Mechanism of increased renal prostaglandin E2 in uranyl nitrate-induced acute renal failure

We have previously demonstrated that decreased cortical prostaglandin metabolism can contribute significantly to an increase in renal tissue levels and activity of prostaglandin E₂ in bilateral ureteral obstruction, a model of acute renal failure. In the present study, we have further investigated whether alterations in prostaglandin metabolism can occur in a nephrotoxic model of acute renal failure. Prostaglandin synthesis, prostaglandin E₂ metabolism (measured as both prostaglandin E₂-9-ketoreductase and prostaglandin E₂-15-hydroxydehydrogenase activity), and tissue concentration of prostaglandin E₂ were determined in rabbit kidneys following an intravenous administration of uranyl nitrate (5 mg/kg). No changes in the rates of cortical microsomal prostaglandin E₂ and prostaglandin F_2α synthesis were noted at the end of 1 and 3 days, while medullary synthesis of prostaglandin E₂ fell by 47% after 1 day and 43% after 3 days. Cortical cytosolic prostaglandin E₂-9-ketoreductase activity was found to be decreased by 36% and 76% after 1 and 3 days respectively. No significant changes were noted in cortical cytosolic prostaglandin E₂-15-hydroxydehydrogenase activity after 3 days. Cortical tissue levels of prostaglandin E₂ increased by 500% at the end of 3 days. These data demonstrate that in nephrotoxic acute renal failure, decreased prostaglandin metabolism (i.e., prostaglandin E₂-9-ketoreductase activity) can result in increased tissue levels of prostaglandin E₂ in the absence of increased prostaglandin synthesis and suggest that alterations in prostaglandin metabolism may be an important regulator of prostaglandin activity in acute renal failure.     

Inhibition of renal PGE2-9-ketoreductase by diuretics

The metabolism of PGE₂ by extracts of renal cortex is species dependent. In the rat PGE₂-15-hydroxydehydrogenase initiates metabolism whereas in the rabbit PGE₂-9-ketoreductase predominates. In man both mechanisms may operate. Each of the metabolic enzymes, which limits the vasodilator-diuretic actions of PGE₂, was inhibited by ethacrynic acid, furosemide and indomethacin. Some inhibition of PGE₂-9-ketoreductase was also observed with chlorthalidone, hydralazine and phentolamine but the thiazide diuretics and a number of other cardiovascular-active agents were without significant effect. We conclude that the inhibition of PGE₂-9-ketoreductase and PGE₂-15-hydroxydehydrogenase could contribute to the mechanism of action of the non-thiazide diuretics in man.     

The effect of sodium intake on renal prostaglandin production

The effect of chronic alterations in dietary sodium intake on renal arachidonic acid (AA) metabolism was studied in male Wistar rats who were maintained for 14 days on a diet consisting of sodium-deficient food and either deionized water (low salt intake, LSI), 1% saline (normal salt intake, NSI), or 2% saline (high salt intake, HSI). 24 h Urinary Sodium (UNaV) and plasma renin activity (PRA) measurements were shown to validate the dietary protocol. Microsomal preparations from the cortices and medullae were incubated with radiolabeled exogenous AA, and endogenous urinary prostaglandin (PG) levels were assayed by RIA to quantify renal PG synthesis. Cortical PGF2 alpha and PGE2 synthesis was found to be the greatest following LSI. In contrast, medullary PGF2 alpha was shown to be the least following LSI and to increase with increased sodium intake. Likewise, urinary PGF2 alpha levels significantly increased with increasing sodium intake. Changes in urinary PGE2 levels showed the same trend as PGF2 alpha but did not achieve statistical significance. These data show that dietary sodium differentially affects renal cortical and medullary PG synthesis and may reflect physiological differences in the regulation of cyclooxygenase in these zones. These data further suggest that the major source of urinary PGs is the renal medulla since the relationship of urinary levels to sodium intake mimics that described for the synthesis of PGs by the medullary tissue.     

