Selective COX-2 inhibition markedly slows disease progression and attenuates altered prostanoid production in Han:SPRD-<i>cy</i>rats with inherited kidney disease

Sankaran, Deepa; Bankovic-Calic, Neda; Ogborn, Malcolm R.; Crow, G. H.; Aukema, Harold M.

doi:10.1152/ajprenal.00257.2006

Cited by 67 publications

(57 citation statements)

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“…Oxylipins have a fundamental role in regulating vascular tone and inflammation. For example, some oxylipins produced from arachidonic acid or linoleic acid have been associated with inflammation, [3][4][5] tissue damage, 6,7 vasoconstriction, 8,9 and oxidative stress. 10 In contrast, the epoxyeicosatrienoic acids (EETs) produced from arachidonic acid are endothelial-derived hyperpolarizing factors that are associated with vasodilation and natriuresis 11,12 and may indirectly propagate vasodilation [13][14][15] by activating endothelial nitric oxide synthase.…”

Section: July 2014mentioning

confidence: 99%

Flaxseed Consumption Reduces Blood Pressure in Patients With Hypertension by Altering Circulating Oxylipins via an α-Linolenic Acid–Induced Inhibition of Soluble Epoxide Hydrolase

et al. 2014

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Abstract-In a randomized, double-blinded, controlled clinical trial, participants with peripheral arterial disease (75% hypertensive) consumed 30 g of milled flaxseed/d for 6 months. The flaxseed group exhibited significant reductions in systolic (−10 mm Hg) and diastolic (−7 mm Hg) blood pressure. Flaxseed contains the n3 fatty acid α-linolenic acid. Plasma α-linolenic acid increased with ingestion of flaxseed and was inversely associated with blood pressure. However, the antihypertensive mechanism was unclear. Oxylipins derived from polyunsaturated fatty acids regulate vascular tone. Therefore, the objective was to examine whether flaxseed consumption altered plasma oxylipins in a manner that influenced blood pressure. Plasma of FlaxPAD (Flaxseed for Peripheral Arterial Disease) participants underwent solid phase extraction and high-performance liquid chromatography-mass spectrometry/mass spectrometry analysis. The flaxseed group exhibited significant decreases in 8 plasma oxylipins versus control. Six of these (5,6-, 8,9-, 11,12-, 14,15-dihydroxyeicosatrienoic acid and 9,10-and 12,13-dihydroxyoctadecenoic acid) were products of soluble epoxide hydrolase, a pharmacological target for antihypertensive treatment. Patients exhibiting a decrease in total plasma soluble epoxide hydrolase-derived oxylipins, exhibited a significant decrease in systolic blood pressure (mean [ and infarction size 23 in animal models. The proposed relationship between epoxygenase-derived oxylipins and hypertension is depicted in Figure 1.95%To test the hypothesis that flaxseed decreased the levels of oxylipins associated with inflammation and vasoconstriction, the study objectives were 3-fold: (1) to characterize and quantify the plasma oxylipin profile of participants with PAD, (2) to compare changes in plasma oxylipin concentrations in the control and flaxseed groups, and (3) to determine the mechanism whereby any changes in oxylipins may have influenced blood pressure in the FlaxPAD Trial. Methods Participants and Food ProductsA randomized, double-blinded, parallel, controlled clinical trial was established to determine the cardiovascular effects of dietary flaxseed in patients with PAD.24 Seventy-five percent of the participants were diagnosed as hypertensive at baseline (blood pressure ≥140/90 mm Hg).2,24 Participants (n=110) consumed food products containing either 30 g of milled flaxseed (treatment) or a combination of mixed dietary oils, milled wheat, and bran (control) for 6 months. Further details of the food product composition, 25,26 participant enrollment, intervention allocation, clinical characteristics, and blood pressure outcomes have been previously published.2,24 The trial is available at http://www.clinicaltrials.gov/ct2/show/NCT00781950?term=grant+p ierce+flax&rank=1.All participants provided informed consent, and all procedures were performed according to institutional guidelines. The trial was approved by Health Canada and its Natural Health Product Directorate, the University of Manitoba Research Ethics Board,...

