Prostacyclin and hemolytic uremic syndrome: from the laboratory to an international registry.
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Epoprostenol↗
Biomedical subjects
C Zoja
Publications and source records attributed to C Zoja.
Tubulo-interstitial lesions mediate renal damage in adriamycin glomerulopathy.
The present study was designed to investigate the relationship between proteinuria, focal sclerosis, and tubulo-interstitial changes in the evolution of renal damage in experimental nephrosis. We utilized an accelerated unilateral model of adriamycin (ADR) nephrosis characterized by morphological changes more severe than in the classical model. The first events in ADR-induced glomerulopathy were epithelial cell damage and proteinuria. Subsequently, tubular casts were formed at the distal level. The cast formation preceded the development of interstitial damage, which was determined by tubular obstruction and breaking of tubular basement membrane (TBM), which in turn promoted an interstitial inflammatory reaction. Despite the severity of tubulo-interstitial damage observed after a long period of heavy proteinuria, the incidence of focal segmental glomerulosclerosis (FSG) was very low. The results of the present study indicate that chronic proteinuria is not necessarily accompanied by the development of focal sclerosis. Tubulo-interstitial lesions appear to be the most important determinant for the progression of renal damage in this model.
Animals↗
Functional significance of exaggerated renal thromboxane A2 synthesis induced by cyclosporin A.
Animals and humans undergoing a chronic treatment with cyclosporin A (CyA) show a reduction in glomerular filtration rate (GFR). The cause of this abnormality has not been established. Since CyA interferes with arachidonic acid (AA) metabolism in various cells, we wished to determine whether alterations in renal AA metabolites contribute to deteriorating renal function in rats on CyA. We show that chronic CyA treatment induces a progressive increase in the renal synthesis of thromboxane (TX) A2. This is a selective abnormality in that CyA does not influence the renal synthesis of prostaglandin E2 (PGE2) and prostacyclin (PGI2). A significant negative correlation has been found between TXB2 urinary excretion rate and inulin clearance. No correlation has been observed between TXB2 excretion and p-aminohippuric acid clearance. The withdrawal of CyA is followed by a normalization of both TXB2 urinary excretion rate and GFR. The administration of a selective TXA2 inhibitor, UK-38,485, resulted in a significant reduction in urinary excretion of TXB2 accompanied by a significant increase in GFR. We conclude that chronic treatment with CyA in rats is associated with a selective increase in renal TXA2 synthesis and suggest that this abnormality may play a role in the reduction of GFR.
Animals↗
Renin-angiotensin system and glomerular prostaglandins in early nephrotoxicity of ciclosporin.
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6-Ketoprostaglandin F1 alpha↗
Role of renal prostaglandins in normal and nephrotic rats with diet-induced hyperfiltration.
Changes in glomerular hemodynamics have been observed in animals and humans after a high-protein feeding. It has been postulated that these changes can induce progressive deterioration of renal function favoring loss of glomerular permselectivity properties and subsequent glomerulosclerosis, especially when the renal mass is already reduced surgically or by a disease process. We studied the consequence of long-term protein supplementation on renal function parameters in normal animals and in animals affected by adriamycin nephrosis, a model of renal damage that closely mimics human "minimal change". We also wanted to investigate whether vasodilatory prostaglandins (PGs) generated at the renal level are responsible for the adaptive hemodynamic changes that follow dietary manipulation in normal animals and in animals with experimental nephrosis. The model of glomerular damage we used is characterized by heavy and persistent proteinuria induced in the rat by adriamycin (ADR). Two isocaloric diets were selected containing 20% and 35% protein. High-protein feeding induced a significant increase in glomerular filtration rate in both normal and nephrotic animals. In normal animals the high-protein diet did not modify the urinary excretion of 6-keto-PGF1 alpha, the stable breakdown product of prostacyclin (PGI2), but significantly reduced urinary excretion of prostaglandin E2. In nephrotic rats, the high-protein diet increased urinary excretion of 6-keto-PGF1 alpha, without modifying urinary excretion of prostaglandin E2. Glomerular synthesis of vasodilatory prostaglandins paralleled the urinary excretion pattern. The cyclooxygenase inhibitor indomethacin effectively inhibited urinary excretion of vasodilatory PGs but did not prevent hyperfiltration in normal animals fed the high-protein diet. At variance, when given to nephrotic animals fed the high-protein diet, indomethacin at a dose that reduced 6-keto-PGF1 alpha and prostaglandin E2 urinary excretion by 84% and 93%, respectively, inhibited hyperfiltration. We conclude that the same hemodynamic changes that occur in normal animals given a high-protein diet also take place when glomeruli are uniformly damaged by a disease process as in ADR nephrosis. However, whereas hyperfiltration in normal animals appears to be independent of renal PGs, in nephrotic animals an enhanced renal synthesis of PGI2 appears to play a crucial role in the adaptive changes responsible for hyperfiltration.
