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      Uremic Toxins: An Alarming Danger Concerning the Cardiovascular System

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          Abstract

          The kidneys and heart share functions with the common goal of maintaining homeostasis. When kidney injury occurs, many compounds, the so-called “uremic retention solutes” or “uremic toxins,” accumulate in the circulation targeting other tissues. The accumulation of uremic toxins such as p-cresyl sulfate, indoxyl sulfate and inorganic phosphate leads to a loss of a substantial number of body functions. Although the concept of uremic toxins is dated to the 1960s, the molecular mechanisms capable of leading to renal and cardiovascular injuries are not yet known. Besides, the greatest toxic effects appear to be induced by compounds that are difficult to remove by dialysis. Considering the close relationship between renal and cardiovascular functions, an understanding of the mechanisms involved in the production, clearance and overall impact of uremic toxins is extremely relevant for the understanding of pathologies of the cardiovascular system. Thus, the present study has as main focus to present an extensive review on the impact of uremic toxins in the cardiovascular system, bringing the state of the art on the subject as well as clinical implications related to patient’s therapy affected by chronic kidney disease, which represents high mortality of patients with cardiac comorbidities.

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          Most cited references177

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          Tryptophan catabolites from microbiota engage aryl hydrocarbon receptor and balance mucosal reactivity via interleukin-22.

          Endogenous tryptophan (Trp) metabolites have an important role in mammalian gut immune homeostasis, yet the potential contribution of Trp metabolites from resident microbiota has never been addressed experimentally. Here, we describe a metabolic pathway whereby Trp metabolites from the microbiota balance mucosal reactivity in mice. Switching from sugar to Trp as an energy source (e.g., under conditions of unrestricted Trp availability), highly adaptive lactobacilli are expanded and produce an aryl hydrocarbon receptor (AhR) ligand-indole-3-aldehyde-that contributes to AhR-dependent Il22 transcription. The resulting IL-22-dependent balanced mucosal response allows for survival of mixed microbial communities yet provides colonization resistance to the fungus Candida albicans and mucosal protection from inflammation. Thus, the microbiota-AhR axis might represent an important strategy pursued by coevolutive commensalism for fine tuning host mucosal reactivity contingent on Trp catabolism. Copyright © 2013 Elsevier Inc. All rights reserved.
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            FGF23 induces left ventricular hypertrophy.

            Chronic kidney disease (CKD) is a public health epidemic that increases risk of death due to cardiovascular disease. Left ventricular hypertrophy (LVH) is an important mechanism of cardiovascular disease in individuals with CKD. Elevated levels of FGF23 have been linked to greater risks of LVH and mortality in patients with CKD, but whether these risks represent causal effects of FGF23 is unknown. Here, we report that elevated FGF23 levels are independently associated with LVH in a large, racially diverse CKD cohort. FGF23 caused pathological hypertrophy of isolated rat cardiomyocytes via FGF receptor-dependent activation of the calcineurin-NFAT signaling pathway, but this effect was independent of klotho, the coreceptor for FGF23 in the kidney and parathyroid glands. Intramyocardial or intravenous injection of FGF23 in wild-type mice resulted in LVH, and klotho-deficient mice demonstrated elevated FGF23 levels and LVH. In an established animal model of CKD, treatment with an FGF-receptor blocker attenuated LVH, although no change in blood pressure was observed. These results unveil a klotho-independent, causal role for FGF23 in the pathogenesis of LVH and suggest that chronically elevated FGF23 levels contribute directly to high rates of LVH and mortality in individuals with CKD.
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              Gut microbiota-dependent trimethylamine N-oxide (TMAO) pathway contributes to both development of renal insufficiency and mortality risk in chronic kidney disease.

              Trimethylamine-N-oxide (TMAO), a gut microbial-dependent metabolite of dietary choline, phosphatidylcholine (lecithin), and l-carnitine, is elevated in chronic kidney diseases (CKD) and associated with coronary artery disease pathogenesis.
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                Author and article information

                Contributors
                URI : http://loop.frontiersin.org/people/1323697/overview
                URI : http://loop.frontiersin.org/people/998108/overview
                URI : http://loop.frontiersin.org/people/1308929/overview
                URI : http://loop.frontiersin.org/people/1283153/overview
                URI : http://loop.frontiersin.org/people/1323494/overview
                URI : http://loop.frontiersin.org/people/1308830/overview
                URI : http://loop.frontiersin.org/people/625970/overview
                Journal
                Front Physiol
                Front Physiol
                Front. Physiol.
                Frontiers in Physiology
                Frontiers Media S.A.
                1664-042X
                14 May 2021
                2021
                : 12
                : 686249
                Affiliations
                [1] 1Laboratory of Cardiovascular Immunology, Center of Natural and Human Sciences (CCNH), Federal University of ABC , Santo André, Brazil
                [2] 2Experimental Nephrology Laboratory, Basic Pathology Department, Universidade Federal do Paraná , Curitiba, Brazil
                Author notes

                Edited by: Adriana Castello Costa Girardi, University of São Paulo, Brazil

                Reviewed by: Jana Holmar, RWTH Aachen University, Germany; Nilberto Robson Falcão Nascimento, State University of Ceará, Brazil

                *Correspondence: Marcela Sorelli Carneiro-Ramos, marcela.ramos@ 123456ufabc.edu.br

                These authors have contributed equally to this work

                This article was submitted to Renal and Epithelial Physiology, a section of the journal Frontiers in Physiology

                Article
                10.3389/fphys.2021.686249
                8160254
                34054588
                eb0384be-4e2f-49d2-b1ae-240c3c83f5f7
                Copyright © 2021 Falconi, Junho, Fogaça-Ruiz, Vernier, da Cunha, Stinghen and Carneiro-Ramos.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 26 March 2021
                : 19 April 2021
                Page count
                Figures: 4, Tables: 2, Equations: 0, References: 177, Pages: 20, Words: 0
                Categories
                Physiology
                Review

                Anatomy & Physiology
                uremic toxins,cardiorenal syndrome,immune sustem,inflammation,cardiovascular diseases,renal diseases

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