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G Remuzzi

Publications and source records attributed to G Remuzzi.

At least 73 records · Page 4Linked to original sources
PubMed1990

Oral zeranol shortens the prolonged bleeding time of uremic rats.

Intravenous conjugated estrogens reduce the prolonged bleeding time in uremic patients and in a rat model of uremia. However, estrogens have major side effects related to their hormonal activity. We investigated whether a beta-resorcylic acid lactone, zeranol (a compound with close spatial similarity to estrogens but with a weak estrogenic activity), improves primary hemostasis in uremic rats and whether the effect is mediated by estrogen receptors. The results showed that single oral administration of zeranol significantly (P less than 0.01) shortened the bleeding time of uremic rats, 20 mg/kg being the minimum effective dose. This effect was long-lasting (72 hours). The dose of 30 mg/kg zeranol reproduced the pattern observed after 20 mg/kg but bleeding time values were still significantly (P less than 0.01) shortened 96 hours after the administration. No changes in hematocrit, platelet and leukocyte count, and serum creatinine were detected after zeranol administration. When uremic rats were pre-treated orally with two estrogen receptor antagonists, tamoxifen and clomiphene (3 mg/kg), zeranol did not shorten the bleeding time, thus suggesting that the hemostatic effect of zeranol was due to an estrogen receptor-mediated mechanisms. These results might have important future implications for the management of uremic bleeding in humans.

Administration, Oral↗
PubMed1990

Role of enhanced glomerular synthesis of thromboxane A2 in progressive kidney disease.

Normotensive rats of the Milan strain (MNS) spontaneously develop focal glomerulosclerosis. In order to explore the contribution of glomerular thromboxane (TX) A2 synthesis to the development of the disease, we have characterized the time course of renal functional and biochemical changes, and their modification by long-term treatment with a TX-synthase inhibitor. Oral administration (150 mg.kg-1 from 1 to 14 months of age) of FCE 22178 suppressed enhanced glomerular TXB2 production at all experimental times (mean inhibition 80%) and proteinuria (varying between 27.1 and 73.0%) while preserving renal blood flow and glomerular filtration rate. These effects of TX-synthase inhibition were seen in the absence of any statistically significant changes in systemic blood pressure. Moreover, FCE 22178 had no antihypertensive effects in hypertensive rats of the Milan strain (MHS) nor in spontaneously hypertensive rats (SHR). Treatment also prevented the age-related hypoalbuminemia and hyperlipidemia observed in control MNS and significantly (P less than 0.01) reduced glomerular histologic damage, as demonstrated by light microscopy studies and measurement of sclerotic area. We conclude that: 1) MNS rats provide an animal model of long-lasting proteinuria characterized by an age-related increase in glomerular TXB2 production paralleled by progressive loss of renal structural integrity and function and by a secondary dyslipidemia; 2) pharmacological inhibition of glomerular TX-synthase attenuates the structural as well as the functional expression of kidney disease, without a primary effect on systemic blood pressure. These data are suggestive of an important modulating role of TXA2 in the progression of MNS renal disease.

Animals↗
PubMed1990

Endothelin and eicosanoid synthesis in cultured mesangial cells.

We investigated the effect of endothelin on the generation of eicosanoids, which are known to regulate basal and stimulated mesangial cell tone. The results showed that endothelin is a potent stimulus of prostaglandin E2 (PGE2), prostacyclin (PGI2), and thromboxane A2 (TxA2) synthesis by bovine mesangial cells. Percentage increases in eicosanoid synthesis induced by endothelin (10(-10) to 10(-6) M), were 50 to 275% for PGE2, 28 to 168% for PGI2 and 42 to 111% for TxA2, respectively. Endothelin-induced eicosanoid synthesis in mesangial cells was concentration, but not time dependent. Aspirin (500 microM) completely prevented endothelin-induced eicosanoid synthesis. The calcium entry blocker nitrendipine (10(-8) M) failed to inhibit endothelin-induced eicosanoid synthesis. These data suggest that endothelin-induced changes in renal circulation and glomerular function in normal and disease conditions may be modulated by the concomitant stimulation of mesangial eicosanoid synthesis.

