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      Identification of AnnexinA1 as an Endogenous Regulator of RhoA, and Its Role in the Pathophysiology and Experimental Therapy of Type-2 Diabetes

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          Abstract

          Annexin A1 (ANXA1) is an endogenously produced anti-inflammatory protein, which plays an important role in the pathophysiology of diseases associated with chronic inflammation. We demonstrate that patients with type-2 diabetes have increased plasma levels of ANXA1 when compared to normoglycemic subjects. Plasma ANXA1 positively correlated with fatty liver index and elevated plasma cholesterol in patients with type-2 diabetes, suggesting a link between aberrant lipid handling, and ANXA1. Using a murine model of high fat diet (HFD)-induced insulin resistance, we then investigated (a) the role of endogenous ANXA1 in the pathophysiology of HFD-induced insulin resistance using ANXA1 −/− mice, and (b) the potential use of hrANXA1 as a new therapeutic approach for experimental diabetes and its microvascular complications. We demonstrate that: (1) ANXA1 −/− mice fed a HFD have a more severe diabetic phenotype (e.g., more severe dyslipidemia, insulin resistance, hepatosteatosis, and proteinuria) compared to WT mice fed a HFD; (2) treatment of WT-mice fed a HFD with hrANXA1 attenuated the development of insulin resistance, hepatosteatosis and proteinuria. We demonstrate here for the first time that ANXA1 −/− mice have constitutively activated RhoA. Interestingly, diabetic mice, which have reduced tissue expression of ANXA1, also have activated RhoA. Treatment of HFD-mice with hrANXA1 restored tissue levels of ANXA1 and inhibited RhoA activity, which, in turn, resulted in restoration of the activities of Akt, GSK-3β and endothelial nitric oxide synthase (eNOS) secondary to re-sensitization of IRS-1 signaling. We further demonstrate in human hepatocytes that ANXA1 protects against excessive mitochondrial proton leak by activating FPR2 under hyperglycaemic conditions. In summary, our data suggest that (a) ANXA1 is a key regulator of RhoA activity, which restores IRS-1 signal transduction and (b) recombinant human ANXA1 may represent a novel candidate for the treatment of T2D and/or its complications.

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          Most cited references37

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          Annexin A1 and glucocorticoids as effectors of the resolution of inflammation.

          Glucocorticoids are widely used for the management of inflammatory diseases. Their clinical application stems from our understanding of the inhibitory effect of the corticosteroid hormone cortisol on several components of the immune system. Endogenous and exogenous glucocorticoids mediate their multiple anti-inflammatory effects through many effector molecules. In this Opinion article, we focus on the role of one such effector molecule, annexin A1, and summarize the recent studies that provide insight into its molecular and pharmacological functions in immune responses. In addition, we propose a model in which glucocorticoids regulate the expression and function of annexin A1 in opposing ways in innate and adaptive immune cells to mediate the resolution of inflammation.
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            Heart failure and kidney dysfunction: epidemiology, mechanisms and management.

            Heart failure (HF) is a major health-care problem and the prognosis of affected patients is poor. HF often coexists with a number of comorbidities of which declining renal function is of particular importance. A loss of glomerular filtration rate, as in acute kidney injury (AKI) or chronic kidney disease (CKD), independently predicts mortality and accelerates the overall progression of cardiovascular disease and HF. Importantly, cardiac and renal diseases interact in a complex bidirectional and interdependent manner in both acute and chronic settings. From a pathophysiological perspective, cardiac and renal diseases share a number of common pathways, including inflammatory and direct, cellular immune-mediated mechanisms; stress-mediated and (neuro)hormonal responses; metabolic and nutritional changes including bone and mineral disorder, altered haemodynamic and acid-base or fluid status; and the development of anaemia. In an effort to better understand the important crosstalk between the two organs, classifications such as the cardio-renal syndromes were developed. This classification might lead to a more precise understanding of the complex interdependent pathophysiology of cardiac and renal diseases. In light of exceptionally high mortality associated with coexisting HF and kidney disease, this Review describes important crosstalk between the heart and kidney, with a focus on HF and kidney disease in the acute and chronic settings. Underlying molecular and cellular pathomechanisms in HF, AKI and CKD are discussed in addition to current and future therapeutic approaches.
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              Positive and negative regulation of insulin signaling through IRS-1 phosphorylation.

