UMLS:C0033687 - FACTA Search

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Query: UMLS:C0033687 (proteinuria)
24,015 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Selective cyclooxygenase-2 (COX-2) inhibitors have anti-inflammatory activity and reduce proteinuria in experimental membranous glomerulonephritis. Antiangiogenic properties of COX-2 inhibitors were recently reported. Whether these properties are relevant to the glomerular healing process in inflammatory glomerular diseases was investigated. For evaluation of the effects of selective COX-2 inhibitors on the glomerular healing process in a rat model of mesangioproliferative glomerulonephritis (induced by anti-Thy 1.1 antibody), a selective COX-2 inhibitor (rofecoxib or celecoxib) or vehicle was administered daily from day 1 after disease induction until euthanasia on day 6. Additional nephritic rats were treated with rofecoxib or vehicle from day 1 to day 10 and were monitored until day 28. Selective COX-2 inhibition led to significant increases in mesangiolysis (up to +71%) on days 2 and 6 and in albuminuria (up to 3.1-fold) on day 6. This augmentation of glomerular capillary damage was associated with rarefaction of glomerular endothelial cells, whereas the proliferation and activation of mesangial cells were not affected. No significant effects on the glomerular influx of polymorphonuclear neutrophils or the infiltration and proliferation of monocytes/macrophages at day 2 were noted. These effects were independent of systemic hemodynamic features, because rofecoxib did not affect systolic BP on day 2 or 5. Nephritic rats treated with rofecoxib for 10 d demonstrated persistent glomerular injury at day 28, as indicated by increased albuminuria (10-fold) and mesangial type IV collagen deposition (+24%). In normal rats, 5-d administration of rofecoxib failed to induce albuminuria or morphologic renal damage. In conclusion, selective COX-2 inhibitors impair glomerular capillary repair after mesangiolysis in rats with anti-Thy 1.1 glomerulonephritis. These data suggest that selective COX-2 inhibitors should be used with caution among patients with inflammatory endocapillary glomerular disorders.
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PMID:Selective cyclooxygenase-2 inhibition impairs glomerular capillary healing in experimental glomerulonephritis. 1196 Oct 14

Data about the nephrotoxicity of selective cyclooxygenase-2 inhibitors are still evolving. Acute interstitial nephritis is a well-described complication of therapy with nonselective nonsteroidal anti-inflammatory drugs. We report a case of biopsy-proven acute interstitial nephritis in a 73-year-old diabetic woman, who had taken celecoxib for more than 1 year before presentation. She presented with clinical findings of subnephrotic proteinuria and acute renal failure that required dialysis. She recovered renal function with cessation of celecoxib therapy after 2 weeks. Other medications were reintroduced safely, without recurrence of renal failure. A kidney biopsy specimen showed acute interstitial nephritis with a prominent eosinophilic infiltrate in the interstitium. This case documents the occurrence of acute interstitial nephritis with celecoxib and emphasizes the need for continued vigilance and care in use of cyclooxygenase-2 inhibitors in high-risk patients.
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PMID:Celecoxib-induced acute interstitial nephritis. 1261 1

Although hyperuricemia has long been associated with renal disease, uric acid has not been considered as a true mediator of progression of renal disease. The observation that hyperuricemia commonly is associated with other risk factors of cardiovascular and renal disease, especially hypertension, has made it difficult to dissect the effect of uric acid itself. However, recent epidemiologic evidence suggests a significant and independent association between the level of serum uric acid and renal disease progression with beneficial effect of decreasing uric acid levels. Furthermore, our experimental data using hyperuricemic animals and cultured cells have provided robust evidence regarding the role of uric acid on progression of renal disease. Hyperuricemia increased systemic blood pressure, proteinuria, renal dysfunction, vascular disease, and progressive renal scarring in rats. Recent data also suggest hyperuricemia may be one of the key and previously unknown mechanisms for the activation of the renin-angiotensin and cyclooxygenase-2 (COX-2) systems in progressive renal disease. Although we must be cautious in the interpretation of animal models to human disease, these studies provide a mechanism to explain epidemiologic data that show uric acid is an independent risk factor for renal progression. Although there is no concrete evidence yet that uric acid bears a causal or reversible relationship to progressive renal disease in humans, it is time to reevaluate the implication of hyperuricemia as an important player for progression of renal disease and to try to find safe and reasonable therapeutic modalities in individual patients based on their clinical data, medication history, and the presence of cardiovascular complications.
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PMID:Uric acid and chronic renal disease: possible implication of hyperuricemia on progression of renal disease. 1566 Mar 34