Animals↗
PubMed1990

Ticlopidine prevents renal disease progression in rats with reduced renal mass.

Functional and morphological studies were done in three groups of male Sprague-Dawley rats after removal of the right kidney and infarction of approximately five-sixths of the left. Group 1 received no specific therapy. Group 2 was treated with ticlopidine, 150 mg/kg per os, for 50 days starting 10 days after surgical ablation. Group 3 was given the thromboxane antagonist, GR 32191, 3 mg/kg b.i.d. orally for 50 days, like ticlopidine. Untreated Group 1 rats developed renal insufficiency, systemic hypertension, progressive proteinuria and glomerulosclerosis. In Group 2 treatment with ticlopidine was associated with less severe impairment of renal function. Proteinuria was significantly lower and animals were partially protected from the development of glomerulosclerosis. These animals had significantly prolonged skin bleeding time. In vitro ADP and arachidonic acid (AA)-induced platelet aggregation was inhibited. Systemic blood pressure was significantly lower than in controls. In Group 3 rats GR 32191 failed to influence progressive proteinuria and severity of glomerulosclerosis which were comparable to those in Group 1. Bleeding time was not prolonged, and in vitro platelet aggregation was inhibited only when AA was used as aggregating agent. Systemic blood pressure was not influenced. These studies suggest that a drug like ticlopidine, which has a broad spectrum of pharmacological actions on platelets and platelet-cell interactions, does retard the development of progressive renal injury when nephron number is reduced. Specific blocking of thromboxane A2 (TxA2) biological activity does not influence progressive renal disease in rats with remnant kidney.

Animals↗
PubMed1990

Glomerular response to hyperglycemia in human diabetic nephropathy.

We have studied the effect of acute hyperglycemia on glomerular function in seven insulin-dependent diabetics with overt nephropathy during hyperglycemic or euglycemic clamp. In all patients glomerular filtration rate (GFR) was higher during hyperglycemia than during euglycemia (35.0 +/- 15.5 vs. 21.4 +/- 10.3 ml.min-1.1.73 m-2, P less than 0.01), whereas renal plasma flow did not change significantly. To establish which determinant of GFR is altered by hyperglycemia, fractional clearances of neutral dextrans of graded molecular size were determined in both glycemic states, and data were analyzed by a theoretical model of hindered transport of macromolecules through a porous membrane. Hyperglycemia significantly increased sieving coefficients of small dextran molecules (28-40 A in radius), whereas fractional clearances of large macromolecules (greater than 44 A) did not change. Theoretical analysis suggested that the ultrafiltration coefficient (Kf) and membrane permeability to small dextrans (less than 40 A) increased in hyperglycemia in respect to euglycemia. Because these results have been obtained in patients with severe renal failure and hypertension, our conclusions do not necessarily apply to the early phase of diabetic nephropathy.

Body Water↗
PubMed1990

Role of platelet-activating factor in renal immune injury and proteinuria.

Platelet-activating factor (PAF) has been implicated as a potential mediator in renal immune injury, but little is known on the mechanisms by which this endogenous phospholipid could contribute to the development of glomerular proteinuria that occurs during immunologically mediated inflammatory reactions. Several experimental models of renal immune injury, including hyperacute kidney allograft rejection, acute serum sickness and nephrotoxic nephritis, and human studies have clearly indicated that renal damage is associated with increased intraglomerular formation of PAF. However, a definitive proof of its pathophysiologic role has been obtained only by pharmacological inhibition of PAF activity at receptor level. In this context we have documented that the PAF receptor antagonist L-652,731 markedly prevented renal function deterioration and development of proteinuria, and reduced glomerular hypercellularity, fibrin deposition in Bowman's space, and tubular cast formation in a rabbit model of nephrotoxic serum nephritis. Concerning the mechanisms by which PAF may induce proteinuria, it has been suggested that PAF increases glomerular permeability to proteins through the release of cationic proteins from platelets and polymorphonuclear neutrophils infiltrating the glomerular tuft, and their deposition in the glomerular capillary wall with loss of fixed anionic charges. We have recently shown that in isolated rat kidney preparations perfused with a cell-free medium, the addition of PAF, but not its vehicle or 2-lyso-PAF, to the perfusate caused a progressive increase in urinary protein excretion. PAF-induced proteinuria was prevented by exposure of isolated kidneys to the PAF receptor antagonist L-652,731.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1990

