamethasone as previously reported for estrogens. Unlike conjugated estrogens and dexamethasone, progesterone had no effect on bleeding time. All these findings would indicate that the effect of estrogens and dexamethasone on primary hemostasis in uremia might be mediated by changes in NO synthetic pathway.

Animals↗
PubMed1991

Constitutive expression of endothelin gene in cultured human mesangial cells and its modulation by transforming growth factor-beta, thrombin, and a thromboxane A2 analogue.

The present study was designed to assess whether human glomerular mesangial cells in culture express preproendothelin gene and whether endothelin gene expression in the mesangium is regulated by factors potentially released by inflammatory cells and platelets infiltrating the glomerular tuft during the course of various types of glomerulonephritis. For this purpose mesangial cells were incubated for 6 hours in the presence of absence of interleukin 1 beta (IL-1 beta), transforming growth factor-beta (TBF-beta), the thromboxane A2 analogue U-46619, and thrombin. Resting mesangial cells expressed a 2.3-kilobase mRNA on blot hybridization analysis with a human cDNA preproendothelin probe, indicating that this type of cells, in addition to glomerular endothelial cells, constitutively expresses endothelin gene. IL-1 beta did not change endothelin mRNA levels in respect to unstimulated mesangial cells. At variance, TGF-beta, U-46619, and thrombin had a marked effect on endothelin mRNA, stimulating a 3- to 8-fold increase over basal levels. Quantification of actin mRNA and analysis of the autoradiographic signals provided validation of the difference in the endothelin mRNA levels. Expression of preproendothelin mRNA in either resting or stimulated mesangial cells was associated with synthesis and release of the corresponding peptide in the cell supernatant as determined by a specific radioimmunoassay for endothelin. Endothelin production from IL-1 beta stimulated mesangial cells was not different from that of unstimulated cells, whereas a significant (p less than 0.01) increase in endothelin production was observed after cell stimulation with TGF-beta, U-46619, and thrombin. The demonstration that mesangial cells constitutively express mRNA for preproendothelin and release endothelin into culture medium, together with the finding that endothelin gene expression and production in mesangial cells are regulated by molecules potentially released at glomerular level during an inflammatory reaction may suggest that endothelin participates in the complex process of glomerular disease progression.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed1991

Effect of dietary proteins and lipids in patients with membranous nephropathy and nephrotic syndrome.

Twenty-four patients with idiopathic membranous nephropathy, long-lasting nephrotic syndrome and serum creatinine less than 2 mg/dl ate sequentially, in a randomized cross-over design, a normal protein diet containing 1.1 +/- 0.3 g/kg/day of proteins and a low protein diet containing 0.7 +/- 0.1 g/kg/day of protein, each diet for a period of 3 months. Both diets were low in fat (less than 30% of total calories) and cholesterol (less than 200 mg/day) content and rich in polyunsaturated fatty acids and in linoleic acid (10% of energy). Random assignment to one of the two 3 month diet periods was done after a RUN-IN period of at least one month on the hypolipidic normal protein diet. Glomerular filtration rate (inulin clearance), 24 hour urinary protein loss and serum albumin concentration did not significantly differ at the end of the two diet periods, indicating that long-term restriction of protein intake does not modify GFR or urinary protein loss in nephrotic patients. Serum total and LDL-cholesterol and daily proteinuria were significantly lower at the end of both diet periods than at the beginning and at the end of the RUN-IN period. We suggest that these changes were a consequence of the manipulation of dietary fat intake.

Adult↗
PubMed1991

Interleukin-1 beta and tumor necrosis factor-alpha induce gene expression and production of leukocyte chemotactic factors, colony-stimulating factors, and interleukin-6 in human mesangial cells.

