Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0920646 (renal ischemia)
 2,515 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

8-epi-prostaglandin F2 alpha (8-epi-PGF2 alpha) and related compounds are novel prostanoid produced by a noncyclooxygenase mechanism involving lipid peroxidation. Renal ischemia-reperfusion injury increased urinary excretion of these compounds by 300% over baseline level. Intrarenal arterial infusion at 0.5, 1, and 2 micrograms/kg per min induced dose-dependent reductions in glomerular filtration rate (GFR) and renal plasma flow, with renal function ceasing at the highest dose. Micropuncture measurements (0.5 microgram/kg per min) revealed a predominant increase in afferent resistance, resulting in a decrease in transcapillary hydraulic pressure difference, and leading to reductions in single nephron GFR and plasma flow. These changes were completely abolished or reversed by a TxA2 receptor antagonist, SQ 29,548. Competitive radioligand binding studies demonstrated that 8-epi-PGF2 alpha is a potent competitor for [3H]SQ 29,548 binding to rat renal arterial smooth muscle cells (RASM) in culture. Furthermore, addition of 8-epi-PGF2 alpha to RASM or isolated glomeruli was not associated with stimulation of arachidonate cyclooxygenase products. Therefore, 8-epi-PGF2 alpha is a potent preglomerular vasoconstrictor acting principally through TxA2 receptor activation. These findings may explain, in part, the beneficial effects of antioxidant therapy and TxA2 antagonism observed in numerous models of renal injury induced by lipid peroxidation.
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PMID:Glomerular actions of a free radical-generated novel prostaglandin, 8-epi-prostaglandin F2 alpha, in the rat. Evidence for interaction with thromboxane A2 receptors. 138 85

The effect of 48 hours of hypothermic renal ischemia utilizing Euro-Collins flush and short term reperfusion on renal prostaglandin synthesis was studied in dogs. Hypothermic ischemia followed by 60 minutes of reperfusion in-vivo resulted in significant elevations in renal Thromboxane B2 (TXB2) production in the outer cortex, inner cortex, and medulla, relative to non-ischemic kidneys. Prostaglandin E2 (PGE2) and 6-keto Prostaglandin F1 alpha (6-K PGF1 alpha) production were not significantly affected by ischemia and reperfusion. Enhanced TXB2 production was not seen with ischemia alone (without reperfusion) or with reperfusion with O2 saturated buffer, indicating a blood born source or stimuli. Early postreperfusion renal blood flow after hypothermic ischemia followed a biphasic pattern; blood flow increased for the first 10 minutes of reperfusion to achieve normal values, and then steadily declined over the next 20 minutes. This pattern was not altered by the cyclooxygenase inhibitors Idomethacin (5 mg/kg, P.O.) or Mefenamic acid (10 mg/kg, I.V.). Administration of the TXA2 synthesis inhibitor CGS-12970 (3 mg/kg, I.V.) or the TXA2/endoperoxide receptor antagonist SQ-29548 (80 micrograms/min, I.A.) significantly increased renal blood flow during reperfusion but neither agent altered the basic time dependent pattern observed in the control group. These data indicate that 48 hours of hypothermic renal ischemia results in dramatic changes in intrarenal TXA2 synthesis at the time of reperfusion. Enhanced TXA2 production is not dependent on reoxygenation per se, but rather requires reperfusion with blood suggesting a circulatory source.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Prostanoids and hypothermic renal preservation injury. 228 Nov 20