Functional implications of decreased renal cortical atrial natriuretic peptide binding in experimental diabetes.

Glomerular hyperfiltration in streptozotocin-induced diabetes mellitus in rats may be mediated by atrial natriuretic peptide (ANP). We wanted to evaluate plasma levels of ANP and plasma volume in relation to renal ANP receptor density and affinity in rats 6 weeks after induction of diabetes. Plasma levels of immunoreactive ANP were significantly higher in hyperglycemic diabetic (75.2 +/- 8.3 pg/ml) than in control animals (34.7 +/- 8.1 pg/ml; p less than 0.01). Administration of insulin to keep diabetic rats normoglycemic normalized plasma levels of immunoreactive ANP (30.5 +/- 5.2 pg/ml). In contrast, plasma volume did not show significant differences among the groups (hyperglycemic diabetes, 46.6 +/- 3.8; normoglycemic diabetes, 42.4 +/- 3.2; controls, 43.2 +/- 2.0 ml/kg body wt). No correlation was found between plasma levels of immunoreactive ANP and plasma volume. By autoradiography a significant reduction in the number of renal cortical ANP receptors was observed in hyperglycemic diabetic rats as compared with controls. At variance, ANP receptor affinity did not change either in the cortex or in the medulla in hyperglycemic diabetics in comparison with control animals. The pathophysiological implication of cortical ANP receptor down-regulation was underscored by the blunted response of glomerular filtration rate to ANP infusion in diabetic animals as compared with controls.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1990

Angiotensin converting enzyme inhibition ameliorates glomerular filtration of macromolecules and water and lessens glomerular injury in the rat.

The effect of enalapril on glomerular hemodynamics and permselectivity and on subsequent sclerosis was studied in male MWF/Ztm rats which spontaneously develop proteinuria and glomerular structural damage. Untreated group 1 and enalapril-treated group 2 (50 mg/liter, in the drinking water) underwent micropuncture studies after 2 mo of observation. After the same period of treatment, group 3 (untreated) and group 4 (enalapril treated) were used for determination of whole-kidney function and neutral dextran clearances. Group 5 (untreated) and group 6 (enalapril treated) were followed for an additional 4 mo and used for kidney function and morphological studies. Enalapril significantly lowered systolic blood pressure, which was elevated in untreated groups, and significantly reduced proteinuria (295 +/- 64 vs. 128 +/- 24 mg/24 h by the end of the study). Despite the reduced renal perfusion pressure, whole-kidney glomerular filtration rate was higher in enalapril-treated than in untreated rats (0.96 +/- 0.14 vs. 0.81 +/- 0.10 ml/min, P less than 0.05) as was the single nephron glomerular filtration rate (54 +/- 7.1 vs. 46 +/- 4.0 nl/min, P less than 0.05). The single glomerular afferent plasma flow was comparable in both groups. Enalapril reduced mean glomerular capillary hydraulic pressure from the normal value of 51 +/- 1 mmHg (untreated rats) to a value lower than normal (44 +/- 1 mmHg, P less than 0.001). These hemodynamic changes were associated with a significant reduction in afferent (approximately 23%) and efferent (approximately 26%) arteriolar resistance. The mean ultrafiltration coefficient was two times higher in the enalapril (0.126 +/- 0.027 nl/s per mmHg) than in the untreated group (0.061 +/- 0.023 nl/s per mmHg). The clearance of dextran macromolecules relative to that of inulin was significantly reduced for all molecular sizes studied (26-64 A) in enalapril-treated vs. untreated rats. Theoretical analysis of dextran fractional clearances using a heteroporous model of neutral solute transport across the glomerular capillary wall indicated that enalapril affected glomerular membrane size selective properties, reducing uniformly the radius of hypothetical membrane pores. Enalapril treatment also significantly limited (P less than 0.01) the development of glomerular structural lesions (mean percentage of sclerotic glomeruli was 4.2 +/- 3.5% [treated] vs. 28 +/- 15% [untreated] rats at the end of the study) as well as tubulo-interstitial damage. These results suggest that the protective effect of enalapril on the development of proteinuria and glomerular sclerosis in this model is due to its property of ameliorating size selectivity and hydraulic permeability of the glomerular capillaries.