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Section: July 2014mentioning

confidence: 99%

Flaxseed Consumption Reduces Blood Pressure in Patients With Hypertension by Altering Circulating Oxylipins via an α-Linolenic Acid–Induced Inhibition of Soluble Epoxide Hydrolase

et al. 2014

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“…Moreover, the PGE 2 concentration in renal tissue isolated from the Han:SPRD model of ADPKD is greater than that measured in littermate controls (35,44), suggesting that excessive autocrine production of PGE 2 may also contribute to the proliferative phenotype. To test whether PGE 2 concentrations are greater in PC-1-deficient cells, we measured PGE 2 in the conditioned media bathing the PC-1-deficient and PC-1-replete IMCD3 cells.…”

Section: Pge 2 a Cox-dependent Prostanoid Regulates Proliferationmentioning

confidence: 89%

“…Recent observations suggest that altered prostanoid production contributes to these pathologic and clinical features. In kidneys of rodent PKD models and in renal cyst fluid from PKD patients, prostanoids, and more specifically PGE 2 , are present at higher concentrations than in controls (2,5,28,35,44). The molecular mechanisms by which mutations of cystogenic genes induce renal PGE 2 production remain unknown, but the levels of renal PGE 2 significantly affect the phenotype of PKD.…”

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“…The molecular mechanisms by which mutations of cystogenic genes induce renal PGE 2 production remain unknown, but the levels of renal PGE 2 significantly affect the phenotype of PKD. Pharmacologic inhibition of PGE 2 synthesis in nonorthologous rodent models of ADPKD reduces water excretion, tubular epithelial cell proliferation, tubulointerstitial fibrosis, and macrophage infiltration (28,35). However, the animal models studied to date have not been genetically orthologous to human ADPKD.…”

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confidence: 99%

“…However, much of the evidence for the effect of PGE 2 on proliferation has been found in models of colon cancer where PGE 2 signals through EP1 (27), EP2 (12), or EP4 (13) receptors to induce cell growth. Conversely, cyclooxygenase (COX) inhibition prevents tumorigenesis in humans (34), and similarly, inhibition of COX reduced proliferation and cystogenesis in genetically nonorthologous models of ADPKD (35). The parallels between epithelial proliferation in models of colon cancer and PKD suggest that PGE 2 , an important renal epithelial metabolite, contributes to the proliferative phenotype of PKD epithelia.…”

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Prostaglandin E₂mediates proliferation and chloride secretion in ADPKD cystic renal epithelia

Liu

Rajagopal

Lee

et al. 2012

American Journal of Physiology-Renal Physiology

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mediates proliferation and chloride secretion in ADPKD cystic renal epithelia. Am J Physiol Renal Physiol 303: F1425-F1434, 2012. First published August 29, 2012 doi:10.1152/ajprenal.00010.2012 contributes to cystogenesis in genetically nonorthologous models of autosomal dominant polycystic kidney disease (ADPKD). However, it remains unknown whether PGE 2 induces the classic features of cystic epithelia in genetically orthologous models of ADPKD. We hypothesized that, in ADPKD epithelia, PGE2 induces proliferation and chloride (Cl Ϫ ) secretion, two archetypal phenotypic features of ADPKD. To test this hypothesis, proliferation and Cl Ϫ secretion were measured in renal epithelial cells deficient in polycystin-1 (PC-1). PC-1-deficient cells increased in cell number (proliferated) faster than PC-1-replete cells, and this proliferative advantage was abrogated by cyclooxygenase inhibition, indicating a role for PGE2 in cell proliferation. Exogenous administration of PGE2 increased proliferation of PC-1-deficient cells by 38.8 Ϯ 5.2% (P Ͻ 0.05) but inhibited the growth of PC-1-replete control cells by 49.4 Ϯ 1.9% (P Ͻ 0.05). Next, we tested whether PGE2-specific E prostanoid (EP) receptor agonists induce intracellular cAMP and downstream ␤-catenin activation. PGE 2 and EP4 receptor agonism (TCS 2510) increased intracellular cAMP concentration and the abundance of active ␤-catenin in PC-1-deficient cells, suggesting a mechanism for PGE 2-mediated proliferation. Consistent with this hypothesis, antagonizing EP4 receptors reverted the growth advantage of PC-1-deficient cells, implicating a central role for the EP4 receptor in proliferation. To test whether PGE 2-dependent Cl Ϫ secretion is also enhanced in PC-1-deficient cells, we used an Ussing chamber to measure short-circuit current (I sc). Addition of PGE 2 induced a fivefold higher increase in Isc in PC-1-deficient cells compared with PC-1-replete cells. This PGE 2-induced increase in Isc in PC-1-deficient cells was blocked by CFTR-172 and flufenamic acid, indicating that PGE 2 activates CFTR and calcium-activated Cl Ϫ channels. In conclusion, PGE2 activates aberrant signaling pathways in PC-1-deficient epithelia that contribute to the proliferative and secretory phenotype characteristic of ADPKD and suggests a therapeutic role for PGE2 inhibition and EP4 receptor antagonism.prostanoid; secretory renal epithelia; cystic epithelia; cyclooxygenase THE IMPORTANCE OF PRECISE regulation of prostaglandin (PG) synthetic and signaling pathways is emphasized by the essential role of PGs in normal physiologic functions, such as the control of sodium (Na ϩ ) and water excretion in the renal collecting duct (CD), as well as in the contribution of PGs to pathologic conditions, such as colon cancer (7,12,38). Autosomal dominant polycystic kidney disease (ADPKD) and autosomal recessive PKD are characterized histopathologically by a hyperproliferative cystic renal epithelium and clinically by polyuria (32). Recent observations suggest that altered prostanoid production contribut...

