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      Pathological cardiac remodeling occurs early in CKD mice from unilateral urinary obstruction, and is attenuated by Enalapril

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          Abstract

          Cardiovascular disease constitutes the leading cause of mortality in patients with chronic kidney disease (CKD) and end-stage renal disease. Despite increasing recognition of a close interplay between kidney dysfunction and cardiovascular disease, termed cardiorenal syndrome (CRS), the underlying mechanisms of CRS remain poorly understood. Here we report the development of pathological cardiac hypertrophy and fibrosis in early stage non-uremic CKD. Moderate kidney failure was induced three weeks after unilateral urinary obstruction (UUO) in mice. We observed pathological cardiac hypertrophy and increased fibrosis in UUO-induced CKD (UUO/CKD) animals. Further analysis indicated that this cardiac fibrosis was associated with increased expression of transforming growth factor β (TGF-β) along with significant upregulation of Smad 2/3 signaling in the heart. Moreover early treatment of UUO/CKD animals with an angiotensin-converting-enzyme inhibitor (ACE I), Enalapril, significantly attenuated cardiac fibrosis. Enalapril antagonized activation of the TGF-β signaling pathway in the UUO/CKD heart. In summary our study demonstrates the presence of pathological cardiac hypertrophy and fibrosis in mice early in UUO-induced CKD, in association with early activation of the TGF-β/Smad signaling pathway. We also demonstrate the beneficial effect of ACE I in alleviating this early fibrogenic process in the heart in UUO/CKD animals.

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          Most cited references 79

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          Cardiac Fibrosis: The Fibroblast Awakens.

          Myocardial fibrosis is a significant global health problem associated with nearly all forms of heart disease. Cardiac fibroblasts comprise an essential cell type in the heart that is responsible for the homeostasis of the extracellular matrix; however, upon injury, these cells transform to a myofibroblast phenotype and contribute to cardiac fibrosis. This remodeling involves pathological changes that include chamber dilation, cardiomyocyte hypertrophy and apoptosis, and ultimately leads to the progression to heart failure. Despite the critical importance of fibrosis in cardiovascular disease, our limited understanding of the cardiac fibroblast impedes the development of potential therapies that effectively target this cell type and its pathological contribution to disease progression. This review summarizes current knowledge regarding the origins and roles of fibroblasts, mediators and signaling pathways known to influence fibroblast function after myocardial injury, as well as novel therapeutic strategies under investigation to attenuate cardiac fibrosis.
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            TGF-β signaling in fibrosis.

            Transforming growth factor β (TGF-β) is a central mediator of fibrogenesis. TGF-β is upregulated and activated in fibrotic diseases and modulates fibroblast phenotype and function, inducing myofibroblast transdifferentiation while promoting matrix preservation. Studies in a wide range of experimental models have demonstrated the involvement of the canonical activin receptor-like kinase 5/Smad3 pathway in fibrosis. Smad-independent pathways may regulate Smad activation and, under certain conditions, may directly transduce fibrogenic signals. The profibrotic actions of TGF-β are mediated, at least in part, through induction of its downstream effector, connective tissue growth factor. In light of its essential role in the pathogenesis of fibrosis, TGF-β has emerged as an attractive therapeutic target. However, the pleiotropic and multifunctional effects of TGF-β and its role in tissue homeostasis, immunity and cell proliferation raise concerns regarding potential side effects that may be caused by TGF-β blockade. This minireview summarizes the role of TGF-β signaling pathways in the fibrotic response.
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              Aspects of immune dysfunction in end-stage renal disease.

              End-stage renal disease (ESRD) is associated with significantly increased morbidity and mortality resulting from cardiovascular disease (CVD) and infections, accounting for 50% and 20%, respectively, of the total mortality in ESRD patients. It is possible that these two complications are linked to alterations in the immune system in ESRD, as uremia is associated with a state of immune dysfunction characterized by immunodepression that contributes to the high prevalence of infections among these patients, as well as by immunoactivation resulting in inflammation that may contribute to CVD. This review describes disorders of the innate and adaptive immune systems in ESRD, underlining the specific role of ESRD-associated disturbances of Toll-like receptors. Finally, based on the emerging links between the alterations of immune system, CVD, and infections in ESRD patients, it emphasizes the potential role of the immune dysfunction in ESRD as an underlying cause for the high mortality in this patient population and the need for more studies in this area.
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                Author and article information

                Contributors
                halu@partners.org
                Journal
                Sci Rep
                Sci Rep
                Scientific Reports
                Nature Publishing Group UK (London )
                2045-2322
                31 October 2018
                31 October 2018
                2018
                : 8
                Affiliations
                [1 ]ISNI 000000041936754X, GRID grid.38142.3c, Center for Systems Biology, Program in Membrane Biology, , Division of Nephrology, Massachusetts General Hospital and Harvard Medical School, ; Boston, MA 02114 USA
                [2 ]ISNI 0000 0001 2256 9319, GRID grid.11135.37, Department of Pharmacology, School of Basic Medical Sciences, , Peking University, ; Beijing, China
                [3 ]ISNI 0000 0001 2355 7002, GRID grid.4367.6, College of Arts & Sciences, , Washington University in St. Louis, ; St. Louis, MO 63130 USA
                [4 ]ISNI 0000 0004 0386 9924, GRID grid.32224.35, Corrigan Minehan Heart Center, , Massachusetts General Hospital and Harvard Medical School, ; Boston, MA 02114 USA
                Article
                34216
                10.1038/s41598-018-34216-x
                6208335
                © The Author(s) 2018

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

                Funding
                Funded by: FundRef https://doi.org/10.13039/100000968, American Heart Association (American Heart Association, Inc.);
                Award ID: 16FTF29630016
                Award ID: 16SFRN31720000
                Award Recipient :
                Funded by: FundRef https://doi.org/10.13039/100000002, U.S. Department of Health & Human Services | National Institutes of Health (NIH);
                Award ID: HL135886
                Award Recipient :
                Funded by: FundRef https://doi.org/10.13039/100000009, Foundation for the National Institutes of Health (Foundation for the National Institutes of Health, Inc.);
                Award ID: HL122987
                Award Recipient :
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