Effects of gonadectomy and steroid treatment on renal prostaglandin 9-ketoreductase activity in the rat

The effect of gonadectomy and treatment with sex-steroids on renal prostaglandin 9-ketoreductase activity in 10-11 week old male and female rats was determined. Rats were gonadectomized or subjected to sham operation at 3 weeks of age. During week 7, rats were injected s.c. twice over a 6-day interval with vehicle (peanut oil, 0.5 ml X kg-1) or with depot forms of testosterone (5 mg X kg-1), estradiol (0.02 mg X kg-1), progesterone (5 mg X kg-1), or estradiol and progesterone combined. Renal prostaglandin 9-ketoreductase activity was about 50% higher in female rats than in males. Gonadectomy decreased 9-ketoreductase activity in females, but not in males, and eliminated the gender difference in enzyme activity. Treatment with estradiol elevated 9-ketoreductase activity in males and females, while treatment with testosterone or progesterone was without effect. Progesterone did, however, antagonize the elevation in 9-ketoreductase activity produced by estradiol.     

Dissociation of hyperreninemia and renal prostaglandin synthesis in the adrenalectomized rat

The aim of this study was to determine whether hyperreninemia in the adrenalectomized (ADX) rat is dependent on renal prostaglandin synthesis, as has been suggested for two other hyperreninemic conditions, Bartter's syndrome and chronic liver disease. Plasma renin concentration (PRC) in anesthetized, ADX rats was significantly increased (delta +480%; p less than 0.001) compared to sham-operated controls. In vivo, indomethacin (10 mg/kg i.v.) significantly reduced PRC of anesthetized, ADX rats after both 45 min (delta -34%; p less than 0.05) and 90 min (delta -47%; p less than 0.05). In vitro renin release from renal cortical slices of ADX rats was also significantly greater (delta +130%; p less than 0.05) than from sham-operated control cortical slices. Renin release from cortical slices of ADX rats given dexamethasone (10 micrograms/kg/day) for 4 days prior to sacrifice did not differ from sham-operated control values. Prostaglandin E2 (PGE2) release from cortical slices of ADX rats did not differ significantly from controls. However, PGE2 synthesis in glomeruli microdissected from ADX rats was significantly increased (delta +110%; p less than 0.001) compared to controls. PGE2 synthesis in glomeruli of dexamethasone-treated ADX rats remained significantly elevated compared to controls. Ibuprofen (10(-6) M) decreased PGE2 synthesis in cortical slices by 80%. However, prostaglandin synthesis inhibition had no effect on renin release from either ADX or control renal cortical slices. These results suggest that despite increased glomerular synthesis, prostaglandins do not directly influence renin release in the ADX rat.     

Metabolism of prostaglandin E1 and of glutathione conjugate of prostaglandin A1 (GSH-prostaglandin A1) by prostaglandin 9-ketoreductase from rabbit kidney.

Rabbit kidney prostaglandin 9-ketoreductase was found to metabolize the glutathione conjugate of prostaglandin A1 (GSH-prostaglandin A1). Apparent Km (GSH-prostaglandin A1) 13 microM and apparent Km (prostaglandin E1) 200 microM. The cytosolic preparation was subjected to gelfiltration and isoelectric focusing, which revealed that metabolism of prostaglandin E1 and GSH-prostaglandin A1 occurs by means of the same fractions. Furthermore, prostaglandin E1 and GSH-prostaglandin A1 are competitive inhibitors of the enzyme, when GSH-prostaglandin A1 and prostaglandin E1 are tested as substrates, respectively. It si concluded, that GSH-prostaglandin A1 is a much better substrate for prostaglandin 9-ketoreductase from rabbit kidney than is prostaglandin E1.     