Animals↗
PubMed1990

Role of endothelium-derived nitric oxide in the bleeding tendency of uremia.

Endothelium-derived relaxing factor, now identified as nitric oxide (NO), is a labile humoral agent formed by vascular endothelial cells from L-arginine. NO mediates the action of substances that induce endothelium-dependent relaxation and plays a role in regulating blood pressure. In this study we investigated whether NO is involved in the pathogenesis of the bleeding tendency associated with renal failure. Rats with extensive surgical ablation of renal mass develop renal insufficiency due to progressive glomerulosclerosis. Like uremic humans, rats with renal mass reduction and uremia have a bleeding tendency that manifests itself by a prolonged bleeding time. We found that N-monomethyl-L-arginine (L-NMMA), a specific inhibitor of NO formation from L-arginine, completely normalized bleeding time when given to uremic rats. L-NMMA injection also increased ex vivo platelet adhesion but did not affect ex vivo platelet aggregation induced by adenosine diphosphate, arachidonic acid, and calcium ionophore A23187. The shortening effect of L-NMMA on bleeding time was completely reversed by giving the animals the NO precursor L-arginine, but not D-arginine, which is not a precursor of NO. It thus appears that NO is a mediator of the bleeding tendency of uremia.

Animals↗
PubMed1990

Thromboxane synthesis inhibition increases renal prostacyclin and prevents renal disease progression in rats with remnant kidney.

Previous studies have demonstrated that inhibition of thromboxane A2-dependent platelet aggregation by the thromboxane A2 synthase inhibitor, OKY 1581, ameliorated the progressive kidney disease of rats with subtotal renal ablation. OKY 1581 also decreased the excessive renal thromboxane A2 synthesis and lowered systemic blood pressure. In the same model, a low dose aspirin and a specific thromboxane A2 receptor antagonist failed to influence proteinuria, glomerulosclerosis, and hypertension, thus excluding a role for either platelet or renal thromboxane A2 in renal disease progression. The aims of this study were to establish (1) whether a thromboxane A2 synthase inhibitor different from OKY 1581 could retard the progression of glomerular disease in rats with remnant kidney and (2) whether this effect was associated with an increase in renal synthesis of the vasodilatory prostacyclin. Treatment of rats with renal mass ablation with FCE 22178 (100 mg/kg by gavage and 200 mg/kg in the drinking water) for 35 days starting 10 days after surgical ablation was associated with an improvement in renal function in comparison with rats receiving the vehicle alone. Proteinuria was significantly lower, and rats were partially protected from the development of glomerulosclerosis. Systolic blood pressure was significantly lower than in animals given the vehicle. Urinary thromboxane B2 excretion was significantly decreased, and urinary 6-keto-prostaglandin F1 alpha increased in respect to vehicle-treated rats. We conclude that FCE 22178 limits glomerular injury in rats with remnant kidney.

6-Ketoprostaglandin F1 alpha↗
PubMed1990

Role of insulin and atrial natriuretic peptide in sodium retention in insulin-treated IDDM patients during isotonic volume expansion.

