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C Zoja

Publications and source records attributed to C Zoja.

At least 73 records · Page 4Linked to original sources
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

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

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

17 beta-estradiol is the most active component of the conjugated estrogen mixture active on uremic bleeding by a receptor mechanism.

We have reported previously that a mixture of conjugated estrogens which is effective in shortening the prolonged bleeding time in uremic patients is also effective on bleeding time in a rat model of uremia. With the present study we took advantage from such a rat model of chronic uremia and decided to identify the component(s) of the conjugated estrogen mixture responsible for shortening the bleeding time. Moreover, we wanted to clarify whether estrogen effect on primary hemostasis is due to a receptor mechanism and can be neutralized by specific estrogen receptor antagonists such as tamoxifen or clomiphene. Both estrone sulfate and 17 beta-estradiol, but not equilin, were effective in shortening the prolonged bleeding time of uremic rats. 17 beta-Estradiol was the most active component of the mixture, reproducing the time course of bleeding time shortening of the entire mixture (effect lasting 48 hr). The effect of estrone sulfate injection lasted only 24 hr. Tamoxifen and clomiphene pretreatment prevented the shortening of bleeding time induced by conjugated estrogen mixture and its active components. These findings indicate that 17 beta-estradiol is the key compound of the conjugated estrogen mixture effective on bleeding time shortening and that the effect of estrogens on primary hemostasis is mediated by a receptor mechanism.

Animals↗
PubMed1989

Abnormalities in arachidonic acid metabolites in nephrotoxic glomerular injury.

Arachidonic acid metabolites are suspected of contributing in various ways to major pathophysiological events that occur in toxic and immune glomerular injury. This paper focuses on the role of arachidonate metabolites in the experimental models of adriamycin nephrosis and cyclosporin A nephrotoxicity in rats as examples, respectively, of a toxic nephropathy characterized by increased glomerular permeability to proteins and a toxic nephropathy with macrophage accumulation and progressively deteriorating renal function. The important pathogenic contribution of thromboxane A2 to the impairment of renal function in these experimental models is discussed.

Animals↗
PubMed1989

Sequence of glomerular changes in experimental endotoxemia: a possible model of hemolytic uremic syndrome.

Glomerular morphological changes produced by 5-hour intravenous infusion of endotoxin (40 micrograms/kg/h) were studied in 57 rabbits. During endotoxin infusion all animals developed signs of endotoxemia, anemia, and transient leukopenia and thrombocytopenia. Acute renal failure also developed in all animals. By light microscopy a marked polymorphonuclear cell infiltration was the prominent finding within 1 h from the beginning of the infusion. At hour 5 fibrin deposits and thrombi were detected in most animals. The abnormalities were reversible. By electron microscopy endothelial damage was detected few minutes after the beginning of endotoxin infusion followed by leukocyte and platelet infiltration in glomerular capillaries. Fibrin appeared at hour 5 as free strands into the lumens or in large clumps along the luminal surface of endothelial layer. Occasionally, occlusive fibrin thrombi were seen. At hour 48 only mild endothelial damage was seen, associated with few polymorphonuclear cells in the glomerular capillary lumens. These results document the sequence of renal changes in the best available animal model of hemolytic uremic syndrome. Beside endothelial damage, leukocyte infiltration in glomerular capillaries is a prominent finding suggesting a role of inflammatory cells in the development of microvascular thrombosis.

Animals↗
PubMed1989

Differential inhibition by aspirin of platelet thromboxane and renal prostaglandins in the rat.