Dual effects of bradykinin on prostaglandin metabolism: Relationship to the dissimilar vascular actions of kinins

Generation of a prostaglandin of the F series by bovine mesenteric veins in response to bradykinin may depend on increased synthesis of PGE and conversion of the latter to PGF after activation of PGE 9-ketoreductase by the kinin. The prostaglandin then mediates the constrictor action of bradykinin on the bovine mesenteric vein. A high speed supernatant (HSS) fraction of bovine mesenteric blood vessels contains the highest activity of PGE 9-ketoreductase. Incubation of PGE₂ with HSS at 37°C in the presence of a NADPH generating system resulted in time-dependent conversion of PGE₂ to PGF_2α. Bradykinin (0.01mM) more than doubled conversion of PGE₂ to PGF_2α by the PGE 9-ketoreductase obtained from mesenteric veins whereas the kinin had little effect on enzymic activity of the HSS fraction of mesenteric arteries. However, after inhibition of kininase catabolism, bradykinin increased PGE 9-ketoreductase activity of arteries and veins to the same degree.Prostaglandin release from veins by bradykinin appears essential to contraction of mesenteric venous strips evoked by the polypeptide as indomethacin treatment abolished this effect. PGE 9-ketoreductase may be an important prostaglandin regulatory mechanism of the vascular wall whereby the functional consequences of changes in rates of prostaglandin synthesis are governed by determining the ratio of PGE to PGF within vascular tissue. Constriction of bovine mesenteric veins evoked by bradykinin may, therefore, depend on increased prostaglandin synthesis and conversion of newly formed PGE to PGF, both steps being affected by the kinin.     

Ovarian and uterine prostaglandin E2-9-ketoreductase activity in cyclic and pregnant ewes.

The regulation of luteal function in sheep appears to be dependent in part upon relative utero-ovarian concentrations of PGE2 and PGF2 alpha. Prostaglandin E2-9-ketoreductase converts PGE2 (a putative antiluteolysin) to PGF2 alpha. Enzymatic activity was measured in a cytosolic subcellular fraction of luteal and endometrial tissues collected on days 10, 13 and 16 of the estrous cycle or pregnancy. Respective days represented times before, during, and after the critical period for maternal recognition of pregnancy. Preparations of enzyme were incubated in the presence of tritiated PGE2. Radiolabeled PGF2 alpha (ie., product) was separated from PGE2 by gel filtration chromatography and quantified by liquid scintillation spectrometry. There were no significant differences due to time of tissue collection or pregnancy status in enzymatic activity of luteal tissues. Prostaglandin E2-9-ketoreductase activity isolated from endometria of open ewes was greater than their pregnant counterparts on days 13 and 16. Thus, the potential capacity of the ovine uterus to generate luteolytic PGF2 alpha from PGE2 substrate is elevated during an infertile estrous cycle.     

Studies on prostaglandin metabolism in corpora lutea of rabbits during pregnancy and pseudopregnancy

Corpora lutea and ovarian stromal tissue were analysed for prostaglandin (PG) concentrations and activities of enzymes involved in PG metabolism at 8, 10, 12, 13 and 15 days after induction of ovulation. In CL of pseudopregnant rabbits, the PGE-2-9-ketoreductase (PGE-2-9-KR) was highly active on Days 10, 12 and 15 when compared with Day 8 (P less than 0.01; P less than 0.001; P less than 0.05). In pregnant animals PGE-2-9-KR activity was only increased on Day 12 (P less than 0.05) but declined to basal levels on Days 13 and 15. Comparing PGE-2-9-KR activity of pseudopregnant and pregnant animals, a significant elevation was found on Day 15 of pseudopregnancy (P less than 0.025). Activities of PG-15-hydroxydehydrogenase did not exhibit any significant changes with time in pseudopregnant or pregnant rabbits. PGE-2 concentrations were increased on Days 12, 13 and 15 (P less than 0.025) when compared with Day 8. Changes in PGF-2 alpha concentrations paralleled those of PGE-2-9-KR. The concentrations of PG metabolites 13,14-dihydro-15-keto-PGE-2 and -PGF-2 alpha were lower than those of the primary PGs and did not show stage-specific changes in pseudopregnant and pregnant animals. These results demonstrate that the rabbit CL possesses enzymes to convert PGE-2 to PGF-2 alpha and to metabolize both PGs. PGE-2-9-KR may be involved in regulating the PGF-2 alpha/PGE-2 ratio and possibly in controlling the life-span of the corpus luteum.     

