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      Gender Differences in the Renin-Angiotensin and Nitric Oxide Systems: Relevance in the Normal and Diseased Kidney

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          Abstract

          Female gender is associated with better renal function and resistance to renal injury, suggesting that an oestrogen-based effect or increased androgenic effects are responsible. Studies in rodents have confirmed a biological basis for this, based on the differential effects of androgens and oestrogens on the normal and diseased kidney. Many researchers in the field believe that the pre-menopausal levels of oestrogen are key to the protection observed in females. The key pressor effects of the renin-angiotensin (RA) system are due to both direct vasoconstrictory properties and alterations in renal control of extracellular fluid volume. Additionally, the RA has been shown to promote diverse aspects of renal injury. RA activity is positively modulated by androgens and antagonized by oestrogens. Nitric oxide (NO) is a potent vasorelaxant with a key role in renal control of extracellular fluid homeostasis. NO can variously have both protective and deleterious effects on renal injury. Endogenous oestrogen has an anti-hypertensive effect as well as protective effects against cell and organ damage, many of which are mediated via increases in NO generation. We examine how the RA- and NO-generating systems may underpin key aspects of gender differences in normal renal function and renal disease.

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          Most cited references 96

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          Angiotensin II stimulates NADH and NADPH oxidase activity in cultured vascular smooth muscle cells.

          The signaling pathways involved in the long-term metabolic effects of angiotensin II (Ang II) in vascular smooth muscle cells are incompletely understood but include the generation of molecules likely to affect oxidase activity. We examined the ability of Ang II to stimulate superoxide anion formation and investigated the identity of the oxidases responsible for its production. Treatment of vascular smooth muscle cells with Ang II for 4 to 6 hours caused a 2.7 +/- 0.4-fold increase in intracellular superoxide anion formation as detected by lucigenin assay. This superoxide appeared to result from activation of both the NADPH and NADH oxidases. NADPH oxidase activity increased from 3.23 +/- 0.61 to 11.80 +/- 1.72 nmol O2-/min per milligram protein after 4 hours of Ang II, whereas NADH oxidase activity increased from 16.76 +/- 2.13 to 45.00 +/- 4.57 nmol O2-/min per milligram protein. The NADPH oxidase activity was stimulated by exogenous phosphatidic and arachidonic acids and was partially inhibited by the specific inhibitor diphenylene iodinium. NADH oxidase activity was increased by arachidonic and linoleic acids, was insensitive to exogenous phosphatidic acid, and was inhibited by high concentrations of quinacrine. Both of these oxidases appear to reside in the plasma membrane, on the basis of migration of the activity after cellular fractionation and their apparent insensitivity to the mitochondrial poison KCN. These observations suggest that Ang II specifically activates enzyme systems that promote superoxide generation and raise the possibility that these pathways function as second messengers for long-term responses, such as hypertrophy or hyperplasia.
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            Renal fibrosis: new insights into the pathogenesis and therapeutics.

             Youhua Liu (2005)
            Renal fibrosis is the inevitable consequence of an excessive accumulation of extracellular matrix that occurs in virtually every type of chronic kidney disease. The pathogenesis of renal fibrosis is a progressive process that ultimately leads to end-stage renal failure, a devastating disorder that requires dialysis or kidney transplantation. In a simplistic view, renal fibrosis represents a failed wound-healing process of the kidney tissue after chronic, sustained injury. Several cellular pathways, including mesangial and fibroblast activation as well as tubular epithelial-mesenchymal transition, have been identified as the major avenues for the generation of the matrix-producing cells in diseased conditions. Among the many fibrogenic factors that regulate renal fibrotic process, transforming growth factor-beta (TGF-beta) is one that plays a central role. Although defective matrix degradation may contribute to tissue scarring, the exact action and mechanisms of the matrix-degrading enzymes in the injured kidney have become increasingly complicated. Recent discoveries on endogenous antifibrotic factors have evolved novel strategies aimed at antagonizing the fibrogenic action of TGF-beta/Smad signaling. Many therapeutic interventions appear effective in animal models; however, translation of these promising results into humans in the clinical setting remains a daunting task. This mini-review attempts to highlight the recent progress in our understanding of the cellular and molecular pathways leading to renal fibrosis, and discusses the challenges and opportunities in developing therapeutic strategies.
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              Progression of kidney dysfunction in the community-dwelling elderly.

              Despite the high prevalence of chronic kidney disease among the elderly, few studies have described their loss of kidney function. We sought to determine the progression of kidney dysfunction among a community-based cohort of elderly subjects. The cohort included 10 184 subjects 66 years of age or older, who had one or more outpatient serum creatinine measurements during each of two time periods: 1 July to 31 December 2001 and 1 July to 31 December 2003. A mixed effects model, including covariates for age, gender, diabetes mellitus, and comorbidity, was used to determine the rate of decline in estimated glomerular filtration rate (eGFR, in ml/min/1.73 m2) per year over a median follow-up of 2.0 years. Subjects with diabetes mellitus had the greatest decline in eGFR of 2.1 (95% CI 1.8-2.5) and 2.7 (95% CI 2.3-3.1) ml/min/1.73 m2 per year in women and men, respectively. The rate of decline for women and men without diabetes mellitus was 0.8 (95% CI 0.6-1.0) and 1.4 (95% CI 1.2-1.6) ml/min/1.73 m2 per year. Subjects with a study mean eGFR<30 ml/min/1.73 m2, both those with and without diabetes mellitus, experienced the greatest decline in eGFR. In conclusion, we found that the majority of elderly subjects have no or minimal progression of kidney disease over 2 years. Strategies aimed at slowing progression of kidney disease should consider underlying risk factors for progression and the negligible loss of kidney function that occurs in the majority of older adults.
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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
                2007
                April 2007
                31 January 2007
                : 30
                : 2
                : 67-80
                Affiliations
                aUCD School of Medicine and Medical Sciences, Conway Institute of Biomolecular and Biomedical Sciences, University College Dublin, and bDepartment of Urology, Mater Misercordiae University Hospital Ltd, Dublin, Republic of Ireland; cInstituto Reina Sofía de Investigación Nefrológica y Departamento de Fisiología y Farmacología, Universidad de Salamanca, Salamanca, España
                Article
                99150 Kidney Blood Press Res 2007;30:67–80
                10.1159/000099150
                17268203
                © 2007 S. Karger AG, Basel

                Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher. 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.

                Page count
                Figures: 1, References: 144, Pages: 14
                Product
                Self URI (application/pdf): https://www.karger.com/Article/Pdf/99150
                Categories
                Review

                Cardiovascular Medicine, Nephrology

                Nitric oxide, Androgen, Oestrogen, Renin-angiotensin system

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