Aspirin (ASA) beside inhibiting platelet thromboxane A2 (TxA2) can suppress the formation of renal prostacyclin (PGI2) and prostaglandin E2 (PGE2) which play a crucial role in the control of renal hemodynamics. Previous studies based on urinary PG measurements have suggested that p.o. ASA can spare renal cyclooxygenase. We wanted to establish by direct measurement whether p.o. ASA has a renal sparing effect and to establish to which extent changes in renal cyclooxygenase activity can be predicted measuring urinary excretion of 6-keto-PGF1 alpha and PGE2. Our results showed that in normal rats 10 mg/kg of ASA given p.o. partially inhibits platelet TxA2 formation (measured as serum TxB2) and does not inhibit glomerular and medullary PGI2 and PGE2 synthesis. Higher doses of ASA (30-200 mg/kg) effectively and completely inhibit platelet TxA2 independently if given p.o. or i.v., and also inhibit glomerular and medullary PG synthesis. The kinetics of the effect of ASA on platelet vs. renal cyclooxygenase is different: the inhibition being irreversible in platelets, but rapidly reversible in glomeruli and medulla. Six hours after the administration of 10 and 30 mg/kg i.v. and 30 mg/kg p.o., kidney cyclooxygenase activity recovers completely. This transient inhibition of renal cyclooxygenase is not reflected by urinary excretion of 6-keto-PGF1 alpha and PGE2 (6- and 24-hr collection periods). In conclusion our present results indicate that doses of ASA enough to inhibit platelet TxA2, transiently inhibit glomerular and medullary PGI2 and PGE2. Although the inhibitory effect on platelets is long lasting, the effect on renal cyclooxygenase is transient and rapidly reversible.(ABSTRACT TRUNCATED AT 250 WORDS)

6-Ketoprostaglandin F1 alpha↗
PubMed1989

Selective inhibition of platelet thromboxane generation with low-dose aspirin does not protect rats with reduced renal mass from the development of progressive disease.

Rats with extensive renal mass reduction develop hypertension, proteinuria and progressive glomerulosclerosis. Previous studies have demonstrated that these changes are associated with an increased urinary excretion of thromboxane compared with normal rats and that the administration of a thromboxane synthetase inhibitor prevents glomerulosclerosis and progressive renal function deterioration. On this basis it has been speculated that the thromboxane synthetase inhibitor, by inhibiting platelet thromboxane, reduces platelet aggregation and prevents the generation of substances that can influence glomerular functional properties. Because the thromboxane synthetase inhibitor also inhibits thromboxane synthesis by resident glomerular cells and lowers blood pressure in these animals, the question of whether platelet thromboxane is indeed the factor implicated in the development of renal disease after renal ablation remains unanswered. To address this issue the authors administered at different time intervals from the surgical procedure a low-dose of oral aspirin (ASA) to rats with remnant kidney. This approach resulted in selective inhibition of platelet cyclooxygenase leading to an almost complete prevention of platelet thromboxane generation. Low-dose ASA spared renal cyclooxygenase as documented by a lack of significant inhibition of glomerular and urinary 6-keto-PGF1 alpha and did not lower blood pressure. Renal function studies showed that low-dose ASA, despite inhibiting platelet aggregation, had no effect on proteinuria and progressive renal insufficiency irrespectively if administered late (ie, 80 days after surgery) and given daily for all the observation period (ie, 20 days) or earlier in the course of the disease (ie, 40 and 10 days after surgery). Histologic data showed that the degree of glomerulosclerosis and tubulo-interstitial damage was not significantly different in rats with reduction of renal mass alone compared with rats with remnant kidney given low-dose ASA. In conclusion, the present findings indicate that inhibition of platelet aggregation and thromboxane formation does not prevent the progressive glomerulosclerosis that develops in rats with surgical reduction of renal mass. It is suggested that the beneficial results obtained previously in the same model by the use of a thromboxane synthesis inhibitor must be attributed either to an effect on resident glomerular cell thromboxane synthesis or to lowering systemic blood pressure.

Animals↗
PubMed1989

Age-related nephropathy and proteinuria in rats with intact kidneys exposed to diets with different protein content.