Selective stimulation of venous prostaglandin E 9-ketoreductase by bradykinin.

The effects of bradykin on prostaglandin metabolism in canine mesenteric vessels were examined. Bradykinin stimulated microsomal prostaglandin synthesis in both artery and vein; this stimulation was more pronounced when [14C] hosphatidylcholine rather than [14C] arachidonate was used as the substrate for prostaglandin synthetase. This suggested that bradykinin enhanced a membrane phospholipase. In addition, bradykinin selectively stimulated prostaglandin E 9-ketoreductase activity from veins but not arteries. This may explain the finding that bradykinin induces the release of prostaglandin E compounds from arteries but prostaglandin F compounds from veins.     

The role of renal metabolism of PGE2 in determining its activity as a renal vasodilator in the dog.

Since the mammalian renal cortex avidly metabolizes prostaglandin E2 (PGE2), we examined the importance of renal metabolism of PGE2 in determining its renal vascular activity in the dog. We used 13, 14 dihydro PGE2 (DHPGE2) as a model compound to study this because DHPGE2 retains similar activity to the parent prostaglandin, PGE2, but is a poorer substrate than PGE2 for both the metabolism and the cellular uptake of the prostaglandins. Using dog renal cortical slices, we found that under similar experimental conditions, PGE2 was metabolized several-fold faster than DHPGE2. Both prostaglandins were metabolized to the 15 keto 13, 14 dihydro PGE2, which was positively identified using GC-MS. In vivo, we infused increasing concentrations of DHPGE2 into the renal artery of dogs and measured renal hemodynamic changes using radioactive microspheres. DHPGE2 was a potent renal vasodilator beginning at an infusion rate of 10(-9)g/kg/min. When compared to PGE2, DHPGE2 was about 10 times more potent in affecting renal vasodilation. The intrarenal redistribution of blood flow towards the inner cortex seen with DHPGE2 was identical to that seen with PGE2. We conclude that renal catabolism of PGE2 is very important in limiting the in vivo biological activity of PGE2, but regional differences in metabolism of PGE2 within the cortex are an unlikely determinant of the pattern of redistribution of renal blood flow.     

Altered glomerular eicosanoid biosynthesis in uranyl nitrate-induced acute renal failure

The present studies were designed (1) to examine the pattern of changes in eicosanoid biosynthesis in isolated rat glomeruli, and (2) to correlate these changes with the previously observed alterations in renal perfusion and glomerular filtration rate which occur after uranyl nitrate administration, a model of toxin-induced acute renal failure. In the first part of this study, the in vitro and the in vivo effects of two cyclooxygenase inhibitors were examined for their ability to inhibit rat glomerular eicosanoid biosynthesis. Inhibition of prostaglandin E2 and prostaglandin F2 alpha generation by 1 mM aspirin in vitro was 76 and 82%, respectively. Similar inhibitions of 85 and 72% of biosynthesis of the above-mentioned lipids by 0.1 mM indomethacin were also noted. Intraperitoneal administration of aspirin (150 mg/kg) resulted in a significant inhibition of 88% or greater of prostaglandin E2, prostaglandin F2 alpha, 6-keto-prostaglandin F2 alpha, and thromboxane B2 biosynthesis. These results indicated that the expected alterations produced under in vivo conditions were detectable by in vitro techniques used in this study. 24 h after the administration of uranyl nitrate (25 mg/kg), significant increases in the biosynthesis of prostaglandin E2 (124%) and prostaglandin F2 alpha (88%) were observed when compared to the control values. No significant changes in prostacyclin or thromboxane formation were noted at this time. A further increase in the biosynthesis of prostaglandin E2 (248%), prostaglandin F2 alpha (262%), and a significant increase in prostacyclin (120%), measured as 6-keto-prostaglandin F1 alpha, were noted at 48 h. No changes in thromboxane B2 biosynthesis were noted. It is concluded that these data are consistent with the hypothesis that the increased glomerular biosynthesis of vasodilator eicosanoids (i.e., prostaglandin E2 and prostacyclin) may play a significant role in the homeostatic regulation of renal perfusion and glomerular filtration after acute toxic injury to the kidney.     