6-Ketoprostaglandin F1 alpha↗
Effect of short-term cyclosporine administration in rats on renin-angiotensin and thromboxane A2: possible relevance to the reduction in glomerular filtration rate.
A short-term treatment with Cyclosporine A (CyA) induces a decrease in glomerular filtration rate (GFR), promptly reversible after withdrawal of the drug. Several lines of evidence are now available as to indicate that this phenomenon is dependent on a hemodynamic perturbation resulting in a renal vasoconstriction. With the present work we have examined the relationship between the reduction in GFR which follows a short-term administration of CyA in rats and the biochemical changes in renin-angiotensin system and renal arachidonic acid metabolism. Our results show that CyA administration (25 mg/kg/day) for 45 days stimulates renin-angiotensin system with an increase in plasma renin activity. These changes are not accompanied by a parallel increase in the renal synthesis of vasodilatory prostaglandin E2 and prostacyclin as it occurs in other conditions of renin-angiotensin stimulation. At variance glomerular synthesis and urinary excretion of thromboxane A2 (TxA2) are increased progressively during CyA treatment. These changes in renal Tx precede the increase in serum creatinine and the decrease in GFR thus indicating that TxA2 might be an additional factor potentiating the effect of angiotensin II on glomerular hemodynamics. In conclusion the early reduction in GFR which follows daily administration of CyA in rats might be the result of a synergic action of angiotensin II and TxA2 on vascular tone and mesangial contraction which is not modulated by an increase in glomerular vasodilatory prostaglandins. If this explanation may be applied to early reduction in GFR observed in humans treated with CyA before tubular toxicity develops needs to be investigated further.
6-Ketoprostaglandin F1 alpha↗
Cyclosporin-induced endothelial cell injury.
The administration of Cyclosporin-A (CyA) to animals and humans may induce an arteriolar damage. It has also been reported that CyA in some instances may cause an hemolytic uremic-like syndrome. This is a syndrome of vascular damage with thrombotic occlusions of the microcirculation. Endothelial injury is considered the first event in the pathogenetic cascade leading to hemolytic-uremic syndrome. We have used bovine aortic endothelial cells in culture to address the issue of CyA-induced arteriolar damage. Exposure of endothelial cells to different concentrations of CyA induced a time- and dose-dependent cell injury in vitro. The damage induced by CyA was characterized by an early cell detachment from culture substrate followed by cell lysis as documented by the increase in lactate dehydrogenase (LDH) and 51Cr release. Both detachment and lysis were negligible after short-term incubation of 1 microM CyA with endothelial cells. One micromolar CyA only induced lysis if incubations were prolonged above 6 hours. Ten and 50 microM CyA both induced marked endothelial cell detachment and lysis; lysis started 3 hours after incubation of endothelial cells with CyA and was maximal at the end of 24 hours incubation. CyA-induced injury was associated with dose- and time-dependent increase in prostacyclin and thromboxane A2 release by endothelial cells exposed to CyA independently from the concentrations of CyA used. CyA-induced generation of prostacyclin and thromboxane A2 was inhibited when the incubations were performed in the presence of aspirin (500 microM). These studies indicate that CyA exerts a direct cytotoxic effect on endothelial cells and might help in understanding the pathogenesis of CyA-induced vascular damage.
Animals↗
Lack of synergism between dazoxiben and dipyridamole following administration to man.
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6-Ketoprostaglandin F1 alpha↗
Low-protein diet prevents glomerular damage in adriamycin-treated rats.
Adriamycin (ADR) induces glomerular damage in rats with persistent proteinuria which develops 13 to 15 days after a single intravenous (i.v.) injection (5 mg/kg). Electron microscopy (EM) shows alterations of glomerular visceral epithelial cells with foot process fusions. The disease resembles minimal change nephropathy in humans. We studied the effect of two isocaloric diets with different protein content on urinary protein excretion, renal function, and glomerular morphology in rats treated with ADR. Six groups of rats were used. Group 1 received a single i.v. injection of ADR and was fed a standard diet containing 20% protein. Group 2 was fed a low-protein diet containing 6% protein starting 7 days before ADR. Group 3 was fed a low-protein diet starting the day after ADR. Group 4 served as control. Two additional groups of rats (5 and 6) were used to study the kidney distribution of ADR. Unlike animals fed the standard diet, animals fed the low-protein diet did not develop proteinuria. The kidney distribution of ADR measured at different intervals after drug injection was not influenced by the diet. Renal function as determined by glomerular filtration rate (GFR) and renal plasma flow (RPF) was not significantly modified in nephrotic rats receiving the standard diet compared to control animals. The low-protein regimen induced a significant elevation in RPF compared to the standard diet, but had no influence on GFR. Light and transmission EM studies showed alterations of glomerular visceral epithelial cells with fusion of foot processes in rats fed the standard diet, whereas no significant abnormalities of glomerular epithelial cells were detectable in animals receiving the low-protein diet.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Partial isolation and function of the prostacyclin regulating plasma factor.