PGI2, or prostacyclin, and PGE2 are major derivatives of arachidonic acid. Arachidonic acid is converted by the cyclooxygenase enzyme to intermediate prostaglandin endoperoxides which are then enzymatically converted to PGI2 and PGE2 as well as to thromboxane A2 and PGF2 alpha. Aspirin and other nonsteroidal anti-inflammatory drugs inhibit the cyclooxygenase enzyme thereby reducing the amount of PGE2 and PGI2 produced. In the kidney, major stimuli of prostaglandin synthesis include vasoconstrictor hormones such as angiotensin II, vasopressin, endothelin and norepinephrine. Renal PGI2 and PGE2 synthesis is also increased after renal ischemia, immune injury to the kidney, and with renal parenchymal disease. Renal prostaglandin production also increases with severe arteriosclerotic cardiovascular disease, congestive heart failure, and severe hepatic disease. The increment of renal prostaglandin synthesis is important since PGI2 and PGE2 act as modulators of renal ischemia and vasoconstriction. The modulatory action leads to a negative feedback loop through which PGE2 and PGI2 and renal blood vessels in glomeruli reduce the vasoconstrictor action of the agonist, such as angiotensin II or norepinephrine. Nonsteroidal anti-inflammatory drugs can have nephrotoxic effects if they are used in clinical situations in which renal prostaglandin synthesis has increased compensatorily. In other words, the administration of indomethacin or other prostaglandin inhibitory drugs will reduce renal blood flow and glomerular filtration rate in patients with congestive heart failure, significant hepatic disease, or renal ischemia and vasoconstriction. PGI2 and PGE2 may have additional beneficial effects within the kidney in addition to being vasodilatory.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Prostaglandin I2 and the kidney. 251 64

1. Adenosine (ADO) can induce renal vasoconstriction and a fall in glomerular filtration rate. When the rate of ATP hydrolysis prevails over the rate of ATP synthesis the kidney generates ADO at an enhanced rate. 2. Tubuloglomerular feedback (TGF) is the vascular response to changes of the NaCl concentration in the tubular fluid at the macula densa segment, which is the result of transepithelial electrolyte reabsorption by the proximal tubule and the loop of Henle. 3. TGF can be inhibited by ADO-A1 receptor antagonists and is potentiated by substances that can elevate extracellular ADO concentrations. These observations led to the hypothesis that ADO is an element of the signal transmission processes in the juxtaglomerular apparatus. 4. Renal ischaemia and nephrotoxic substances can induce acute renal failure (ARF). ADO receptor antagonists have been shown to ameliorate renal function in several different models of ARF in laboratory animals and humans. 5. A number of factors, such as extracellular volume contraction, low NaCl diet, angiotensin II and cyclooxygenase inhibitors enhance to a similar extent: (a) the renal vascular response to endogenous and exogenous ADO; (b) the TGF response of the nephron; and (c) the severity of ARF. All three phenomena are susceptible to antagonism by ADO receptor antagonists. 6. Therefore, we conclude that ADO plays a significant role in normal and pathological states of kidney function.
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PMID:Role of adenosine in tubuloglomerular feedback and acute renal failure. 913 20

Non-opioid analgesics are some of the most widely used therapeutic agents in clinical practice today. The number of patients at risk for adverse events related to the use of these agents is rapidly expanding. While the gastrointestinal toxicity of these medications is well known, it has become increasingly apparent that the kidney is also an important target for untoward clinical events. Evidence of the nephrotoxicity of analgesic preparations is not sufficiently completed and available in our region. Analgesic-related renal injury has been classified based on mechanism of action into "classic" analgesic nephropathy and NSAID-related renal toxicity. From clinical point of view the renal side effects induced by analgesics can be classified into hemodynamic (functional) side effects and idiosyncratic side effects. The common link in both types of side effects seems to be renal ischemia related to prostaglandin synthesis inhibition. Key enzyme in this process is cyclooxygenase occurring in two isoforms: COX-1 and COX-2. Antiinflammatory effect of NSAIDs is mediated by COX-2 inhibition, while the side effects (gastrotoxicity, nephrotoxicity) by inhibition of COX-1. COX-1 was more inhibited by indomethacin and piroxicam and COX-2 by 6-MNA (active metabolite of nabumetone), diclofenac and ibuprofen. Nimesulide and meloxicam selectively block COX-2 and are recommended to patients at risk or treated with diuretics. (Tab. 2, Fig. 2, Ref. 38.)
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PMID:Renal damage induced by the treatment with non-opioid analgesics--theoretical assumption or clinical significance. 1115 63