The present study was performed to evaluate the effects of sodium intake and of chronic cyclooxygenase-2 (COX-2) inhibition on systolic blood pressure (SBP) in heterozygous male transgenic rats harboring the mouse Ren-2 renin gene (TGR) and in transgene-negative normotensive Hannover Sprague-Dawley (HanSD). Twenty-eight days old TGR and HanSD were randomly assigned to groups fed either normal salt (NS) or low sodium (LS) diets. COX-2 blockade was achieved with NS-398 (1 mg x kg(-1).day(-1) in drinking water). During an experimental period of 26 days, SBP was repeatedly measured by tail plethysmography in conscious animals. We found that the LS diet prevented the development of hypertension in TGR and did not change SBP in HanSD. Low sodium intake also prevented proteinuria and cardiac hypertrophy in TGR. On the other hand, irrespective of sodium intake chronic COX-2 inhibition did not alter the course of SBP in either TGR or HanSD. The present data indicate that TGR exhibit an important salt-sensitive component in the developmental phase of hypertension. They also suggest that systemic COX-2-derived prostaglandins do not act as vasodilatory counterregulatory agents in TGR in which an exaggerated vascular responsiveness to angiotensin II is assumed as the pathophysiological mechanism in the development of hypertension.
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PMID:Effects of sodium restriction and cyclooxygenase-2 inhibition on the course of hypertension, proteinuria and cardiac hypertrophy in Ren-2 transgenic rats. 1571 37

Selective cyclooxygenase-2 (COX-2) inhibitors are relatively newer anti-inflammatory drugs that produce comparable antiinflammatory and analgesic effects to the nonselective nonsteroidal antiinflammatory drugs (NSAIDs); but with fewer symptomatic gastric and duodenal ulcers. Limited data are available concerning the toxicity associated with COX-2 inhibitors outside the gastrointestinal tract. The NSAIDs have been known for their nephrotoxic potentials including minimal-change disease (MCD) with interstitial nephritis. Although the recent data suggests that COX-2 inhibitors may have the same adverse renal effect as NSAIDs, there is only one case report describing minimal change disease and acute interstitial nephritis (AIN) associated with a COX-2 inhibitor, celecoxib. We are reporting a case of MCD and acute tubular necrosis (ATN) but without interstitial nephritis in a patient treated with celecoxib. Although the proteinuria in our patient resolved completely after discontinuation of celecoxib, the renal function did not. We suggest that heightened suspicion of this side effect of COX-2 inhibitors should be maintained in all patients taking this class of drugs who present with nephrotic syndrome.
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PMID:Cyclooxygenase-2 inhibitor-associated minimal-change disease. 1590 98

