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      Blockade of Endothelin Receptors Attenuates End-Organ Damage in Homozygous Hypertensive Ren-2 Transgenic Rats

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          Background/Aims: A growing body of evidence suggests that the interplay between the endothelin (ET) and the renin-angiotensin systems (RAS) plays an important role in the development of the malignant phase of hypertension. The present study was performed to evaluate the role of an interaction between ET and RAS in the development of hypertension and hypertension-associated end-organ damage in homozygous male transgenic rats harboring the mouse Ren-2 renin gene (TGRs) under conditions of normal-salt (NS, 0.45% NaCl) and high-salt (HS, 2% NaCl) intake. Methods: Twenty-eight-day-old homozygous male TGRs and age-matched transgene-negative male normotensive Hannover Sprague-Dawley (HanSD) rats were randomly assigned to groups with NS or HS intake. Nonselective ET<sub>A/B</sub> receptor blockade was achieved with bosentan (100 mg/kg/day). Systolic blood pressure (BP) was measured in conscious animals by tail plethysmography. Rats were placed into metabolic cages to determine proteinuria and clearance of endogenous creatinine. At the end of the experiment the final arterial BP was measured directly in anesthetized rats. Kidneys were taken for morphological examination. Results: All male HanSD fed either the NS or HS diet exhibited a 100% survival rate until 180 days of age (end of experiment). The survival rate in untreated homozygous male TGRs fed the NS diet was 41%, which was markedly improved by treatment with bosentan to 88%. The HS diet reduced the survival rate in homozygous male TGRs to 10%. The survival rate in homozygous male TGRs on the HS diet was significantly improved by bosentan to 69%. Treatment with bosentan did not influence either the course of hypertension or the final levels of BP in any of the experimental groups of HanSD rats or TGRs. Although the ET-1 content in the renal cortex did not differ between HanSD rats and TGRs, ET-1 in the left heart ventricle of TGRs fed the HS diet was significantly higher compared with all other groups. Administration of bosentan to homozygous male TGRs fed either the NS or HS diet markedly reduced proteinuria, glomerulosclerosis and attenuated the development of cardiac hypertrophy compared with untreated TGR. Conclusions: Our data show that nonselective ET<sub>A/B</sub> receptor blockade markedly improves the survival rate and ameliorates end-organ damage in homozygous male TGRs without significantly lowering BP.

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          Most cited references 39

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          Transcription factor-kappa B (NF-kappa B) and renal disease.

           C Guijarro,  J. Egido (2001)
          Transcription factor-kappa B (NF-kappa B) and renal disease. Nuclear factor-kappa B (NF-kappa B) comprises a family of dimeric transcription factors that regulate the expression of numerous genes involved in inflammation and cell proliferation. Although NF-kappa B was initially identified in lymphocytes, it has been found to be a transcription factor present in virtually all cell types. In resting cells, NF-kappa B dimers remain in the cytoplasm in an inactive form bound to the inhibitory subunit I kappa B. Upon stimulation, I kappa B is phosphorylated, ubiquitinylated, and ultimately degraded by proteolytic cleavage by the proteasome system. As a result, NF-kappa B dimers are translocated into the nucleus and activate the transcription of target genes. Increasing data suggest a pivotal role for NF-kappa B in a variety of pathophysiological conditions in which either inflammation or cell number control are critical events. NF-kappa B has been found to be activated in experimental renal disease. Importantly, both in vivo and in vitro, NF-kappa B activation can be modulated by pharmacological maneuvers. Indeed, it is now widely acknowledged that the anti-inflammatory action of steroids is basically obtained through the inhibition of the transactivation of NF-kappa B-dependent genes. In addition, some of the beneficial effects of angiotensin-converting enzyme inhibitors and statins may, at least in part, be mediated by an inhibition of NF-kappa B activation. A better understanding of the mechanisms involved in NF-kappa B regulation and its modulation may provide new tools to improve the treatment of renal diseases with a better sound pathophysiological approach.
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            Endothelin-1 transgenic mice develop glomerulosclerosis, interstitial fibrosis, and renal cysts but not hypertension.

            The human endothelin-1 (ET-1) gene under the control of its natural promoter was transferred into the germline of mice. The transgene was expressed predominantly in the brain, lung, and kidney. Transgene expression was associated with a pathological phenotype manifested by signs such as age-dependent development of renal cysts, interstitial fibrosis of the kidneys, and glomerulosclerosis leading to a progressive decrease in glomerular filtration rate. This pathology developed in spite of only slightly elevated plasma and tissue ET-1 concentrations. Blood pressure was not affected even after the development of an impaired glomerular filtration rate. Therefore, these transgenic lines provide a new blood pressure-independent animal model of ET-1-induced renal pathology leading to renal fibrosis and fatal kidney disease.
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              Tissue renin-angiotensin systems: new insights from experimental animal models in hypertension research.

              Renin was first isolated in the kidney by Tigerstedt and Bergman over 100 years ago. Almost 50 additional years were necessary to isolate the renin substrate angiotensinogen and to show its cleavage to angiotensin (Ang). Further studies were then needed to demonstrate that Ang I is converted via an angiotensin-converting enzyme to Ang II. The circulating renin-angiotensin system, with blood pressure regulatory and aldosterone stimulatory roles, served well for decades. However, more recent information on Ang II and its action in terms of cell proliferation, hypertrophy, and hyperplasia as well as immune-modulatory and even intracellular functions, have focused attention on local Ang II generation and effects. These investigations necessarily began in the kidney, but quickly moved to other organs including the brain, heart, adrenal gland, and vessel wall and formed the basis for the concept of independent tissue renin-angiotensin systems. Both renin and Ang II have even been implicated in intracellular activities. This review presents some selected aspects of the historical development of this concept and summarizes discoveries relying primarily on animal models which demonstrate that Ang II is generated locally and acts in tissues as a local peptidergic system. Comprehensiveness in such an endeavor is not possible. We focus largely on work from our own group, not because the work is necessarily worthy of such scrutiny but rather because of our own familiarity with the contents.

                Author and article information

                Kidney Blood Press Res
                Kidney and Blood Pressure Research
                S. Karger AG
                September 2004
                08 September 2004
                : 27
                : 4
                : 248-258
                aCenter for Experimental Medicine, Institute for Clinical and Experimental Medicine, Prague, Czech Republic; bSection of Nephrology, Medical Policlinic, Department of Medicine, University of Bonn, Bonn, Germany; cDepartment of Nephrology, 1st Department of Medicine, 1st Medical Faculty, Charles University, Prague, Czech Republic; dMax Delbrück Center for Molecular Medicine and Franz Volhard Clinic, Berlin-Buch, Germany; eDepartment of Pediatrics, 2nd Medical Faculty, and fDepartment of Pathology, 3rd Medical Faculty, Charles University, Prague, Czech Republic
                80052 Kidney Blood Press Res 2004;27:248–258
                © 2004 S. Karger AG, Basel

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                Page count
                Figures: 5, Tables: 3, References: 48, Pages: 11
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