The detrimental role of oxidative stress has been widely described in tissue damage caused by ischemia-reperfusion. A nonenzymatic, reactive oxygen species-related pathway has been suggested to produce 8-iso-prostaglandin F(2alpha) (8-iso-PGF(2alpha)), an epimer of prostaglandin F(2alpha) (PGF(2alpha)), which has been proposed as an indicator of oxidative stress. Using an in vivo ischemia-reperfusion model in rat kidneys, we investigated intrarenal accumulation of 8-iso-PGF(2alpha) and PGF(2alpha). Both prostanoids accumulated in the ischemic kidney and disappeared upon reperfusion. In addition, a nonselective (acetylsalicylic acid) or selective cyclooxygenase (COX) 1 inhibitor (SC-560) completely abrogated the 8-iso-PGF(2alpha) and PGF(2alpha) formation in kidneys subjected to ischemia. COX2 inhibition had no effect on the production of these prostanoids. Therefore the two metabolites of arachidonic acid seemed to be produced via an enzymatic COX1-dependent pathway. Neither COX overexpression nor COX activation was detected. We also investigated renal glutathione, which is considered to be the major thiol-disulfide redox buffer of the tissue. Total and oxidized glutathione was decreased during the ischemic period, whereas no further decrease was seen for up to 60 min of reperfusion. These data demonstrate that a dramatic decrease in antioxidant defense was initiated during warm renal ischemia, whereas the 8-iso-PGF(2alpha) was related only to arachidonate conversion by COX1.
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PMID:Cyclooxygenase 1-dependent production of F2-isoprostane and changes in redox status during warm renal ischemia-reperfusion. 1505 44

Renal ischaemia-reperfusion (I/R) injury is a clinically significant problem and an invariable consequence of renal transplantation. The problem begins at the onset of acute tubular necrosis (ATN), when the transplantation takes a long ischaemic interval by using the cardiac arrest donor's kidney. In addition, the longer the ischaemic interval, the higher the incidence rate of ATN. It is clinically important that renal I/R injury is reduced. The antisense oligodeoxynucleotide (AS-ODN), developed as a therapy for intractable diseases at the gene level, has recently been established as an important method in examining specific gene functions. The authors have previously demonstrated that AS-ODN/tissue factor (TF) prevents renal I/R injury. This review discusses the efficacy of AS-ODN/TF and AS-ODN/intercellular adhesion molecule-1 as existing targets, and the potential of AS-ODN/nuclear factor-kappaB, AS-ODN/cyclooxygenase and AS-ODN/5-lipoxygenase as prospective targets.
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PMID:Prospects of antisense oligodeoxynucleotides to alleviate renal ischaemia-reperfusion injury. 1557 55

PGF(2)-like compounds are formed in abundance in vivo by the free radical-induced peroxidation of arachidonic acid, independent of the cyclooxygenase enzyme. These compounds are collectively referred to as F(2)-isoprostanes because of their structural similarity to cyclooxygenase-derived PGF(2alpha). Certain findings suggest a potential role for isoprostanes as mediators of some of the adverse sequelae of ischemia-reperfusion injury to kidney. Recent evidence also suggests a potentially important role for isoprostanes in the pathogenesis of hepatorenal syndrome. Cell culture studies suggest that cisplatin-induced LLC-PK1 cell injury may be attended by increased isoprostane production through a mechanism involving thiol depletion. Another area in which a role for free radical-induced lipid peroxidation and F(2)-isoprostanes has been suggested is in the pathogenesis of ciclosporin (CSA)-induced renal toxicity. A recent study also suggests that enhanced formation renal F(2)-isoprostanes may be relevant to the progressive reduction in renal blood flow demonstrable in aging kidneys. This emerging evidence suggests that further studies are warranted to determine the importance of F(2)-isoprostanes in human renal diseases characterized by renal vasoconstriction, such as renal ischemia, hepatorenal syndrome, renal senescence and toxic nephropathies.
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PMID:F2-isoprostanes and the kidney. 1561 48