Selective stimulation of venous prostaglandin E 9-ketoreductase by bradykinin

The effects of bradykin on prostaglandin metabolism in canine mesenteric vessels were examined. Bradykinin stimulated microsomal prostaglandin synthesis in both artery and vein; this stimulation was more pronounced when [¹⁴C]phosphatidylcholine rather than [¹⁴C]arachidonate was used as the substrate for prostaglandin synthetase. This suggested that bradykinin enhanced a membrane phospholipase. In addition, bradykinin selectively stimulated prostaglandin E 9-ketoreductase activity from veins but not arteries. This may explain the finding that bradykinin induces the release of prostaglandin E compounds from arteries but prostaglandin F compounds from veins.     

Studies on the mechanism of non-oliguric experimental acute renal failure.

Although acute renal failure, caused either by renal ischemia or nephrotoxic agents, is usually characterized by oliguria, a severe fall in glomerular filtration rate, and a fall in renal blood flow, some patients and experimental models display a non-oliguric pattern of renal injury. The present study was designed to evaluate the mechanism of preservation of high urinary flow rate under this condition. Following the administration of the aminoglycoside gentamicin to rats for five days, a decrease in concentrating ability was demonstrated, caused by impaired vasopressin-mediated water transport. Further treatment resulted in a fall in Cin to 15 percent of control, although RBF was reduced to only 67 percent of control, and urine flow rate rose above control levels. Induction of acute and renal failure with dichromate was associated with variable high or low urinary flow rates according to pre-injury intake of sodium. Urine volume correlated directly with cortical blood flow. These data suggest that the non-oliguric pattern of acute renal injury is caused by preservation of cortical perfusion in the setting of severe tubular injury.     

Regional decreases in renal oxygenation during graded acute renal arterial stenosis: a case for renal ischemia

Ischemic nephropathy describes progressive renal failure, defined by significantly reduced glomerular filtration rate, and may be due to renal artery stenosis (RAS), a narrowing of the renal artery. It is unclear whether ischemia is present during RAS since a decrease in renal blood flow (RBF), O(2) delivery, and O(2) consumption occurs. The present study tests the hypothesis that despite proportional changes in whole kidney O(2) delivery and consumption, acute progressive RAS leads to decreases in regional renal tissue O(2). Unilateral acute RAS was induced in eight pigs with an extravascular cuff. RBF was measured with an ultrasound flow probe. Cortical and medullary tissue oxygen (P(t(O(2)))) of the stenotic kidney was measured continuously with sensors during baseline, three sequentially graded decreases in RBF, and recovery. O(2) consumption decreased proportionally to O(2) delivery during the graded stenosis (19 +/- 10.8, 48.2 +/- 9.1, 58.9 +/- 4.7 vs. 15.1 +/- 5, 35.4 +/- 3.5, 57 +/- 2.3%, respectively) while arterial venous O(2) differences were unchanged. Acute RAS produced a sharp reduction in O(2) efficiency for sodium reabsorption (P < 0.01). Cortical (P(t(O(2)))) decreases are exceeded by medullary decreases during stenosis (34.8 +/- 1.3%). Decreases in tissue oxygenation, more pronounced in the medulla than the cortex, occur despite proportional reductions in O(2) delivery and consumption. This demonstrates for the first time that hypoxia is present in the early stages of RAS and suggests a role for hypoxia in the pathophysiology of this disease. Furthermore, the notion that arteriovenous shunting and increased stoichiometric energy requirements are potential contributors toward ensuing hypoxia with graded and progressive acute RAS cannot be excluded.     

