COX‐2 inhibition and prostaglandin receptors in experimental nephritis

Waldner, Christoph; Heise, Gunhild; Schrör, Karsten; Heering, Peter

doi:10.1046/j.1365-2362.2003.01256.x

Cited by 9 publications

(6 citation statements)

References 28 publications

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“…A similar deregulation of cortical EP 3 responses is proposed to play a role in the progression of kidney disease in rats with passive Heymann nephritis (45). Our group and others have demonstrated an important role for PGE 2 in the collecting duct to limit AVP responses (17)(18)(19); thus the elevated EP 3 receptor levels reported here could serve to oppose AVP-mediated H 2 O reabsorption and reduce volume expansion in diabetes (2).…”

Section: Discussionsupporting

confidence: 70%

Renal prostaglandin E₂ receptor (EP) expression profile is altered in streptozotocin and B6-Ins2^Akita type I diabetic mice

Nasrallah¹,

Xiong²,

Hébert³

2007

American Journal of Physiology-Renal Physiology

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The homeostatic function of prostaglandin E(2) (PGE(2)) is dependent on a balance of EP receptor-mediated events. A disruption in this balance may contribute to the progression of renal injury. Although PGE(2) excretion is elevated in diabetes, the expression of specific EP receptor subtypes has not been studied in the diabetic kidney. Therefore, the purpose of this study was to characterize the expression profile of four EP receptor subtypes (EP(1-4)) in 16-wk streptozotocin (STZ) and B6-Ins2(Akita) type I diabetic mice. In diabetic mice, the ratio of kidney weight to body weight was increased twofold compared with controls, blood glucose was elevated, but urine albumin was only increased in B6-Ins2(Akita) mice. The excretion of PGE(2) and its metabolite was augmented two- to fourfold as determined by enzyme immunoassay. Accordingly, renal cyclooxygenases were also increased in diabetic mice, with isoform-specific and regional differences in each model. Finally, there was altered EP(1-4) receptor expression in diabetic kidneys, with significant differences between STZ and B6-Ins2(Akita) mice (fold-control). In STZ mice, cortical EP(1) increased by 1.6, EP(3) increased by 2.3, and EP(4) decreased by 0.63; yet in B6-Ins2(Akita) mice, cortical EP(1) increased by 2.4, but there was a general decrease in the remaining subtypes. Similarly, in the STZ medulla EP(3) increased by 3.6, but both EP(1) and EP(3) increased by 5.5 and 1.95, respectively, in B6-Ins2(Akita) mice. Therefore, knowing the pattern of change in relative EP receptor expression in the kidney could be useful in identifying specific EP targets for the prevention of various components of diabetic kidney disease.

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Section: Discussionsupporting

confidence: 70%

Renal prostaglandin E₂ receptor (EP) expression profile is altered in streptozotocin and B6-Ins2^Akita type I diabetic mice

Nasrallah¹,

Xiong²,

Hébert³

2007

American Journal of Physiology-Renal Physiology

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“…The fact that a substantial reduction in testicular PGE 2 was seen in this study further validates the fact that COX-2 is responsible for the majority of prostaglandin production in this organ (Winnall et al, 2007). In several inflammation models in humans and rodents, daily doses of celecoxib comparable with, or even less than, those administered in this study have been found to reduce PGE 2 levels by between 60 and 80% (McAdam et al, 1999;Berenguer et al, 2002;Waldner et al, 2003;Kumar & Shivkar, 2004;Schafers et al, 2004), similar to the degree of inhibition observed in the testis. In contrast, celecoxib caused a compensatory increase in expression of the Cox-2 gene in the testis, evidence for a negative feed back loop, although this did not lead to changes at the protein level.…”

Section: Discussionsupporting

confidence: 84%

Effects of chronic celecoxib on testicular function in normal and lipopolysaccharide‐treated rats

