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      Up-Regulation of Intrarenal Renin-Agiotensin System Contributes to Renal Damage in High-Salt Induced Hypertension Rats

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          Abstract

          Background/Aims: To investigate the change of intrarenal renin-agiotensin system (RAS) and its role in high-salt induced hypertension. Methods: Wistar rats were divided into normal-salt (NS), high-s alt diet (HS) and high-salt diet with Losartan group (HS+L), for 6 weeks. Systolic blood pressure (SBP) was monitored. Blood and urine samples were collected every 2 weeks. Angiotensinogen (AGT) was measured by ELISA. AGT mRNA and protein were measured by real-time PCR and immunohistochemistry. Renin activity and angiotensin II (Ang II) were measured by radioimmunoassay. Results: HS versus NS group, SBP increased from 2<sup>nd</sup> week ( P<0.05), urinary protein increased at 6<sup>th</sup> week ( P<0.05). Although plasma renin, AGT and Ang II had no significant changes ( P>0.05), renal cortex renin, AGT, and Ang II increased significantly in HS ( P<0.05). In HS+L, Losartan failed to reduce SBP ( P>0.05) but abolished the increase of proteinuria ( P<0.01), renal cortex renin, AGT, Ang II and urinary AGT reduced ( P<0.05) while plasma renin, AGT and Ang II enhanced ( P<0.05) when compared with HS. Urinary AGT was positively correlated with renal AGT (r=0.592, P <0.01) and Ang II (r=0.726, P <0.01). Conclusion: Inappropriate response of the renal RAS to a high salt diet may contribute to hypertension and renal damage, and urinary AGT could reflect intrarenal RAS activity.

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          Most cited references29

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          The intrarenal renin-angiotensin system: from physiology to the pathobiology of hypertension and kidney disease.

          In recent years, the focus of interest on the role of the renin-angiotensin system (RAS) in the pathophysiology of hypertension and organ injury has changed to a major emphasis on the role of the local RAS in specific tissues. In the kidney, all of the RAS components are present and intrarenal angiotensin II (Ang II) is formed by independent multiple mechanisms. Proximal tubular angiotensinogen, collecting duct renin, and tubular angiotensin II type 1 (AT1) receptors are positively augmented by intrarenal Ang II. In addition to the classic RAS pathways, prorenin receptors and chymase are also involved in local Ang II formation in the kidney. Moreover, circulating Ang II is actively internalized into proximal tubular cells by AT1 receptor-dependent mechanisms. Consequently, Ang II is compartmentalized in the renal interstitial fluid and the proximal tubular compartments with much higher concentrations than those existing in the circulation. Recent evidence has also revealed that inappropriate activation of the intrarenal RAS is an important contributor to the pathogenesis of hypertension and renal injury. Thus, it is necessary to understand the mechanisms responsible for independent regulation of the intrarenal RAS. In this review, we will briefly summarize our current understanding of independent regulation of the intrarenal RAS and discuss how inappropriate activation of this system contributes to the development and maintenance of hypertension and renal injury. We will also discuss the impact of antihypertensive agents in preventing the progressive increases in the intrarenal RAS during the development of hypertension and renal injury.
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            Tissue renin-angiotensin-aldosterone systems: Targets for pharmacological therapy.

            The renin-angiotensin-aldosterone system is one of the most important systems in cardiovascular control and in the pathogenesis of cardiovascular diseases. Therefore, it is already a very successful drug target for the therapy of these diseases. However, angiotensins are generated not only in the plasma but also locally in tissues from precursors and substrates either locally expressed or imported from the circulation. In most areas of the brain, only locally generated angiotensins can exert effects on their receptors owing to the blood-brain barrier. Other tissue renin-angiotensin-aldosterone systems are found in cardiovascular organs such as kidney, heart, and vessels and play important roles in the function of these organs and in the deleterious actions of hypertension and diabetes on these tissues. Novel components with mostly opposite actions to the classical renin-angiotensin-aldosterone systems have been described and need functional characterization to evaluate their suitability as novel drug targets.
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              AT1A angiotensin receptors in the renal proximal tubule regulate blood pressure.

              Hypertension affects more than 1.5 billion people worldwide but the precise cause of elevated blood pressure (BP) cannot be determined in most affected individuals. Nonetheless, blockade of the renin-angiotensin system (RAS) lowers BP in the majority of patients with hypertension. Despite its apparent role in hypertension pathogenesis, the key cellular targets of the RAS that control BP have not been clearly identified. Here we demonstrate that RAS actions in the epithelium of the proximal tubule have a critical and nonredundant role in determining the level of BP. Abrogation of AT(1) angiotensin receptor signaling in the proximal tubule alone is sufficient to lower BP, despite intact vascular responses. Elimination of this pathway reduces proximal fluid reabsorption and alters expression of key sodium transporters, modifying pressure-natriuresis and providing substantial protection against hypertension. Thus, effectively targeting epithelial functions of the proximal tubule of the kidney should be a useful therapeutic strategy in hypertension. Copyright © 2011 Elsevier Inc. All rights reserved.
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                Author and article information

                Journal
                KBR
                Kidney Blood Press Res
                10.1159/issn.1420-4096
                Kidney and Blood Pressure Research
                S. Karger AG
                1420-4096
                1423-0143
                2014
                December 2014
                29 November 2014
                : 39
                : 6
                : 526-535
                Affiliations
                Department of Nephrology, Peking University Third Hospital, Beijing 100191, China
                Author notes
                *WANG Yue, M.D., Ph.D., Professor in Medicine, Department of Nephrology, Peking University Third Hospital, 49 North Garden road,, Haidian district, Beijing 100191 (P.R. China), Tel. +86 010 82266978, E-Mail bjwangyue@sina.com
                Article
                368463 Kidney Blood Press Res 2014;39:526-535
                10.1159/000368463
                25531334
                93b11a7c-4d44-4f42-9699-9916955a1d67
                © 2014 S. Karger AG, Basel

                Open Access License: This is an Open Access article licensed under the terms of the Creative Commons Attribution-NonCommercial 3.0 Unported license (CC BY-NC) ( http://www.karger.com/OA-license), applicable to the online version of the article only. Distribution permitted for non-commercial purposes only. Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug. Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

                History
                : 17 October 2014
                Page count
                Pages: 10
                Categories
                Original Paper

                Cardiovascular Medicine,Nephrology
                Hypertension,Intrarenal RAS,Angiotensinogen,Angiotensin II,High-salt diet

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