Tubulointerstitial damage and glomerular sclerosis are findings commonly observed in the experimental models of adriamycin and puromycin aminonucleoside nephrosis. It has been suggested that in such models proteinuria might be an important mediator of tubulo-interstitial damage which in turn may determine the progression of the disease favoring the development of glomerulosclerosis. The objective of the present investigation was to establish the temporal relationship between proteinuria, tubulo-interstitial damage and glomerulosclerosis in aging rats with intact kidneys exposed to diets with different protein content. There were six groups of rats studied. Animals of groups 1, 5, and 6 (N = 10) were fed diets containing 20, 35, and 6% protein, respectively, for 20 months and sacrificed at the end of the experimental period. Rats in groups 3 and 4 (N = 6) exhibited marked and mild proteinuria, respectively, after 14 months of maintenance on standard diet, and followed for two additional months after the onset of proteinuria with the aim of evaluating the pattern of renal damage after a relatively short period of proteinuria. Rats in group 2 (N = 10) were fed standard diet and sacrificed before (5 months) and at the onset of proteinuria (10 months). Protein excretion and plasma creatinine were measured for each animal every month. Pathologic examination was performed by light and electron microscopy. At the onset of proteinuria neither renal structural nor functional abnormalities were detected. After 20 months, rats fed standard diet developed tubulo-interstitial damage (score: 1.29 +/- 1.05) and focal glomerular sclerosis (percentage of glomeruli with focal segmental glomerular sclerosis: 16.70 +/- 16.40). A significant correlation was found between the degree of tubulo-interstitial damage and the percentage of glomeruli with focal glomerular sclerosis (r = 0.99, p less than 0.01). Development of tubulo-interstitial damage and focal glomerular sclerosis were correlated with heavy and sustained proteinuria. The high protein diet significantly worsened proteinuria (at month 20: 247.08 +/- 101.73 mg/day), tubulo-interstitial changes (score: 1.99 +/- 0.70), focal glomerular sclerosis (percentage of glomeruli with focal segmental glomerular sclerosis: 21.50 +/- 9.44) and was associated with deteriorating renal function (at month 20, plasma creatinine: 1.20 +/- 0.50 mg/dl).(ABSTRACT TRUNCATED AT 400 WORDS)

Aging↗
PubMed1989

Tumor necrosis factor induces glomerular damage in the rabbit.

Tumor necrosis factor (TNF) is a polypeptide hormone produced by activated macrophages detectable in the circulation of experimental animals given endotoxin. Recent evidence strongly suggests that many of the deleterious effects of endotoxin in experimental animals are mediated by TNF. Because endotoxemia in experimental animals and humans is associated with glomerular damage the present investigation was designed to establish whether TNF directly induces glomerular functional and structural changes. Twenty-three rabbits were given human recombinant TNF at the doses of 0.08, 0.8, and 8.0 micrograms/kg/h as a continuous 5-hour intravenous infusion. Animals were killed at the end of the infusion. All rabbits given 0.8 and 8.0 micrograms/kg/h TNF developed anemia (Ht value decrease at 5 hours: 0.8 microgram/kg/h, 15%; 8.0 micrograms/kg/h, 16%); leukopenia (leukocyte count decrease at 5 hours: 0.8 micrograms/kg/h, 47%; 8.0 micrograms/kg/h, 59%); thrombocytopenia (platelet count decrease at 5 hours; 0.8 micrograms/kg/h, 45%; 8.0 micrograms/kg/h, 57%). Rabbits given 8.0 micrograms/kg/h also had renal failure (serum creatinine from 1.02 +/- 0.15 to 1.64 +/- 0.34 mg/dl). By light microscopy only occasional polymorphonuclear leukocytes in the glomerular capillaries were detectable in rabbits infused with 0.08 micrograms/kg/h TNF, whereas with 0.8 micrograms/kg/h TNF the presence of inflammatory cells in the glomerular capillaries was the prominent finding. With 8.0 micrograms/kg/h TNF beside leukocyte accumulation, fibrin was detected in the glomerular capillary lumens of two of eight animals. Electron microscopy found dose-dependent glomerular endothelial cell damage in animals given TNF with fibrinlike material in the capillary lumens. Glomerular changes induced by TNF were remarkably similar to those previously found in animals given endotoxin. Thus, TNF is likely to be the mediator of endotoxin-induced glomerular damage and can be regarded as a new mediator of macrophage-dependent damage in glomerulonephritis.

6-Ketoprostaglandin F1 alpha↗
PubMed1988

Prolonged bleeding time and increased vascular prostacyclin in rats with chronic renal failure: effects of conjugated estrogens.

