Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0033687 (proteinuria)
 24,015 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Acute renal failure (ARF) induced with large doses of Gentamicin (GM) (an aminoglycoside) was associated with increased urinary TXB (TXA) excretion which provoked a decrease of the ratios of urinary PGE2/TXB2 and 6-keto-PGF1 alpha (PGI2)/TXB2 excretions. Furthermore, as indicated by light microscopy most of the epithelial cells lining the proximal tubules show obvious lesions varying from swelling of their cytoplasm to complete necrosis. Either the inhibitor, OKY-O46, of TXA-synthetase, or volume expansion (VE) with isotonic saline (IS) of the experimental animals diminished urinary TXB excretion which provoked 1) augmentation of the ratios of urinary PGE/TXB and 6-keto-PGF1 alpha/TXB excretions, 2) elevation of creatinine clearance (Ccr) and 3) diminution of proteinuria (PU). This protection against ARF-by OKY-O46 and VE can a can be seen in microscopic sections where necrosis of proximal tubules is almost absent. Only a few proximal tubules show swelling of their epithelial cells and some focal areas of tubule necrosis. We suggest that the metabolites of arachidonic acid (AA), TXA2 a (potent vasoconstrictor agent) and prostaglandins (PGE2 and PGI2), (potent vasodilator factors), play an important role in the development (TXA2) or in the prevention (PGs) of ARF induced by this antibiotic.
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PMID:Does gentamicin induce acute renal failure by increasing renal TXA2 synthesis in rats? 156 Dec 32

Repeated subcutaneous (SC) injections of mercuric chloride (MC) in Brown Norway (BN) rats induce an autoimmune glomerulonephritis (GN) due to antiglomerular basement membrane (BM) antibody deposition in the glomeruli. The aim of this study was to investigate the effects on MC-induced autoimmune GN of OKY-046, a selective TXA-synthetase inhibitor herring oil (HO), which is rich in eicosapentaenoic acid (EPA) (5.6%) precursor of the three series of prostaglandins (PGs) and of (inactive) thromboxane (TXA3), and evening primrose oil (EPO), which is rich in linoleic acid (LA) (72%) and gamma-linolenic acid (GLNA) (9%), precursors of the one series of PGs, mainly PGE1, and of (inactive) TXA1. The administration of OKY-046 significantly inhibited proteinuria, partially prevented fibrin thrombi (FT) formation in the glomeruli, decreased urinary TXB, enhanced 6ketoPGF excretion and, increased survival rate of the animals from 60% (group receiving only MC) to 86%. However, OKY-046 did not prevent body weight (BW) loss or the development and deposition of IgG in the glomeruli. Increased intake of HO (80 days prior and throughout the experiment) and avoidance of arachidonic acid (AA) intake produced an effect comparable to that of OKY-046 in the rats. Furthermore, HO significantly inhibited the deposition of IgG in the glomeruli, increased the survival rate of the animals to 100% and further enhanced the increased urinary PGE excretion induced by MC. However, HO did not prevent BW loss in the animals. Increased intake of EPO and avoidance of AA intake produced an effect comparable to that of HO. Additionally, EPO completely prevented BW loss induced by MC in these animals. These findings suggest that the metabolites of AA, EPA and GLNA play an important role either in the development or in the modulation of this model of MC induced GN.
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PMID:Alteration of mercuric chloride-induced autoimmune glomerulonephritis in brown-Norway rats by herring oil, evening primrose oil and OKY-046 a selective TXA-synthetase inhibitor. 347 24