Urinary prostaglandin E2 excretion in renal allotransplantation in man

The urinary prostaglandin E₂ excretion was measured daily for 28 days in 15 patients (10 men and 5 women) after renal allotransplantation. Patients with acute oliguric renal failure immediately after the transplantation showed high urinary PGE₂ concentrations, but no or minimal increase in the total excretion rates. The median PGE₂ excretion was 211 μg/24 h after establishment of stable renal function, but with great individual variations. Rejection crises were characterized by a two-fold increase in PGE₂ excretion, with a subsequent fall induced by the steroid treatment. The PGE₂ excretion correlated better with urinary sodium excretion than diuresis.The pathophysiological role of the renal prostaglandin ssynthesis remains incompletely defined. The prostaglandin E₂ (PGE₂) appears to act as a modulator of the renal salt and water excretion (1,2) and prostaglandins are important mediators of the immunresponses (3,4). The eraly renal allograft rejection is an event characterized by salt and water retention together with decreasing renal function (5). Antibodies against renal tissue as well as cytotoxic leukocytes (“killer cells”) are active in the process (6,7) and many hormonal systems are involved, among them renin and vasopressin (8). Both hormones are known to stimulate the synthesis of prostaglandin in the kidneys and interact with its effect (9,10,11). The present material was therefore designed to study the urinary excretion of PGE₂ in the kidney allografts before and during rejection crises.     

Effect of the beta-receptor blocker pindolol on survival in HgCl2 induced acute renal failure in dogs

The effect of the beta receptor blocker pindolol on survival was investigated in HgCl2 intoxicated dogs. A single injection of 100 microgram/kg b.w. pindolol intravenously (i.v.) caused a significant rise in urinary sodium excretion and a significant decrease of plasma renin activity (PRA) and urinary norepinephrine (NE) and epinephrine (E) excretion in control dogs. A single injection of 3 mg/kg HgCl2 i.v. resulted in death of the animals within 3-5 days. Pretreatment with the above dose of pindolol increased length of survival 4-8 days, two dogs recovering from acute renal failure (ARF). The degree of azotemia was smaller in the pretreated group than in the control dogs given HgCl2 only. Pindolol prevented the HgCl2 induced marked increases of urinary catecholamine excretion and PRA. These findings support the hypothesis that increased activity of the sympathetic nervous system is involved in the pathomechanism of the nephrotoxic model of ARF. Pindolol pretreatment decreases the severity of ARF though it can not prevent it.     

Interleukin-1 beta and transforming growth factor-beta 2 enhance cytosolic high-molecular-mass phospholipase A2 activity and induce prostaglandin E2 formation in rat mesangial cells.

