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      Increased Expression of Renal Cyclooxygenase-2 and Neuronal Nitric Oxide Synthase in Hypertensive Cx40-Deficient Mice

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          Cx40-deficient mice (Cx40–/–) are hypertensive due to increased renin secretion. We evaluated the renal expression of neuronal nitric oxide synthase (nNOS) and cyclooxygenases COX-1 and COX-2, three macula densa enzymes. The levels of nNOS were increased in kidneys of Cx40–/– mice, as well as in those of wild-type (WT) mice subjected to the two-kidney one-clip model of hypertension. In contrast, the levels of COX-2 expression were only increased in the hypoperfused kidney of Cx40–/– mice. Treatment with indomethacin lowered blood pressure and renin mRNA in Cx40–/– mice without affecting renin levels, indicating that changes in COX-2 do not cause the altered secretion of renin. Suppression of NOS activity by N<sup>G</sup>-nitro- L-arginine methyl ester ( L-NAME) decreased renin levels in Cx40–/– animals, indicating that NO regulates renin expression in the absence of Cx40. Treatment with candesartan normalized blood pressure in Cx40–/– mice, and decreased the levels of both COX-2 and nNOS. After a treatment combining candesartan and L-NAME, the blood pressure of Cx40–/– mice was higher than that of WT mice, showing that NO may counterbalance the vasoconstrictor effects of angiotensin II in Cx40–/– mice. These data document that renal COX-2 and nNOS are differentially regulated due to the elevation of renin-dependent blood pressure in mice lacking Cx40.

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          Most cited references 27

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          Cyclooxygenase-2 is associated with the macula densa of rat kidney and increases with salt restriction.

          The kidney is a rich source of prostaglandins. These eicosanoids, formed by cyclooxygenase-dependent metabolism of arachidonic acid, are important physiologic mediators of renal glomerular hemodynamics and tubular sodium and water reabsorption. Two separate isoforms of cyclooxygenase (COX) have now been identified: constitutive COX-1, encoded by a 2.8-kb mRNA, and mitogen-activated COX-2, encoded by a 4.0-4.5-kb mRNA. COX-2 expression increases during development and inflammation, but, except for brain, constitutive expression is low. It has been generally accepted that physiologic renal production of prostaglandins is mediated by COX-1. However, in the absence of inflammation, low levels of COX-2 mRNA are also detectable in the kidney. To examine the role of COX-2 in the kidney and determine its intrarenal localization, we used a 1.3-kb cDNA probe specific for the 3' untranslated region of rat COX-2 and COX-2-specific antiserum. The COX-2-specific cDNA probe hybridized with a 4.4-kb transcript in total RNA from adult rat kidney. Immunoblots of microsomes isolated from kidney cortex and papilla indicated immunoreactive COX-2 in both locations. In situ hybridization and immunohistochemistry indicated that renal cortical COX-2 expression was localized to the macula densa of the juxtaglomerular apparatus and to adjacent epithelial cells of the cortical thick ascending limb of Henle. In addition, COX-2 immunoreactivity was detected in interstitial cells in the papilla. No COX-2 message or immunoreactive protein was detected in arterioles, glomeruli, or cortical or medullary collecting ducts. When animals were chronically sodium restricted, the level of COX-2 in the region of the macula densa increased threefold (from 0.86 +/- 0.08 to 2.52 +/- 0.43/mm2) and the total area of the COX-2 immunoreactive cells in cortex increased from 34 microns2/mm2 of cortex to 226 microns2/mm2 of cortex. The intrarenal distribution of COX-2 and its increased expression in response to sodium restriction suggest that in addition to its proposed role in inflammatory and growth responses, this enzyme may play an important role in the regulation of salt, volume, and blood pressure homeostasis.
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            Nitric oxide in the kidney: functions and regulation of synthesis.

             Sarah Power,  P Mount (2006)
            In the kidney nitric oxide (NO) has numerous important functions including the regulation of renal haemodynamics, maintenance of medullary perfusion, mediation of pressure-natriuresis, blunting of tubuloglomerular feedback, inhibition of tubular sodium reabsorption and modulation of renal sympathetic neural activity. The net effect of NO in the kidney is to promote natriuresis and diuresis. Significantly, deficient renal NO synthesis has been implicated in the pathogenesis of hypertension. All three isoforms of nitric oxide synthase (NOS), namely neuronal NOS (nNOS or NOS1), inducible NOS (iNOS or NOS2) and endothelial NOS (eNOS or NOS3) are reported to contribute to NO synthesis in the kidney. The regulation of NO synthesis in the kidney by NOSs is complex and incompletely understood. Historically, many studies of NOS regulation in the kidney have emphasized the role of variations in gene transcription and translation. It is increasingly appreciated, however, that the constitutive NOS isoforms (nNOS and eNOS) are also subject to rapid regulation by post-translational mechanisms such as Ca(2+) flux, serine/threonine phosphorylation and protein-protein interactions. Recent studies have emphasized the role of post-translational regulation of nNOS and eNOS in the regulation of NO synthesis in the kidney. In particular, a role for phosphorylation of nNOS and eNOS at both activating and inhibitory sites is emerging in the regulation of NO synthesis in the kidney. This review summarizes the roles of NO in renal physiology and discusses recent advances in the regulation of eNOS and nNOS in the kidney by post-translational mechanisms such as serine/threonine phosphorylation.
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              Mice lacking connexin40 have cardiac conduction abnormalities characteristic of atrioventricular block and bundle branch block.

              Activation of cardiac muscle is mediated by the His-Purkinje system, a discrete pathway containing fast-conducting cells (Purkinje fibers) which coordinate the spread of excitation from the atrioventricular node (AV node) to ventricular myocardium [1]. Although pathologies of this specialized conduction system are common in humans, especially among the elderly [2], their molecular bases have not been defined. Gap junctions are present at appositions between Purkinje fibers and could provide a mechanism for propagating impulses between these cells [3]. Studies of the expression of connexins - the family of proteins from which gap junctions are formed - reveal that connexin40 (Cx40) is prominent in the conduction system [4]. In order to study the role of gap junction communication in cardiac conduction, we generated mice that lack Cx40. Using electrocardiographic analysis, we show that Cx40 null mice have cardiac conduction abnormalities characteristic of first-degree atrioventricular block with associated bundle branch block. Thus, gap junctions are essential for the rapid conduction of impulses in the His-Purkinje system.

                Author and article information

                J Vasc Res
                Journal of Vascular Research
                S. Karger AG
                April 2009
                24 September 2008
                : 46
                : 3
                : 188-198
                aDepartment of Medicine, University Hospital, Lausanne, bDepartment of Internal Medicine, University of Geneva, School of Medicine, HUG, and cDepartment of Cell Physiology and Metabolism, University of Geneva, School of Medicine, CMU, Geneva, Switzerland
                156704 J Vasc Res 2009;46:188–198
                © 2008 S. Karger AG, Basel

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                Page count
                Figures: 5, Tables: 2, References: 56, Pages: 11
                Research Paper


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