High glucose concentration, which provides the chief driving force in peritoneal dialysis, has been considered to be an important initial factor that contributes to peritoneal thickening and fibrosis. Human peritoneal mesothelial cells (HPMCs) and the expansion of extracellular matrix (ECM) play important roles in the pathological process of peritoneal fibrosis. Peritoneal matrix accumulation is a characteristic of peritoneal fibrosis (PF). Continuous ambulatory peritoneal dialysis (CAPD) patients with upregulation of transforming growth factor-beta1 (TGF-beta1) in their drained effluent show an increased risk of PF. Inhibition of TGF-beta1 expression in human peritoneal mesothelial cells (HPMCs) may provide a potential treatment for PF. sc58236, a highly selective cyclooxygenase-2 (COX-2) inhibitor, reduces proteinuria and mRNA expression of TGF-beta1 and collagen III and IV in the remnant kidney, but their effects on ECM turnover in HPMCs are unknown. The aims of this study were to investigate the effects of sc58236 on TGF-beta1 expression and matrix production in HPMCs. HPMCs were cultured from human omentum by an enzyme digestion method. To examine the effect of sc58236 on TGF-beta1 and ECM secretion, HPMC were incubated in medium F12 with high concentration of D-glucose (4.25%) in the presence and absence of 20 microM sc58236. The mRNA expression of COX-2, TGF-beta1 and collagen I (Col I) were determined by semi-quantification reverse transcription PCR (RT-PCR). Prostaglandin E2 (PGE2) concentration in the culture medium was measured by enzyme-linked immunosorbent assay (ELISA). The protein of TGF-beta1 was determined by ELISA and the activity of TGF-beta1 present in the conditioned media was measured using the mink lung epithelial cell (MLEC) growth inhibition assay. Proteins of COX-2 and Col were determined by Western blot. The results showed that primary cultures of HPMCs do express the mRNA for COX-2 and stimulation of these cells with 4.25% D-glucose induced a marked increase in COX-2 mRNA expression and protein. PGE2 expression was obviously up-regulated with stimulation by 4.25% D-glucose. Addition of 20 microM sc58236 significantly inhibited PGE2 release into the culture medium. mRNA expression and bioactive and total protein of TGF-beta1 and Col I were significantly increased in HPMCs stimulated with 4.25% D-glucose compared to the control group with F12 media, which was reversed in the presence of sc58236 (20 microM). An obvious decrease in TGF-beta1 mRNA expression and bioactive and total protein were found in sc58236 treated groups compared to the group stimulated with 4.25% D-glucose. Exposure of HPMCs to sc58236 reduced Col I secretion. Sc58236 reduces the expression of TGF-beta1 in HPMCs stimulated by 4.25% D-glucose and reduces ECM production through PGE2 production. These studies suggest that sc58236, a highly selective cyclooxygenase-2 (COX-2) inhibitor, may have a specific role in ameliorating the course of progressive peritoneal fibrosis under long-term peritoneal dialysis states.
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PMID:A selective cyclooxygenase-2 inhibitor decreases transforming growth factor-beta1 synthesis and matrix production in human peritoneal mesothelial cells. 1719 3

Preeclampsia is a potentially fatal complication of human pregnancy characterized by hypertension, proteinuria, and edema. Placental oxidative stress is a key element in the pathogenesis of the syndrome and results in the release of a cocktail of factors, including proinflammatory cytokines and apoptotic debris, that in turn cause activation of the maternal endothelium. The intermediary molecular mechanisms underlying this release are unknown, but they represent a potential target for therapeutic interventions. We examined activation of signaling pathways during hypoxia-reoxygenation of villous explants in vitro. Hypoxia-reoxygenation activated the p38 and stress-activated protein kinase mitogen-activated protein kinase (MAPK) and the nuclear factor-kappaB pathways. Downstream consequences included increased tissue concentrations and secretion of tumor necrosis factor-alpha and interleukin-1 beta, increased expression of cyclooxygenase-2, and increased apoptosis. Administration of vitamins C and E to explants blocked activation of the p38 and stress-activated protein kinase MAPK and nuclear factor-kappaB pathways. Vitamin administration or p38 pathway inhibition also reduced cyclooxygenase-2 expression, tumor necrosis factor-alpha and interleukin-1 beta secretion, and the levels of apoptosis. We conclude that oxidative stress is a potent inducer of placental synthesis and release of proinflammatory factors. Most of these effects are mediated through the p38 MAPK and nuclear factor-kappaB pathways and can be effectively blocked by vitamins C and E in vitro.
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PMID:Nuclear factor-kappa B, p38, and stress-activated protein kinase mitogen-activated protein kinase signaling pathways regulate proinflammatory cytokines and apoptosis in human placental explants in response to oxidative stress: effects of antioxidant vitamins. 1745 58