Hypertensive diseases represent the most frequent disorders among medical complications of pregnancy. Numerous studies have proven the central role of prostaglandins in these complex diseases. Thus, determination of urinary prostaglandins may lead to a better understanding of the pathomechanismus and may be a basis for therapeutic approaches. Our study included 59 patients with pregnancy-induced hypertension. From these 18 women had a proteinuria > 300 mg/l and were classified as pre-eclamptic. As controls 53 normotensive pregnancies were investigated. Quantification of 6-keto-PGF1 alpha, 2,3-dinor-6-keto-PGF1 alpha, TxB2, 11-Dehydro-TxB2 and PGE2 was performed with radio or enzyme immunoassays after purification with solid phase extraction and partly HPLC. In the third trimester of pregnancy following alterations were found in urine concentrations of prostaglandins in preeclamptic women compared to controls: 6-keto-PGF1 alpha - 54%, 2,3-dinor-6-keto-PGF1 alpha - 29%, PGE beta 2-41%, TxB2-29% and 11-Dehydro-TxB2 + 21%. Thus, our results show a disturbed balance between vasodilatory and vasoconstrictive prostaglandins in PIH patients. This imbalance correlated to the severity of the disease and was more pronounced in preeclamptic patients. The decrease of PGI2- and PGE2-production was more distinct than the increase of thromboxane production. We conclude that the endothelial damage, rather than an overproduction of TxA2 predominantly is responsible for some pathophysiological events in PIH.
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PMID:[Prostaglandins in the urine of hypertensive pregnant patients]. 804 88

In the passive Heymann nephritis (PHN) model of membranous nephropathy, C5b-9 induces glomerular epithelial cell (GEC) injury and proteinuria, which is partially mediated via production of eicosanoids. Using rat GEC in culture, we demonstrated that sublytic C5b-9 induced tyrosine phosphorylation of the epidermal growth factor receptor (EGF-R), Neu, fibroblast growth factor receptor-2, and hepatocyte growth factor receptor. In addition, C5b-9 stimulated increases in tyrosine(204) phosphorylation of extracellular signal-regulated kinase-2 (ERK2), as well as free [(3)H]arachidonic acid (AA) and prostaglandin E(2) (PGE(2)). Phosphorylated EGF-R bound the adaptor protein, Grb2, and the EGF-R-selective tyrphostin, AG1478, blocked the C5b-9-induced ERK2 phosphorylation, [(3)H]AA release, and PGE(2) production by 45 to 65%, supporting a functional role for EGF-R kinase in mediating the activation of these pathways. Glomeruli isolated from rats with PHN demonstrated increases in ERK2 tyrosine(204) phosphorylation and PGE(2) production, as compared with glomeruli from control rats, and these increases were partially inhibited with AG1478. Thus, C5b-9 induces transactivation of receptor tyrosine kinases, in association with ERK2 activation, AA release, and PGE(2) production in cultured GEC and glomerulonephritis in vivo. Transactivated tyrosine kinases may serve as scaffolds for assembly and/or activation of proteins, which then lead to activation of the ERK2 cascade and AA metabolism.
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PMID:Complement C5b-9 induces receptor tyrosine kinase transactivation in glomerular epithelial cells. 1055 Mar 26

In the passive Heymann nephritis (PHN) model of membranous nephropathy, complement C5b-9 induces glomerular epithelial cell (GEC) injury and proteinuria, which is partially mediated by eicosanoids. This study addresses the role of cyclooxygenase (COX)-1 and -2 in C5b-9-mediated eicosanoid production in GEC. Unstimulated rat GEC in culture primarily express COX-1. When stimulated with sublytic C5b-9, COX-2 was significantly up-regulated, whereas COX-1 was not affected. Compared with control, complement-treated GEC produced 32% more prostaglandin (PG) E(2) in the presence of exogenous substrate, and the increase was abolished with the COX-2-selective inhibitor, NS-398. Release of arachidonic acid from GEC phospholipids via C5b-9-induced activation of cytosolic phospholipase A(2) was associated with a marked stimulation of PGE(2) production, which was inhibited by 60% with NS-398. The results in cultured GEC were extended to GEC injury in vivo by examining COX-1 and -2 expression in PHN. Glomeruli from rats with PHN expressed significantly more COX-1 and COX-2, as compared with normal rats. PGE(2) production in glomeruli of rats with PHN was about twofold greater than in control glomeruli, and the increase was partially inhibited with NS-398. Thus, in GEC in culture and in vivo, C5b-9-induced eicosanoid production is regulated by both isoforms of COX. The inducible COX-2 may be an important novel mediator of C5b-9-induced glomerular injury.
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PMID:Complement C5b-9-mediated arachidonic acid metabolism in glomerular epithelial cells : role of cyclooxygenase-1 and -2. 1085 30

