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      Prostaglandin Receptors in the Kidney: A New Route for Intervention?

      Cardiorenal Medicine

      S. Karger AG

      PGE2 , Cyclooxygenase, Hypertension, Transport, Hemodynamics

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          Prostaglandins comprise a structurally diverse family of cyclooxygenase metabolites of arachidonic acid, including thromboxane A<sub>2</sub>, PGD<sub>2</sub>, PGE<sub>2</sub>, PGF<sub>2α</sub> and PGI<sub>2</sub>. These prostaglandins are now known to act via different G-protein-coupled receptors. PGE<sub>2</sub>, the major prostaglandin synthesized along the nephron, interacts with at least four E-prostanoid (EP) receptors, three of which are highly expressed in distinct regions of the kidney. Each EP receptor also preferentially couples to a different signal transduction pathway, including stimulation of cAMP generation by the EP<sub>2</sub> and EP<sub>4</sub> receptors; inhibition of cAMP generation, via G<sub>i</sub> by EP<sub>3</sub> receptors, and activation of phosphatidylinositol hydrolysis by EP<sub>1</sub> receptor. Other intrarenal prostanoid receptors include the thromboxane A<sub>2</sub> receptor and the prostacyclin receptor. These receptors also exhibit a discrete intrarenal distribution. The possibility of pharmacologically targeting each renal prostanoid receptor may provide a unique approach to modifying renal function in disease states.

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          Most cited references 15

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          A comparison of continuous intravenous epoprostenol (prostacyclin) with conventional therapy for primary pulmonary hypertension.

          Primary pulmonary hypertension is a progressive disease for which no treatment has been shown in a prospective, randomized trial to improve survival. We conducted a 12-week prospective, randomized, multicenter open trial comparing the effects of the continuous intravenous infusion of epoprostenol (formerly called prostacyclin) plus conventional therapy with those of conventional therapy alone in 81 patients with severe primary pulmonary hypertension (New York Heart Association functional class III or IV). Exercise capacity was improved in the 41 patients treated with epoprostenol (median distance walked in six minutes, 362 m at 12 weeks vs. 315 m at base line), but it decreased in the 40 patients treated with conventional therapy alone (204 m at 12 weeks vs. 270 m at base line; P < 0.002 for the comparison of the treatment groups). Indexes of the quality of life were improved only in the epoprostenol group (P < 0.01). Hemodynamics improved at 12 weeks in the epoprostenol-treated patients. The changes in mean pulmonary-artery pressure for the epoprostenol and control groups were -8 percent and +3 percent, respectively (difference in mean change, -6.7 mm Hg; 95 percent confidence interval, -10.7 to -2.6 mm Hg; P < 0.002), and the mean changes in pulmonary vascular resistance for the epoprostenol and control groups were -21 percent and +9 percent, respectively (difference in mean change, -4.9 mm Hg/liter/min; 95 percent confidence interval, -7.6 to -2.3 mm Hg/liter/min; P < 0.001). Eight patients died during the study, all of whom had been randomly assigned to conventional therapy (P = 0.003). Serious complications included four episodes of catheter-related sepsis and one thrombotic event. As compared with conventional therapy, the continuous intravenous infusion of epoprostenol produced symptomatic and hemodynamic improvement, as well as improved survival in patients with severe primary pulmonary hypertension.
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            Complementation by the protein tyrosine kinase JAK2 of a mutant cell line defective in the interferon-gamma signal transduction pathway.

            Interferons (IFNs) alpha/beta (type I) and gamma (type II) bind to distinct cell surface receptors, inducing transcription of overlapping sets of genes by intracellular pathways that have recently attracted much attention. Previous studies using cell lines selected for their inability to respond to IFN-alpha (ref. 4) have shown that the protein kinase Tyk2 plays a central role in the IFN alpha/beta response. Here we report the isolation of the cell line gamma 1A, selected for its inability to express IFN-gamma-inducible cell-surface markers, that is deficient in all aspects of the IFN-gamma response tested, but responds normally to IFNs alpha and beta. The mutant cells can be complemented by the expression of another member of the JAK family of protein tyrosine kinases, JAK2 (refs 6-9). Unlike IFNs alpha and beta, IFN-gamma induces rapid tyrosine phosphorylation of JAK2 in wild-type cells, and JAK2 immunoprecipitates from these cells show tyrosine kinase activity. These responses are absent in gamma 1A cells. JAK2 is therefore required for the response to IFN-gamma but not to IFNs alpha and beta.
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              Cloning and expression of cDNA for a human thromboxane A2 receptor.

              Thromboxane A2 is a very unstable arachidonate metabolite, yet a potent stimulator of platelet aggregation and a constrictor of vascular and respiratory smooth muscles. It has been implicated as a mediator in diseases such as myocardial infarction, stroke and bronchial asthma. Using a stable analogue of this compound we recently purified the human platelet thromboxane A2 receptor to apparent homogeneity. Using an oligonucleotide probe corresponding to its partial amino-acid sequence, we have obtained a complementary DNA clone encoding this receptor from human placenta and a partial clone from cultured human megakaryocytic leukaemia cells. The placenta cDNA encodes a protein of 343 amino acids with seven putative transmembrane domains. The protein expressed in COS-7 cells binds drugs with affinities identical to those of the platelet receptor, and that in Xenopus oocytes opens Ca2(+)-activated Cl- channel on agonist stimulation. Northern blot analysis and nucleotide sequences of the two clones suggest that an identical species of the thromboxane A2 receptor is present in platelets and vascular tissues. This first report on the molecular structure of an eicosanoid receptor will promote the molecular pharmacology and pathophysiology of these bioactive compounds.

                Author and article information

                Nephron Exp Nephrol
                Cardiorenal Medicine
                S. Karger AG
                June 1998
                22 May 1998
                : 6
                : 3
                : 180-188
                Department of Veterans Affairs Medical Center and Vanderbilt University, Division of Nephrology, Departments of Medicine and Molecular Physiology and Biophysics, Nashville, Tenn., USA
                20521 Exp Nephrol 1998;6:180–188
                © 1998 S. Karger AG, Basel

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                Page count
                Figures: 1, Tables: 1, References: 96, Pages: 9
                Self URI (application/pdf):

                Cardiovascular Medicine, Nephrology

                Hypertension, Transport, Hemodynamics, PGE2 , Cyclooxygenase


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