Previous studies from our own group and others have demonstrated that cyclooxygenase-2 (COX-2) inhibitors could reduce proteinuria in some experimental models of progressive renal disease. To investigate a possible role of COX-2 in podocytes during the course of self-limited glomerular injury, we administered puromycin nucleoside (PAN) on day 1 (15 mg/100 g BW) and day 3 (30 mg/100 g BW) to wild-type and transgenic mice with podocyte-specific COX-2 expression driven by a nephrin promoter. An additional group received both PAN and the COX-2-specific inhibitor, SC58236 (6 mg/l in drinking water). There was no significant difference in the albumin (microg)/creatinine (mg) ratio between wild-type (26.3 +/- 4.2, n = 8) and transgenic (28.9 +/- 2.3, n = 8) mice under baseline conditions. PAN induced significant albuminuria only in the transgenic mice with a peak at day 3: 72.1 +/- 8.9 microg/mg creatinine (n = 12, p < 0.05, compared with basal level), which remitted by day 10 (37.4 +/- 4.4 microg/mg, n = 7, p < 0.05, compared with day 3). Electron microscopy demonstrated that PAN caused 56.7 +/- 4.2% foot process effacement in transgenic mice compared with 38.8 +/- 4.1% in wild type at day 3. PAN increased immunoreactive COX-2 in glomeruli from transgenic mice (day 3: 1.47 +/- 0.08 fold; day 10: 1.25 +/- 0.16 fold, n = 5-9, p < 0.05 compared with basal level), which was restricted to podocytes. Real time PCR indicated that endogenous COX-2 mRNA increased (2.6 +/- 0.1 fold of wild-type control at day 3 and 2.2 +/- 0.2 at day 10, n = 4, p < 0.05), while the nephrin-driven COX-2 mRNA was unchanged. Nephrin mRNA and protein expression were decreased by PAN in the transgenic mice. The COX-2-specific inhibitor, SC58236, reduced foot process effacement in transgenic mice administered PAN to 21.7 +/- 5.2% and significantly reduced the albuminuria at day 3 (42.2 +/- 3.8, n = 13, p < 0.05 compared with untreated) without significantly altering COX-2 expression. In summary, in transgenic mice with podocyte COX-2 overexpression, PAN increased albuminuria and induced foot process fusion. Thus, increased COX-2 expression increased podocyte susceptibility to further injury.
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PMID:Puromycin induces reversible proteinuric injury in transgenic mice expressing cyclooxygenase-2 in podocytes. 1789 Aug 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

The selective cyclooxygenase-2 (COX-2) and 5-lipoxygenase (LOX) inhibitors might inhibit prostaglandin synthesis and reduce proteinuria. The present study was designed to investigate the anti-proteinuric effects of nordihydroguaiaretic acid (NDGA) as compared with celecoxib in puromycin aminonucleoside (PAN) nephrosis rats. Fifty five male Sprague-Dawley rats were divided into 4 groups; A, normal control; B, PAN group; C, PAN+COX-2 inhibitor (celecoxib) group; and D, PAN+5-LOX inhibitor (NDGA) group. After induction of PAN nephrosis through repeated injections of PAN (7.5 and 15 mg/100 g body weight), rats were treated with celecoxib, NDGA, or vehicle for 2 weeks. Twenty four hour urine protein excretions were significantly lower in PAN+celecoxib and PAN+NDGA groups than in PAN group. Serum creatinine (SCr) concentrations and 24 hr urine creatinine clearances (CCr) were not significantly different in the four groups. Electron microscopy showed that podocyte morphology was changed after the induction of PAN nephrosis and was recovered after celecoxib or NDGA administration. Celecoxib significantly recovered the expressions of nephrin, CD2AP, COX-2, and TGF-beta. NDGA also recovered TGF-beta expression, but did not alter the expressions of nephrin, CD2AP and COX-2. The present study suggested that celecoxib and NDGA might effectively reduce proteinuria in nephrotic syndrome without impairing renal function.
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PMID:Effects of celecoxib and nordihydroguaiaretic acid on puromycin aminonucleoside-induced nephrosis in the rat. 1919 50

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