The aim of our study was to assess whether the development of chronic uremia in rats with extensive renal mass ablation was associated with an impairment of primary hemostasis as occurs in humans with terminal uremia. We also wanted to assess whether uremic rats had an increased generation of vascular prostacyclin (PGI2) and whether conjugated estrogens could influence such an abnormality. Our results showed that the development of chronic renal failure in rats was associated with a significant prolongation of bleeding time as reported in humans. Thoracic aorta and inferior vena cava specimens from uremic rats produced significantly more 6-keto-prostaglandin F1 alpha (the stable breakdown product of PGI2) than did specimens from the corresponding controls. Conjugated estrogens significantly shortened the bleeding time of uremic rats. The effect on bleeding time was detectable in the majority of animals within 4 hours from conjugated estrogen injection, reached its maximum at 24 hours, and returned to preinjection values within 72 hours from conjugated estrogen injection. Estrogen administration did not influence the generation of vascular PGI2. It is concluded that the model of extensive renal ablation in the rat is a suitable one to study changes in primary hemostasis in chronic renal failure and that the effect of estrogens on primary hemostasis in uremia is not mediated by changes in vascular PGI2.

Animals↗
PubMed1987

Indomethacin reduces proteinuria in passive Heymann nephritis in rats.

Indomethacin has been used to lower proteinuria in human glomerular diseases with controversial results. The mechanism of indomethacin beneficial effects has not been established. A possible explanation is that indomethacin reduces proteinuria by inhibiting the synthesis of renal prostaglandins (PGs); however, appropriate studies to address this issue have never been done. The objectives of the present study were: to investigate whether indomethacin influences protein excretion in an experimental model of immunologically-mediated glomerular disease; to establish if the possible favorable effect of indomethacin on proteinuria is related to a reduction in glomerular filtration rate (GFR); to establish the possible association between the antiproteinuric effect of indomethacin and its inhibitory effect on arachidonic acid (AA) metabolites of renal or extrarenal origin; and to further investigate the relationship between proteinuria and renal thromboxane (Tx) synthesis previously demonstrated in experimental models of nephrotoxic nephritis and adriamycin (ADR) nephrosis. To this purpose we used an experimental immune-complex disease, passive Heymann nephritis (PHN) which was induced in the rat by a single intravenous (i.v.) injection of heterologous serum directed against a brush border component (gp 330 antigen). Indomethacin at a dose of 6 mg/kg intraperitoneally (i.p.) administered for four consecutive days to PHN animals during the period of heavy proteinuria, effectively reduced urinary protein excretion. The reduction in proteinuria does not appear to be a consequence of a reduction in GFR as documented by inulin clearance. Glomerular synthesis and urinary excretion of vasodilatory prostacyclin (PGI2) and PGE2 were decreased or unchanged in PHN animals in respect to control animals.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1987

Glomerular size selectivity in nephrotic rats exposed to diets with different protein content.

Glomerular size-selective properties in animals made nephrotic by adriamycin (ADR) injection and fed standard (20% protein) or high-protein (35% protein) diets were investigated using dextran fractional clearances. To interpret filtration and dextran-sieving data, a theoretical approach previously developed for analysis of experimental data in healthy and nephrotic humans was used. Four types of hypothetical pore-radius distributions were compared in order to establish the best tool for describing membrane pore structure in normal and nephrotic rats. This analysis revealed that a spread distribution of pores, the lognormal probability distribution, is the most adequate in representing membrane intrinsic characteristics. ADR animals on standard diet developed massive proteinuria and a lower glomerular filtration rate (GFR) than control animals. High-protein feeding in ADR rats induced a further increase in urinary protein excretion and in GFR. Dextran fractional clearance was more elevated for larger dextran fractions (greater than 46 A) in ADR animals on the standard diet than in control rats. No differences were observed in dextran-sieving curves between ADR rats on the standard and high-protein diet. Theoretical analysis of filtration and fractional clearance data revealed comparable changes in the intrinsic parameters of glomerular size selectivity in the two groups of nephrotic animals. These observations indicate that increased traffic of plasma proteins through the glomerular capillary wall does not imply, in our experimental condition, a further loss of glomerular size-selective properties. The greater urinary protein excretion of ADR animals on high-protein diet than ADR animals on a standard diet cannot be explained by further impairment of glomerular size selectivity but more likely reflects hemodynamic changes.

Animals↗