Rat aortic rings stop producing prostacyclin upon prolonged washing in buffer. This 'exhaustion' is caused by inhibition of cyclo-oxygenase, since these rings still convert cyclic endoperoxides but not arachidonic acid into prostacyclin, and most probably is due to high concentrations of peroxides: it can be accelerated by H2O2 or by interrupting the glutathione cycle, while it is delayed by reduced glutathione. Incubation of exhausted rings in human plasma or in a plasma filtrate restores to some extent prostacyclin formation. This filtrate, in particular from uraemic subjects, also inhibits the H2O2 initiated oxidation of guaiacol by ram seminal vesicle microsomes or horseradish peroxidase. The prostacyclin regulating plasma factor has been partially purified and identified as a stable and very polar molecule of mol. wt. 300-400, able to reactivate prostacyclin generation by exhausted rings. We suggest that one or more low mol. wt. plasma components prolong vascular prostacyclin formation by acting as reducing cofactor for cyclo-oxygenase peroxidase. The main physiological role of this plasma activity is probably to protect the vascular prostacyclin forming system from exhaustion during persistent irritation.
6-Ketoprostaglandin F1 alpha↗
Dipyridamole inhibits platelet aggregation in whole blood.
Dipyridamole possesses antithrombotic properties in the animal and in man but it does not inhibit platelet aggregation in plasma. We evaluated the effect of dipyridamole ex vivo and in vitro on platelet aggregation induced by collagen and adenosine-5'-diphosphate (ADP) in human whole blood with an impedance aggregometer. Two hundred mg dipyridamole induced a significant inhibition of both ADP- and collagen-induced aggregation in human blood samples taken 2 hr after oral drug intake. Administration of the drug for four days, 400 mg/day, further increased the antiplatelet effect. A significant negative correlation was found between collagen-induced platelet aggregation in whole blood and dipyridamole levels in plasma (p less than 0.001). A statistically significant inhibition of both collagen (p less than 0.0025) and ADP-induced (p less than 0.005) platelet aggregation was also obtained by incubating whole blood in vitro for 2 min at 37 degrees C with dipyridamole (3.9 microM). No such effects were seen in platelet-rich plasma, even after enrichment with leukocytes. Low-dose adenosine enhanced in vitro inhibition in whole blood. Our results demonstrate that dipyridamole impedes platelet aggregation in whole blood by an interaction with red blood cells, probably involving adenosine.
Adenosine↗
Plasmatic regulation of vascular prostacyclin in pregnancy.
Activity of prostacyclin-stimulating factor was measured in six normal, non-pregnant women, six women in early normal pregnancy, six in late normal pregnancy, and six in late pregnancy complicated by severe pre-eclampsia. The activity was lower in the women in late pregnancy than in those in early pregnancy and the controls but was about normal in those with severe pre-eclampsia. These results may be relevant to the physiology of pregnancy and the pathogenesis of pre-eclampsia.
Adolescent↗
Reduced umbilical and placental vascular prostacyclin in severe pre-eclampsia.
Prostacyclin production was significantly depressed in foetal and placental vascular tissues from five patients with severe pre-eclampsia in comparison to vascular tissues from women with uncomplicated pregnancy. Such an abnormality may be responsible for a reduced blood flow and defective fetal nutrition thus playing a major role in the pathogenesis of this syndrome.
Adolescent↗
Angiotensin II blockade limits tubular protein overreabsorption and the consequent upregulation of endothelin 1 gene in experimental membranous nephropathy.