Because insulin shows an antinatriuretic effect in healthy humans, insulin therapy resulting in circulating hyperinsulinemia may lead to sodium retention and in turn to hypertension in individuals with insulin-dependent diabetes mellitus (IDDM). Moreover, it has been proved that atrial natriuretic peptide (ANP) plays a major role in modulating natriuresis in humans. This study investigated the relationship between insulin and ANP in modulating sodium metabolism in normotensive and hypertensive IDDM subjects compared with control groups of normotensive and hypertensive nondiabetic subjects. IDDM normotensive and hypertensive subjects had mean +/- SE duration of IDDM of 7 +/- 2 and 8 +/- 2 yr, respectively, and had no clinical features of diabetic nephropathy. All subjects received a saline infusion (2 mmol.kg-1.90 min-1) during euglycemia. IDDM normotensive and hypertensive subjects received a subcutaneous insulin infusion (15 mU.kg-1.h-1), resulting in twofold higher plasma free-insulin levels (16 +/- 2 and 19 +/- 3 microU/ml, respectively) than in nondiabetic normotensive and hypertensive subjects (7 +/- 2 and 8 +/- 2 microU/ml, respectively). During saline challenge, sodium excretion increased by 22 +/- 4% in normotensive and 49 +/- 9% in hypertensive nondiabetic subjects but by only 11 +/- 0.4% in normotensive (P less than 0.01) and 8 +/- 2% in hypertensive (P less than 0.01) IDDM subjects. The impaired natriuretic response to saline challenge was mainly due to greater rates of sodium reabsorption by kidney proximal tubules in IDDM than nondiabetic subjects. At baseline, plasma ANP concentrations were significantly higher in both IDDM groups than in control groups (normotensive IDDM and control subjects: 38 +/- 4 and 19 +/- 2 pg/ml, respectively, P less than 0.01; hypertensive IDDM and control subjects: 45 +/- 6 and 27 +/- 4 pg/ml, respectively, P less than 0.05). After saline challenge, ANP concentrations rose to 39 +/- 4 pg/ml in normotensive and 49 +/- 5 pg/ml in hypertensive control subjects, whereas no significant change above baseline value was seen in IDDM subjects. Both IDDM groups showed a 10-12% greater exchangeable Na+ pool than control subjects regardless of the presence of hypertension. Subcutaneous insulin infusion, resulting in circulating plasma free-insulin levels in normotensive control subjects comparable to those in IDDM patients, inhibited natriuresis, increased proximal tubule sodium reabsorption at the level of the kidney, and inhibited an adequate ANP stimulation by saline challenge. We conclude that hyperinsulinemia leads to increased proximal tubule sodium reabsorption and impaired ANP response during saline administration. Both mechanisms account for sodium retention in normotensive and hypertensive IDDM patients.(ABSTRACT TRUNCATED AT 400 WORDS)

Adult↗
PubMed1990

Tissue plasminogen activator therapy of rabbit nephrotoxic nephritis.

To study the efficacy of tissue plasminogen activator (PA) therapy to prevent deteriorating renal function in experimental proliferative glomerulonephritis we used a model of nephrotoxic nephritis induced in rabbits by injection of antiglomerular basement membrane antiserum. Saline or recombinant tissue plasminogen activator (rt-PA, 1.3 mg/kg body weight) was infused daily for 7 days starting from day 7 after the injection of antiglomerular basement membrane antiserum when the disease had been already triggered. Animals were killed on day 14. Rabbits given saline had abundant deposits of fibrin and crescents in about 67% of glomeruli. rt-PA significantly protected animals from glomerular fibrin deposition and crescent formation with respect to saline-treated animals. Renal function measured as creatinine clearance was dramatically impaired in rabbits given saline. Treatment with rt-PA ameliorated the renal function impairment of nephrotoxic nephritis. rt-PA did not produce a systemic fibrinolytic state as indicated by alpha 2-antiplasmin level measurement. These results suggest that tissue PA may have important implications in preventing renal function deterioration in humans with crescentic glomerulonephritis and fibrin depositions.