Cyclosporine (CsA) (45 mg/kg/day for 7 days) administration in female Wistar rats induced significant decrease in creatinine clearance (Ccr) and body weight loss (BWL). Urine volume (V) was not altered and proteinuria (PU) not provoked. These changes were associated with increased urinary endothelin 1 (ET-1) and thromboxane B(2)(TXB(2)) concentrations, and decreased urinary ratios of prostaglandin (6ketoPGF(1 alpha)and PGE(2)) to TXB(2)excretions. Nifedipine (NFD) (0.1 mg/kg/day for 7 days), a calcium channel blocker, administrated in addition to CsA, to another group of animals, significantly augmented Ccr and urine V but did not prevent BWL in comparison to CsA-only treated rats. The urinary ET-1 and TXB(2)concentrations displayed significant and non-significant decrease respectively, while the urinary excretion ratios of 6ketoPGF(1 alpha)/TXB(2)and PGE(2)/TXB(2)were significantly enhanced.These observations indicate that the partial protection of NFD in CsA-induced nephrotoxicity could be attributed to augmented urinary prostanoid ratios of renal vasodilators (6ketoPGF(1 alpha)and PGE(2)) to vasoconstrictor (TXB(2)) excretions, and also to reduced release of rather renal origin ET-1, the most potent mamalian vasoconstrictor peptide known to date. In a previous study, we found that NFD only slightly prevented structural renal damage, induced by CsA. So, the NFD protection refers only to functional toxicity and not to structural damage, mediated at least in part by the preservation of relatively high renal TXB(2)levels. However, other nephrotoxic factors and additional mechanisms could also be implicated in this CsA-induced syndrome.
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PMID:Effect of nifedipine in cyclosporine-induced nephrotoxicity in rats: roles of the thromboxane and endothelin systems. 1109 Feb 52

Local production of prostaglandins (PGs) in the kidney is increased in clinical and experimental diabetic nephropathy, but the role of PGs in the pathogenesis and progression of diabetic nephropathy has remained unclear. It is here shown that an orally active antagonist selective for the PGE receptor EP1 subtype potently prevents the progression of nephropathy in streptozotocin-induced diabetic rats. The effects are shown by ameliorated renal and glomerular hypertrophy, decreased mesangial expansion, inhibited transcriptional activation of transforming growth factor-beta (TGF-beta) and fibronectin, and complete suppression of proteinuria. In vitro, this agent completely inhibits TGF-beta and fibronectin upregulation in mesangial cells cultured under high-glucose conditions. These data indicate that the PGE2-EP1 system plays a crucial role in the development of diabetic renal injury in rats. It is further shown that both the EP1 antagonist and aspirin, a nonselective PG synthase inhibitor, markedly attenuate mesangial expansion, whereas only the EP1 antagonist inhibits glomerular hypertrophy and proteinuria, which suggests that these changes are caused by different mechanisms. This study reveals a potential usefulness of selective EP1 blockade as a novel therapeutic strategy for diabetic nephropathy and also brings a new insight into our understanding of this disease.
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PMID:Prevention of diabetic nephropathy in rats by prostaglandin E receptor EP1-selective antagonist. 1208 71

PGE(2) and PGI(2) reduce extracellular matrix deposition and their production is altered after ACE inhibitor (ACEi) treatment. We therefore hypothesized that cyclooxygenase (COX)-2 inhibition would exacerbate renal injury and antagonize the effects of ACEi. To test these hypotheses, WKY and SHR were uninephrectomized (UNX) and treated with either vehicle, enalapril, NS398 or enalapril+NS398. NS398 did not affect systolic blood pressure nor antagonize the antihypertensive effect of enalapril. Urinary protein excretion in UNX WKY was significantly decreased after treatment with either enalapril or NS398. In UNX SHR, enalapril reduced proteinuria, but NS398 alone had no effect. Administration of both drugs, however, further reduced proteinuria. In UNX WKY, treatment with either NS398 alone or both drugs reduced glomerular volume and similar results were observed in SHR. Surprisingly, these results disprove our original hypothesis and suggest that inhibition of COX-2 provides additional renoprotection to that of enalapril alone.
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PMID:COX-2 inhibition potentiates the antiproteinuric effect of enalapril in uninephrectomized SHR. 1253 86

