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      Acute Effects of Cyclooxygenase-2 Inhibition on Renal Function in Heterozygous Ren-2-Transgenic Rats on Normal or Low Sodium Intake

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          Background/Aims: Since there are no data available so far on the role of renal cyclooxygenase-2 (COX-2) in hypertensive Ren-2-transgenic rats (TGR), in the present study we evaluated renal cortical COX-2 protein expression and prostaglandin E<sub>2</sub> (PGE<sub>2</sub>) concentrations as well as renal functional responses to acute COX-2 inhibition in male heterozygous TGR and in normotensive Hannover Sprague-Dawley (HanSD) rats fed either a normal-sodium (NS) or a low-sodium (LS) diet. Methods: In rats fed either the NS or the LS diet for 12 days and prepared for clearance experiments with left ureteral catheterization, the renal functional responses of the left kidney were evaluated after intrarenal COX-2 inhibition with DuP-697 or NS-398. In renal cortical tissue, COX-2 protein expression was assessed by immunoblotting, and the concentration of PGE<sub>2</sub> as a marker of COX-2 activity was determined by enzyme immunoassay. Mean arterial pressure in the right femoral artery was monitored by means of a pressure transducer. Results: In heterozygous TGR, to our surprise, the LS diet normalized the mean arterial pressure. Despite significantly higher renocortical expression of COX-2 and PGE<sub>2</sub> concentrations as well as urinary PGE<sub>2 </sub>excretion in TGR as compared with HanSD rats kept on the NS diet, selective intrarenal COX-2 inhibition did not influence renal function either in TGR or in HanSD rats. The LS diet increased renocortical COX-2 expression and PGE<sub>2</sub> concentrations as well as urinary PGE<sub>2 </sub>excretion significantly stronger in TGR than in HanSD rats. Regardless of these increases, the intrarenal COX-2 inhibition caused comparable decreases in glomerular filtration rate, in absolute and fractional sodium excretion, as well as in urinary PGE<sub>2 </sub>excretion in TGR and HanSD rats kept on the LS diet. Conclusions: The present data show that a LS diet normalizes the mean arterial pressure in heterozygous male TGR. This first study on the role of renal COX-2 in TGR also demonstrates that COX-2-derived vasodilatory prostanoids do not act as renal compensatory vasodilator and natriuretic substances in this model of hypertension.

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          Most cited references 15

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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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            Immunohistochemical and functional correlations of renal cyclooxygenase-2 in experimental diabetes.

            Prostaglandins (PGs) generated by the enzyme cyclooxygenase (COX) have been implicated in the pathological renal hemodynamics and structural alterations in diabetes mellitus, but the role of individual COX isoenzymes in diabetic nephropathy remains unknown. We explored COX-1 and COX-2 expression and hemodynamic responses to the COX-1 inhibitor valeryl salicylate (VS) or the COX-2 inhibitor NS398 in moderately hyperglycemic, streptozotocin-diabetic (D) and control (C) rats. Immunoreactive COX-2 was increased in D rats compared with C rats and normalized by improved glycemic control. Acute systemic administration of NS398 induced no significant changes in mean arterial pressure and renal plasma flow in either C or D rats but reduced glomerular filtration rate in D rats, resulting in a decrease in filtration fraction. VS had no effect on renal hemodynamics in D rats. Both inhibitors decreased urinary excretion of PGE(2). However, only NS398 reduced excretion of thromboxane A(2). In conclusion, we documented an increase in renal cortical COX-2 protein expression associated with a different renal hemodynamic response to selective systemic COX-2 inhibition in D as compared with C animals, indicating a role of COX-2-derived PG in pathological renal hemodynamic changes in diabetes.
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              Contribution of Angiotensin-(1–7) to Blood Pressure Regulation in Salt-Depleted Hypertensive Rats

              We exposed 63 adult spontaneously hypertensive rats (SHR) and 10 (mRen-2)27 transgenic hypertensive rats to a 12-day regimen of either a normal diet (0.5%) or a low-salt diet (0.05%) to evaluate the hypothesis that the vasodepressor heptapeptide, angiotensin-(1-7) [Ang-(1-7)], buffers the pressor effects of angiotensin II during endogenous stimulation of the renin-angiotensin system. Catheters were inserted into a carotid artery and jugular vein under light anesthesia the day before the experiment. Separate groups of conscious instrumented SHR were given short-term infusions of an affinity-purified monoclonal Ang-(1-7) antibody or the neprilysin inhibitor SCH 39370. In addition, SHR and (mRen-2)27 rats were given the Ang-(1-7) receptor antagonist [D-Ala(7)]Ang-(1-7). Exposure to the low-salt diet increased plasma renin activity and elevated plasma levels of angiotensin I and angiotensin II in SHR by 81% and 68%, respectively, above values determined in SHR fed a normal salt diet. Concentrations of angiotensin I and angiotensin II were also higher in the kidney of salt-depleted SHR, whereas plasma and renal tissue levels of Ang-(1-7) were unchanged. Infusion of the Ang-(1-7) antibody produced dose-dependent pressor and tachycardic responses in salt-depleted SHR but no effect in SHR maintained on a normal-salt diet. A comparable cardiovascular response was produced in salt-depleted SHR given either SCH 39370 or [D-Ala(7)]Ang-(1-7). These agents had negligible effects on SHR fed a normal-salt diet. Blockade of Ang-(1-7) receptors produced a similar cardiovascular response in (mRen-2)27 transgenic hypertensive rats fed a low-salt diet. Injections of the heat-inactivated antibody or the subsequent infusion of the antibody to rats given [D-Ala(7)]Ang-(1-7) produced no additional effects. The data support the hypothesis that the hemodynamic effects of neurohormonal activation after salt restriction stimulate a tonic depressor action of Ang-(1-7).

                Author and article information

                Kidney Blood Press Res
                Kidney and Blood Pressure Research
                S. Karger AG
                September 2004
                08 September 2004
                : 27
                : 4
                : 203-210
                aCenter of Experimental Medicine, Institute for Clinical and Experimental Medicine, Prague, Czech Republic; bSection of Nephrology, Medical Policlinic, Department of Medicine, University of Bonn, Bonn, and cMax Delbrück Center for Molecular Medicine Berlin-Buch, Berlin, Germany
                79865 Kidney Blood Press Res 2004;27:203–210
                © 2004 S. Karger AG, Basel

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                Figures: 5, Tables: 1, References: 34, Pages: 8
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