Interleukin-1 beta induces gene expression and secretion of group-II phospholipase A2 and release of prostaglandin E2 from rat mesangial cells. The interleukin-1 beta-induced synthesis of group-II phospholipase A2 is prevented by transforming growth factor-beta 2, whereas transforming growth factor-beta 2 potentiated the interleukin-1 beta-evoked prostaglandin E2 production. Transforming growth factor-beta 2 itself did not induce synthesis of group-II phospholipase A2, although it stimulated prostaglandin E2 formation. Here we describe the effect of interleukin-1 beta and transforming growth factor-beta 2 on a cytosolic phospholipase A2 activity and prostaglandin E2 formation in rat mesangial cells. Based on the resistance to dithiothreitol and migration profiles on a Mono-Q anion-exchange column and a Superose 12 gel-filtration column, the cytosolic phospholipase A2 activity was assigned to a high-molecular-mass phospholipase A2. Measured with 1-stearoyl-2-[1-14C]arachidonoylglycero-phosphocholine as substrate, both interleukin-1 beta and transforming growth factor-beta 2 enhanced the high-molecular-mass phospholipase A2 activity. The stimulation of rat mesangial cells with interleukin-1 beta and transforming growth factor-beta 2 was time- and dose-dependent with maximal cytosolic phospholipase A2 activities at 10 nM and at 10 ng/ml respectively, after 24 h of stimulation. Under these conditions, interleukin-1 beta and transforming growth factor-beta 2 enhanced the cytosolic phospholipase A2 activity 2.2 +/- 0.6-fold and 2.5 +/- 0.6-fold, respectively. These results strongly suggest that an enhanced cytosolic high-molecular-mass phospholipase A2 activity is involved in the formation of prostaglandin E2 mediated by transforming growth factor-beta 2. Whether interleukin-1 beta induced group-II phospholipase A2 and/or interleukin-1 beta-enhanced cytosolic phospholipase A2 activity is involved in prostaglandin E2 formation in rat mesangial cells is discussed.     

Quinacrine antagonizes the effects of Na,K-ATPase inhibitors on renal prostaglandin E2 release but not their effects on renin secretion

Previous results have demonstrated that two inhibitors of Na-and-K-activated adenosine triphosphatase (ouabain, vanadate) lead to stimulated prostaglandin E2 release and to inhibited renin secretion in the rat renal cortical slice preparation. It was speculated that stimulation of phospholipase A2 activity accounted for the effect on prostaglandin E2 release. We used the same preparation in the present experiments, and showed that another inhibitor of Na-and-K-activated adenosine triphosphatase (K-free incubation medium) stimulates prostaglandin E2 release and inhibits renin secretion. Quinacrine antagonized the stimulatory effects of ouabain, vanadate, and K-free medium on prostaglandin E2 release (consistent with phospholipase A2 involvement), but did not antagonize their inhibitory effects on renin secretion. Collectively, these observations lend further weight to the argument against a mediatory role of prostaglandin synthesis in the renin secretory process.     

Dissociation of hyperreninemia and renal prostaglandin synthesis in the adrenalectomized rat

The aim of this study was to determine whether hyperreninemia in the adrenalectomized (ADX) rat is dependent on renal prostaglandin synthesis, as has been suggested for two other hyperreninemic conditions, Bartter's syndrome and chronic liver disease.Plasma renin concentration (PRC) in anesthetized, ADX rats was significantly increased (Δ +480%; p < 0.001) compared to sham-operated controls. , indomethacin (10 mg/kg i.v.) significantly reduced PRC of anesthetized, ADX rats after both 45 min (Δ −34%; p < 0.05) and 90 min (Δ −47%; p < 0.05). renin release from renal cortical slices of ADX rats was also significantly greater (Δ +130%; p < 0.05) than from sham-operated control cortical slices. Renin release from cortical slices of ADX rats given dexamethasone (10 μg/kg/day) for 4 days prior to sacrifice did not differ from sham-operated control values.Prostaglandin E₂ (PGE₂) release from cortical slices of ADX rats did not differ significantly from controls. However, PGE₂ synthesis in glomeruli microdissected from ADX rats was significantly increased (Δ +110%; p < 0.001) compared to controls. PGE₂ synthesis in glomeruli of dexamethasone-treated ADX rats remained significantly elevated compared to controls. Ibuprofen (10⁻⁶ M) decreased PGE₂ synthesis in cortical slices by 80%. However, prostaglandin synthesis inhibition had no effect on renin release from either ADX or control renal cortical slices.These results suggest that despite increased glomerular synthesis, prostaglandins do not directly influence renin release in the ADX rat.