With the rising incidence of obesity and the metabolic syndrome, obesity-associated nephropathy also has increased. One of the earliest pathologies in the development of this nephropathy is glomerular hyperfiltration and hypertrophy. Dietary soy protein (SP) ameliorates disease progression in several models of renal disease, and vegetable sources of protein, as compared to animal sources of protein, alter renal hemodynamics. Therefore, the effect of dietary SP on early renal disease and prostanoid production was examined in the obese fa/fa Zucker rat. Rats, 6 weeks of age, were given diets containing 17% protein from either SP or egg white (EW) for 8 weeks. Feed consumption and body and kidney weights were significantly greater in fa/fa rats as compared to lean rats. The fa/fa rats also had 139% more proteinuria and kidneys with 43% larger glomeruli. SP feeding did not alter body weights or proteinuria but did result in 6% lower kidney weights (g/100 g body weight) and 16% smaller glomeruli in fa/fa rats. Cyclooxygenase activity as determined by 6-keto prostaglandin F(1alpha) (6-keto PGF(1alpha)) synthesis was lower in fa/fa rats given SP-based diets as compared to those given EW-based diets. Ratios of renal thromboxane (TX) B(2)/6-keto PGF(1alpha) and PGE(2)/6-keto PGF(1alpha) were higher, while TXB(2)/PGE(2) levels were not different in rats given SP diets as compared to those given EW diets, also indicating that dietary SP reduced renal 6-keto PGF(1alpha) levels. These findings suggest that attenuation of early glomerular hypertrophy in young obese fa/fa rats by dietary SP may be mediated by the lower levels of 6-keto PGF(1alpha) since this would be expected to reduce glomerular hyperfiltration.
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PMID:Dietary soy protein reduces early renal disease progression and alters prostanoid production in obese fa/fa Zucker rats. 1765 81

Cyclooxygenase-2 (COX-2)-dependent prostaglandin E(2) (PGE(2)) synthesis correlates with the onset of proteinuria and increased glomerular capillary pressure (P(gc)) glomerular disease models. We previously showed that an in vitro surrogate for P(gc) (cyclical mechanical stretch) upregulates the expression of both COX-2 and the PGE(2) responsive E-Prostanoid receptor, EP(4) in cultured mouse podocytes. In the present study we further delineate the signaling pathways regulating podocyte COX-2 induction. Time course experiments carried out in conditionally-immortalized mouse podocytes revealed that PGE(2) transiently increased phosphorylated p38 MAPK levels at 10 min, and induced COX-2 protein expression at 4 h. siRNA-mediated knockdown of EP(4) receptor expression, unlike treatment with the EP(1) receptor antagonist SC 19220, completely abrogated PGE(2)-induced p38 phosphorylation and COX-2 upregulation suggesting the involvement of the EP(4) receptor subtype. PGE(2)-induced COX-2 induction was abrogated by inhibition of either p38 MAPK or AMP activated protein kinase (AMPK), and was mimicked by AICAR, a selective AMPK activator, and by the cAMP-elevating agents, forskolin (FSK) and IBMX. Surprisingly, neither PGE(2) nor FSK/IBMX-dependent p38 activation and COX-2 expression were blocked by PKA inhibitors or mimicked by 8-cPT-cAMP a selective EPAC activator, but were instead abrogated by Compound C, suggesting the involvement of AMPK. These results indicate that in addition to mechanical stretch, PGE(2) initiates a positive feedback loop in podocytes that drives p38 MAPK activity and COX-2 expression through a cAMP/AMPK-dependent, but PKA-independent signaling cascade. This PGE(2)-induced signaling network activated by increased P(gc) could be detrimental to podocyte health and glomerular filtration barrier integrity.
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PMID:PGE(2) induces COX-2 expression in podocytes via the EP(4) receptor through a PKA-independent mechanism. 1876 48


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