The capacity of human cultured mesangial cells to produce soluble factors potentially relevant for mechanisms of inflammation and immunity at the glomerular site was analyzed. The nature of the secreted factors initially was investigated by Northern blot analysis using total cellular RNAs isolated from resting and activated mesangial cells. On exposure of mesangial cells to human recombinant interleukin-1 beta (IL-1 beta), high levels of interleukin-8 (IL-8) and monocyte chemotactic protein-1 (MCP-1) mRNAs were detected. Similar transcripts were found after stimulation with human recombinant tumor necrosis factor-alpha (TNF-alpha). Active secretion of IL-8 was documented by radioimmunoassay in supernatants of mesangial cells activated by either IL-1 beta or TNF-alpha. Using an in vitro migration assay, supernatants from resting mesangial cells were found to be devoid of any chemotactic activity for granulocytes or monocytes. On stimulation with IL-1 beta, however, mesangial cell supernatants expressed MCP-1 biologic activity detected as induction of a strong migratory response for human monocytes but not for granulocytes. In addition, IL-1 beta and TNF-alpha induced high levels of granulocyte-macrophage colony-stimulating factor (GM-CSF) and macrophage colony-stimulating factor (M-CSF) mRNAs. Similarly IL-1 beta and TNF-alpha induced the interleukin-6 (IL-6) gene and active secretion of its mature protein. These data strongly support an effector role for mesangial cells in modulating immune-inflammatory responses in glomeruli. Release of cytokines may activate not only infiltrating inflammatory cells through short paracrine pathways, but also mesangial cells themselves through an autocrine pathway.

Cells, Cultured↗
PubMed1990

Renal metabolism and urinary excretion of platelet-activating factor in the rat.

The origin of platelet-activating factor (PAF) in the urine remains ill defined. The present study documents that [3H]PAF (3.5 mu Ci) injected into the renal artery of isolated control rat kidney preparations perfused at constant pressure with a cell-free medium containing 1% bovine serum albumin (BSA) was excreted in negligible amounts (0.034%) in the urine, whereas 6% was retained by the kidney. When kidneys were perfused with a BSA-free medium, 0.029 and 71% of the total radioactivity added to the perfusate was recovered in the urine and in the renal tissue, respectively. [3H]PAF urine excretion in proteinuric kidneys from adriamycin-treated rats was still negligible (0.015%). Analysis of the renal tissue-retained radioactivity in control and proteinuric kidneys perfused with 1% BSA indicated metabolism into long chain acyl-sn-glycero-3-phosphorylcholine species, lyso-PAF, glycerols, and intact PAF. Thin layer chromatography analysis of [3H]glycerol fraction in these renal extracts showed two major components comigrating with 1-O-alkylglycerol and 1-O-alkyl-2-fatty acylglycerol. Isolated proximal tubules, but not glomeruli from nephrotic rats exposed to increasing concentrations of BSA (0-4%), had a higher PAF uptake than control tubules for BSA concentrations ranging from 0 to 0.1%. Our findings in the isolated perfused kidneys indicate that, in normal conditions, circulating PAF is excreted in the urine in negligible amounts and that the altered glomerular permeability to proteins does not affect this excretion rate. Moreover, analysis of renal tissue radioactivity documented that the renal metabolism of PAF is comparable in control and nephrotic kidneys.

Animals↗
PubMed1990

Preliminary report: renal thromboxane A2 synthesis in children with frequent relapsing nephrotic syndrome.

An evaluation was made of the possible relation between renal thromboxane (Tx)A2 synthesis (measured as urinary excretion of TxB2) and the loss of glomerular permeability to proteins, in 5 children with seven episodes of minimal change nephrotic syndrome. Urinary TxB2 excretion was significantly higher in children with minimal change nephrotic syndrome than in 14 healthy controls, and reached its maximum at the time of peak proteinuria. During remission of nephrotic syndrome urinary excretion of TxB2 was still significantly higher than in healthy controls. A significant positive correlation between urinary excretion of TxB2 and proteinuria was observed in 3 patients. The results suggest that renal TxA2 could be regarded as one of the possible mediators of the altered glomerular permeability to proteins in minimal change nephrotic syndrome.

Child↗