Animals↗
PubMed1990

Endothelin mediates the renal vasoconstriction induced by cyclosporine in the rat.

The effect of cyclosporine on renal function was first investigated in the isolated perfused rat kidney. Kidneys from normal male Sprague-Dawley rats were perfused at constant pressure. After control clearance periods, cyclosporine (0.6, 1.2, or 3 mg/min) or vehicle was infused over 5 min period in the renal artery and then four 10-min experimental periods followed. Cyclosporine, but not vehicle caused a dose dependent fall in renal perfusate flow associated with a concomitant increase in renal vascular resistance. Glomerular filtration rate was also decreased in parallel. We also examined whether endogenous endothelin mediates cyclosporine-induced acute renal vasoconstriction. In isolated kidneys pre-exposed to specific anti-endothelin antibody and then challenged with cyclosporine (1.2 mg/min) the renal perfusate flow, renal resistance, and glomerular filtration rate were 22.3 +/- 1.8 ml/min, 4.50 +/- 0.36 mmHg/ml.min-1, 1.06 +/- 0.05 ml/min, respectively, as compared with 12.9 +/- 1.2 ml/min, 7.8 +/- 1.2 mmHg/ml.min-1, 0.55 +/- 0.06 ml/min (P less than 0.01) measured in isolated kidneys pre-exposed to a non-immunized rabbit serum. The effectiveness and specificity of anti-endothelin antibody were confirmed by its capability of preventing the renal function deterioration caused by a single bolus dose (150 pmol) of synthetic endothelin, but not by infusion of angiotensin II, norepinephrine, or thromboxane A2 mimetic U-46619 in isolated kidneys. To test further the relationship between endogenous endothelin and cyclosporine-induced renal vasoconstriction, a second series of in vivo studies was performed in normal rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Acute Kidney Injury↗
PubMed1990

Thrombotic thrombocytopenic purpura and related disorders.

This article provides us with background information on the disease. Clinical features, variants and classification, laboratory findings, and pathology are discussed. Knowledge of the disease's pathogenesis has increased recently and specific causes discussed are predisposing factors, triggering agents, endothelial damage, defective PGI2 bioavailability, FVIII/vWF multimeric structure abnormalities, platelet activation, and hemolytic anemia. Proposed specific therapies discussed are steroids, heparin, antiplatelet agents, prostacyclin, splenectomy, immunosuppressive agents, plasma infusion, and plasma exchange.

Adolescent↗
PubMed1990

Thromboxane receptor blockade attenuates the toxic effect of cyclosporine in experimental renal transplantation.

Renal dysfunction, manifested as a dose-dependent reduction in glomerular filtration rate (GFR), is a common complication of cyclosporine A (CyA) administration to laboratory animals and humans. We have recently shown that chronic CyA treatment in normal rats is associated with a selective increase in renal thromboxane A2 (TXA2) synthesis, which may play a role in GFR reduction. The present experiments were designed to investigate whether pharmacological inhibition of TXA2 activity could reduce CyA nephrotoxicity in a rat model of renal transplantation. To discriminate the possible biochemical changes due to rejection episodes from those due to CyA nephrotoxicity, we selected a model of renal isograft free of graft rejection processes. We demonstrated that oral CyA administration for 30 days to rats undergoing renal isograft is associated with the development of renal insufficiency, as indicated by a progressive increase in serum creatinine concentration and reduction in creatinine clearance. In the same animals, a parallel increase in the urinary excretion of TXB2 was found. Combination of the specific thromboxane receptor antagonist GR32191 with CyA treatment partially prevented the deterioration in renal function observed in animals given CyA alone, without modifying the urinary TXB2 excretion. In contrast, renal-isografted rats given GR32191 alone or vehicle alone for 30 days did not show any changes in serum creatinine, creatinine clearance, and urinary TXB2 excretion throughout the experimental period. Mild hypercellularity of the glomerular tuft was observed in isografted kidneys chronically exposed to either CyA or CyA plus GR32191.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