Proteinuric renal diseases are associated with excessive renal synthesis of endothelin 1 (ET-1) either in experimental animals or humans. This has been interpreted as an upregulation of ET-1 gene in proximal tubular cells secondary to overreabsorption of an unusual amount of filtered proteins. Here we used a model of chronic proteinuria, passive Heymann nephritis (PHN), to localize the structure of the kidney responsible for excessive ET-1 expression and synthesis and to clarify whether drugs that reduce glomerular protein trafficking modified the distribution of ET-1 mRNA and the corresponding peptide in the kidney. PHN was induced in Sprague-Dawley rats after injection of rabbit anti-Fx1A antibody. Group 1 (n = 5) was untreated, group 2 (n = 5) was given daily the angiotensin-converting enzyme inhibitor lisinopril (40 mg/l) plus the angiotensin II receptor antagonist L-158,809 (50 mg/l) from day 7--when rats were already proteinuric--to month 12. An additional group of normal rats (n = 5) was used as controls. Urinary excretion of ET-1 was significantly increased in PHN rats as compared with controls and normalized by the treatment. By in situ hybridization a weak signal for ET-1 mRNA was detectable in glomeruli, distal tubular segments, and proximal tubules of control kidneys. By contrast, a strong labeling was found in the kidneys of rats with PHN which was mainly localized to proximal tubules and renal interstitium. The pattern of renal ET-1-like immunoreactivity was remarkably consistent with ET-1 mRNA expression. In animals with PHN given the angiotensin II blocking therapy, the urinary excretion of proteins normalized, and the structural integrity of the kidney was well preserved. In the kidney tissue taken from these animals, both ET-1 mRNA and protein staining were quite comparable to controls. These data suggest a link between excessive protein tubular reabsorption and enhanced renal ET-1 in chronic nephropathies and provide a novel explanation for the renoprotective effect in vivo of drugs that, by blocking the biological activity of angiotensin II, reduce glomerular protein traffic and possible deleterious effects of excessive tubular protein overloading.
Angiotensin II↗
Protein overload activates proximal tubular cells to release vasoactive and inflammatory mediators.
Chronic renal diseases with highly enhanced glomerular permeability to proteins are accompanied by tubulointerstitial inflammation and scarring and progression to renal failure. As a consequence of increased glomerular permeability, proteins filtered through the glomerular capillary in excessive amount have intrinsic renal toxicity at least partially linked to their accumulation in the proximal tubular cell cytoplasm during the process of reabsorption along the nephron. Experimental evidence is available showing that protein overload per se activates proximal tubular epithelial cells in culture to upregulate genes encoding for endothelin, chemokines and cytokines. These vasoactive and inflammatory substances, formed in excessive quantities by the tubular cells, are released mainly into the basolateral compartment, a pattern of secretion that in the kidney would favor recruitment and activation of inflammatory cells into the renal interstitium and fibrogenic reaction leading to renal scarring.
Absorption↗
Interleukin-1 and glomerular mesangial cells.
Our previous in vitro study demonstrated that interleukin-1 (IL-1) stimulates gene expression and production of leukocyte chemotactic factors, colony-stimulating factors and interleukin-6 in human mesangial cells in culture. Here we investigated whether IL-1 regulates its own gene expression in human mesangial cells. Northern blot experiments showed that IL-1 induced IL-1 mRNA expression in a dose-dependent manner. The action of IL-1 on mesangial cells was mediated through the IL-1 receptor type I, which is constitutively expressed by mesangial cells. Recombinant IL-1 receptor antagonist blocked the IL-1 mRNA as well as interleukin-6 and interleukin-8 gene expression induced by IL-1. These data support the crucial role played by IL-1 in regulating mesangial cell cytokine genes within the glomerulus during immunological or inflammatory processes.
Blotting, Northern↗
Reduced fibrinolytic activity in glomeruli isolated from rabbits infused with tumor necrosis factor.
Glomerular fibrin deposition may result from local activation of blood coagulation and/or impaired removal by the fibrinolytic system. We evaluated the fibrinolytic activity of glomeruli isolated from rabbits infused for 5 h with tumor necrosis factor (TNF) at the doses of 0.8 micrograms/kg/h (n = 5) and 8 micrograms/kg/h (n = 3) or with endotoxin (8 micrograms/kg/h, n = 7). Animals infused with vehicle (n = 11) served as control group. Plasminogen activator (PA) activity of glomerular extracts from rabbits infused with 8 micrograms/kg/h of TNF or endotoxin was significantly lower than that of samples from control animals (p = 0.013 and p = 0.003, respectively). At the dose of 0.8 micrograms/kg/h, TNF caused a reduction in glomerular PA activity which, however, did not reach statistical significance. Neither plasminogen-independent activity nor PA inhibitor activity was detected in glomerular extracts. Fibrin autography of control extracts revealed the presence of two main fibrinolytic activities comigrating with purified urokinase-type and tissue-type PAs. In treated samples, the bands corresponding to free PAs were markedly reduced, with no evidence of enzyme-inhibitor complex formation. Local reduction of fibrinolytic capacity may contribute to intraglomerular fibrin deposition during endotoxemia or in renal inflammatory diseases associated with TNF production.
Animals↗
The role of the endothelium in hemolytic uremic syndrome.
Hemolytic uremic syndrome (HUS), which is the most common cause of acute renal failure in children, is caused by Shiga toxin-producing Escherichia coli infection. This infection leads to renal and other organ microvascular thrombosis. Endothelial injury has been recognized as the trigger event in the development of microangiopathic process. Evidence suggests that leukocyte as well as platelet activation participate in endothelial damage. Intrinsic abnormalities of the complement system may also play a role in HUS.
Complement System Proteins↗