              This review will provide insight on the current understanding of the regulation of insulin signaling in both physiological and pathological conditions through modulations that occur with regards to the functions of the insulin receptor substrate 1 (IRS1). While the phosphorylation of IRS1 on tyrosine residue is required for insulin-stimulated responses, the phosphorylation of IRS1 on serine residues has a dual role, either to enhance or to terminate the insulin effects. The activation of PKB in response to insulin propagates insulin signaling and promotes the phosphorylation of IRS1 on serine residue in turn generating a positive-feedback loop for insulin action. Insulin also activates several kinases and these kinases act to induce the phosphorylation of IRS1 on specific sites and inhibit its functions. This is part of the negative-feedback control mechanism induced by insulin that leads to termination of its action. Agents such as free fatty acids, cytokines, angiotensin II, endothelin-1, amino acids, cellular stress and hyperinsulinemia, which induce insulin resistance, lead to both activation of several serine/threonine kinases and phosphorylation of IRS1. These agents negatively regulate the IRS1 functions by phosphorylation but also via others molecular mechanisms (SOCS expression, IRS degradation, O-linked glycosylation) as summarized in this review. Understanding how these agents inhibit IRS1 functions as well as identification of kinases involved in these inhibitory effects may provide novel targets for development of strategies to prevent insulin resistance.
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                Author and article information

                Contributors
                Journal
                Front Immunol
                Front Immunol
                Front. Immunol.
                Frontiers in Immunology
                Frontiers Media S.A.
                1664-3224
                27 March 2019
                2019
                : 10
                : 571
                Affiliations
                [1] 1Department of Translational Medicine and Therapeutics, Bart's and The London School of Medicine and Dentistry, The William Harvey Research Institute, Queen Mary University of London , London, United Kingdom
                [2] 2Department of Drug Science and Technology, University of Turin , Turin, Italy
                [3] 3Department of Pharmacological and Biomolecular Sciences, Università Degli Studi di Milano , Milan, Italy
                [4] 4Centro SISA per lo studio del'Aterosclerosi, Bassini Hospital , Lombardy, Italy
                [5] 5Department of Clinical and Biological Sciences, University of Turin , Turin, Italy
                [6] 6Department of Molecular Biotechnology and Sciences for the Health, University of Turin , Turin, Italy
                [7] 7Department of Biochemistry, Cardiovascular Research Institute, Maastricht University , Maastricht, Netherlands
                [8] 8IRCCS Multimedica , Lombardy, Italy
                [9] 9Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università Degli Studi di Napoli “Federico II” , Naples, Italy
                Author notes

                Edited by: Manuela Mengozzi, University of Sussex, United Kingdom

                Reviewed by: Paola Patrignani, Università degli Studi G. d'Annunzio Chieti e Pescara, Italy; Sina Maren Coldewey, Universitätsklinikum Jena, Germany

                *Correspondence: Egle Solito e.solito@ 123456qmul.ac.uk
                Christoph Thiemermann c.thiemermann@ 123456qmul.ac.uk

                This article was submitted to Inflammation, a section of the journal Frontiers in Immunology

                †These authors have contributed equally to this work

                Article
                10.3389/fimmu.2019.00571
                6446914
                30972066
                f8515b98-9c16-4939-a5a9-561935015c24
                Copyright © 2019 Purvis, Collino, Loiola, Baragetti, Chiazza, Brovelli, Sheikh, Collotta, Cento, Mastrocola, Aragno, Cutrin, Reutelingsperger, Grigore, Catapano, Yaqoob, Norata, Solito and Thiemermann.

                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
                : 11 January 2019
                : 04 March 2019
                Page count
                Figures: 8, Tables: 2, Equations: 0, References: 45, Pages: 16, Words: 10596
                Funding
                Funded by: British Heart Foundation 10.13039/501100000274
                Funded by: Fondazione Italiana Sclerosi Multipla 10.13039/100007366
                Categories
                Immunology
                Original Research

                Immunology
                type-2 diabetes,metabolism,annexin a1,nephropathy,hepatosteatosis,rho a
                Immunology
                type-2 diabetes, metabolism, annexin a1, nephropathy, hepatosteatosis, rho a

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