et al. 2009

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Celecoxib (Celebrex), an inhibitor of cyclooxygenase-2 (COX-2; prostaglandin-endoperoxide synthase 2; EC 1.14.99.1), is widely used in the treatment of chronic inflammation and pain. COX-2 is constitutively expressed in the testis, where it is responsible for prostaglandin production, so inhibition of this enzyme should have effects on testicular function. The effects of administering celecoxib (oral with feed, 0.15% w/w) for 5 weeks on normal testis function and the response to low dose (0.1 mg/kg body weight) or high dose (5.0 mg/kg) lipopolysaccharide (LPS) were examined in adult male rats. Celecoxib caused a 60% reduction in testicular interstitial fluid (IF) prostaglandin E(2) (PGE(2)) concentrations, accompanied by a compensatory increase in COX-2 mRNA expression. Celecoxib increased IF volume by 30%, but had no effect on testis weight, testis morphology or serum testosterone levels. In the celecoxib-fed rats, the dose-dependent inhibitory effects of LPS on testis weight, IF volume and serum testosterone levels were significantly diminished. However, celecoxib had no effect on COX-2 protein levels or LPS-induced expression of the inflammatory mediators interleukin-1beta, tumour necrosis factor-alpha or inducible nitric-oxide synthase. A similar lack of inhibition of LPS-induced cytokine expression by another COX-2 inhibitor, NS-398, was observed in vitro. These data indicate that celecoxib reduces intratesticular activity of COX-2 (as indicated by PGE(2) levels) and inhibits IF formation in the testis, but has no appreciable effect on steroidogenesis or spermatogenesis, at least in the short term. Celecoxib does not appear to alter the ability of the testis to mount an inflammatory response but opposes the deleterious effects of inflammation on IF formation and testosterone production. These results indicate significant roles for products of the COX-2 pathway in testicular vascular control and steroidogenesis, which may have implications for men with marginal fertility taking celecoxib for extended periods, but also highlight the potential of this drug to ameliorate testicular damage caused by systemic or local inflammation.

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“…Moreover, recent clinical reports of the side effects associated with the COX-2 inhibitors led us to consider that a better strategy for treating ischemic injury might lay in modulating the PGs and PG receptors downstream of the COX pathway. PGE 2 has been reported to execute its toxic actions mainly via the EP3 receptor in a rat model of passive Heymann nephritis (Waldner et al, 2003). Furthermore, EP3 receptor and COX-2 immunoreactivity have been reported to colocalize and increase in rat placenta after ischemiareperfusion of the uterine artery (Yamazaki et al, 2005).…”

Section: Discussionmentioning

confidence: 99%

Stimulation of prostaglandin E2-EP3 receptors exacerbates stroke and excitotoxic injury

Ahmad¹,

Ahmad²,

Zhuang³

et al. 2007

Journal of Neuroimmunology

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The effect of PGE 2 EP3 receptors on injury size was investigated following cerebral ischemia and induced excitotoxicity in mice. Treatment with the selective EP3 agonist ONO-AE-248 significantly and dose-dependently increased infarct size in the middle cerebral artery occlusion model. In a separate experiment, pretreatment with ONO-AE-248 exacerbated the lesion caused by N-methyl-D-aspartic acid-induced acute excitotoxicity. Conversely, genetic deletion of EP3 provided protection against N-methyl-D-aspartic acid-induced toxicity. The results suggest that PGE 2 , by stimulating EP3 receptors, can contribute to the toxicity associated with cyclooxygenase and that antagonizing this receptor could be used therapeutically to protect against stroke-and excitotoxicityinduced brain damage.

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COX‐2 inhibition and prostaglandin receptors in experimental nephritis

Abstract: These data suggest a predominant role of the EP3 receptor in the transduction of PGE2-actions in PHN. It was concluded that COX-2-dependent PGE2 is able to potentiate its effects in the kidney by up-regulating its own receptors.

Cited by 9 publications

References 28 publications

Renal prostaglandin E₂ receptor (EP) expression profile is altered in streptozotocin and B6-Ins2^Akita type I diabetic mice

Renal prostaglandin E₂ receptor (EP) expression profile is altered in streptozotocin and B6-Ins2^Akita type I diabetic mice

Effects of chronic celecoxib on testicular function in normal and lipopolysaccharide‐treated rats

Stimulation of prostaglandin E2-EP3 receptors exacerbates stroke and excitotoxic injury

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COX‐2 inhibition and prostaglandin receptors in experimental nephritis

Abstract: These data suggest a predominant role of the EP3 receptor in the transduction of PGE2-actions in PHN. It was concluded that COX-2-dependent PGE2 is able to potentiate its effects in the kidney by up-regulating its own receptors.

Cited by 9 publications

References 28 publications

Renal prostaglandin E2 receptor (EP) expression profile is altered in streptozotocin and B6-Ins2Akita type I diabetic mice

Renal prostaglandin E2 receptor (EP) expression profile is altered in streptozotocin and B6-Ins2Akita type I diabetic mice

Effects of chronic celecoxib on testicular function in normal and lipopolysaccharide‐treated rats

Stimulation of prostaglandin E2-EP3 receptors exacerbates stroke and excitotoxic injury

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Renal prostaglandin E₂ receptor (EP) expression profile is altered in streptozotocin and B6-Ins2^Akita type I diabetic mice

Renal prostaglandin E₂ receptor (EP) expression profile is altered in streptozotocin and B6-Ins2^Akita type I diabetic mice