The processes involved in the renal damage resulting from ischemia-reperfusion injury are poorly understood. This study examined the contribution of prostaglandins and nitric oxide (NO) in the vascular responses to ischemia-reperfusion injury in the kidneys of normotensive and hypertensive rats. Groups of Wistar and stroke-prone spontaneously hypertensive rats (SHRSP) were dosed with polyethylene glycol vehicle, aspirin (53.5 mg.kg(-1).day(-1)), NO-aspirin (100 mg.kg(-1).day(-1)), or celecoxib (10 mg.kg(-1).day(-1)) for 7 days. On day 7, rats were anesthetized with chloralose/urethane and the left kidney was exposed to a 30-min period of ischemia followed by 90-min reperfusion. Renal cortical and medullary perfusions were monitored throughout using laser-Doppler flowmetry. In the vehicle- and celecoxib-treated Wistar rats, cortical and medullary postischemic perfusion was reduced to 66 and 62% and 53 and 62%, respectively (all P < 0.05), of baseline. The ischemia-induced reductions in cortical and medullary flux were ameliorated in the aspirin and NO-aspirin groups where flux fell to 96 and 78% and 105 and 83%, respectively (P < 0.05). There was a fall in cortical and medullary flux in the postischemic period in the vehicle-treated SHRSP to 82 and 77% (P < 0.05). These findings show that nonselective cyclooxygenase (COX) inhibition, and to an even greater extent NO donation, provided protection to the renal vasculature from ischemic injury in the Wistar rat but not in the SHRSP. This would suggest that prostaglandins are less important in the development of renal ischemia-reperfusion injury during hypertension and both COX isoforms must be inhibited to offset the decrease in renal hemodynamics.
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PMID:Effect of COX inhibitors and NO on renal hemodynamics following ischemia-reperfusion injury in normotensive and hypertensive rats. 1595 74

Exacerbated inflammation plays an important role in the pathogenesis of ischemic renal injury (IRI), which is the major cause of intrinsic acute renal failure. Clinical studies suggest that long-term treatment with omega-3 polyunsaturated fatty acids (PUFA) improves renal function and lowers the risk of death or end-stage renal disease. Docosahexaenoic acid, a principle omega-3 PUFA of fish oils, is of particular interest as it is found in most human tissues and is converted to protectin D1 (PD1), which exhibits antiinflammatory and proresolving bioactions. We set out to investigate the impact of acute dietary modulation of omega-3 or omega-6 PUFA on IRI and renal lipid autacoid circuits, using an established mouse model and liquid chromatography-mass spectroscopy/mass spectroscopy-based lipidomics. Thirty minutes of renal ischemia significantly elevated serum creatinine in the omega-6 diet group while renal function remained normal in the matched omega-3 diet group. Notably, extending ischemia to 45 min caused 100% mortality in the omega-6 group, in sharp contrast to 0% mortality in the omega-3 group. Protection against IRI in the omega-3 group correlated with decreased polymorphonuclear leukocyte recruitment, chemokine and cytokine levels, abrogated formation of lipoxygenase- and cyclooxygenase-derived eicosanoids, and increased renal levels of PD1. Systemic treatment with PD1 reduced kidney polymorphonuclear leukocyte influx and, more importantly, amplified renoprotective heme-oxygenase-1 protein and mRNA expression in injured and uninjured kidneys. These findings suggest therapeutic or dietary amplification of PD1 circuits restrains acute renal injury and that short-term changes in dietary omega-3 and omega-6 PUFA dramatically impacts renal lipid autacoid formation and outcome of IRI.
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PMID:Acute changes in dietary omega-3 and omega-6 polyunsaturated fatty acids have a pronounced impact on survival following ischemic renal injury and formation of renoprotective docosahexaenoic acid-derived protectin D1. 1923 20


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