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Cyclooxygenase Metabolites in the Kidney

Harris

Zhang

2011

Comprehensive Physiology

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In the mammalian kidney, prostaglandins (PGs) are important mediators of physiologic processes, including modulation of vascular tone and salt and water. PGs arise from enzymatic metabolism of free arachidonic acid (AA), which is cleaved from membrane phospholipids by phospholipase A2 activity. The cyclooxygenase (COX) enzyme system is a major pathway for metabolism of AA in the kidney. COX are the enzymes responsible for the initial conversion of AA to PGG2 and subsequently to PGH2, which serves as the precursor for subsequent metabolism by PG and thromboxane synthases. In addition to high levels of expression of the "constitutive" rate-limiting enzyme responsible for prostanoid production, COX-1, the "inducible" isoform of cyclooxygenase, COX-2, is also constitutively expressed in the kidney and is highly regulated in response to alterations in intravascular volume. PGs and thromboxane A2 exert their biological functions predominantly through activation of specific 7-transmembrane G-protein-coupled receptors. COX metabolites have been shown to exert important physiologic functions in maintenance of renal blood flow, mediation of renin release and regulation of sodium excretion. In addition to physiologic regulation of prostanoid production in the kidney, increases in prostanoid production are also seen in a variety of inflammatory renal injuries, and COX metabolites may serve as mediators of inflammatory injury in renal disease.

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Selective COX-2 inhibition markedly slows disease progression and attenuates altered prostanoid production in Han:SPRD-cyrats with inherited kidney disease

Cited by 67 publications

References 58 publications

Flaxseed Consumption Reduces Blood Pressure in Patients With Hypertension by Altering Circulating Oxylipins via an α-Linolenic Acid–Induced Inhibition of Soluble Epoxide Hydrolase

Flaxseed Consumption Reduces Blood Pressure in Patients With Hypertension by Altering Circulating Oxylipins via an α-Linolenic Acid–Induced Inhibition of Soluble Epoxide Hydrolase

Prostaglandin E₂mediates proliferation and chloride secretion in ADPKD cystic renal epithelia

Cyclooxygenase Metabolites in the Kidney

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Selective COX-2 inhibition markedly slows disease progression and attenuates altered prostanoid production in Han:SPRD-cyrats with inherited kidney disease

Cited by 67 publications

References 58 publications

Flaxseed Consumption Reduces Blood Pressure in Patients With Hypertension by Altering Circulating Oxylipins via an α-Linolenic Acid–Induced Inhibition of Soluble Epoxide Hydrolase

Flaxseed Consumption Reduces Blood Pressure in Patients With Hypertension by Altering Circulating Oxylipins via an α-Linolenic Acid–Induced Inhibition of Soluble Epoxide Hydrolase

Prostaglandin E2mediates proliferation and chloride secretion in ADPKD cystic renal epithelia

Cyclooxygenase Metabolites in the Kidney

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Prostaglandin E₂mediates proliferation and chloride secretion in ADPKD cystic renal epithelia