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      SOCS2 Silencing Improves Somatic Growth without Worsening Kidney Function in CKD

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          Abstract

          Background: Growth hormone (GH) resistance in CKD is partly due to increased expression of SOCS2, a GH signaling negative regulator. In SOCS2 absence, body growth is exaggerated. However, GH overexpression in mice causes glomerulosclerosis. Accordingly, we tested whether lack of SOCS2 improves body growth, but accelerates kidney damage in CKD. Methods: Eight-week-old mutant SOCS2-deficient high growth (HG) and normal wild-type mice (N) underwent 5/6 nephrectomy (CKD) or sham operation (C) and were sacrificed after 12 weeks, generating 4 groups: C-N, C-HG, CKD-N, CKD-HG. Results: Somatic growth, inhibited in CKD-N, increased significantly in CKD-HG. Liver p-STAT5, a key intracellular signal of GH receptor (GHR) activation, was decreased in CKD-N but not in CKD-HG. Serum Cr as well as histopathological scores of renal fibrosis were similar in both CKD groups. Kidney fibrogenic (TGF-β and collagen type IV mRNA) and inflammatory precursors (IL6, STAT3, and SOCS3 mRNA) were similarly increased in C-HG, CKD-HG, and CKD-N versus C-N. Renal GHR mRNA was decreased in C-HG, CKD-HG, and CKD-N versus C-N. Kidney p-STAT5 was decreased in CKD-N but not elevated in CKD-HG. Conclusions: CKD-related growth retardation is overcome by SOCS2 silencing, in association with increased hepatic STAT5 phosphorylation. Renal insufficiency is not worsened by SOCS2 absence, as kidney GHR and STAT5 are not upregulated. This may be due to elevated kidney proinflammatory cytokines and their mediators, phospho-STAT3 and SOCS3, which may counteract for the absence in SOCS2 and explain the renal safety of prolonged GH therapy in CKD.

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          Most cited references 22

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          Suppressor of cytokine signaling (SOCS) 2, a protein with multiple functions.

          Cytokine receptors act through a complex signaling network, involving Janus kinases (JAKs) and the signal transducers and activators of transcription (STATs), to regulate diverse biological processes which control growth, development, homeostasis and immune function, among others. The JAK/STAT signaling pathway is attenuated via three mechanisms controlling the initiation, magnitude, and duration of the signal: the PIAS proteins, which prevent STAT dimerization or DNA interaction, the SHP phosphatases, which dephosphorylate activating tyrosine phosphorylations, and the suppressors of cytokine signaling (SOCS), which are transcribed in response to cytokine stimulation and use several interconnected mechanisms to downregulate the signal. Specific studies targeting the SOCS genes in vivo have unveiled SOCS2 as the main regulator of somatic growth through regulation of GH/IGF-1 signaling. In addition, several studies indicate that SOCS2 also has important actions in the central nervous system, the regulation of metabolism, the immune response, the mammary gland development, cancer, and other cytokine-dependent signaling pathways. Consistent with the role of cytokines in human physiology, any SOCS2 imbalance could result in a broad range of pathologies such as cardiovascular diseases, insulin resistance, cancer, and severe infections, among others. Thus, determining the importance of SOCS2 in health and disease will no doubt aid in the development of novel therapeutic strategies. In this review, we attempt to summarize the available information, including our results, regarding the role of SOCS2 in several biological processes.
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            SOCS2 negatively regulates growth hormone action in vitro and in vivo.

            Mice deficient in SOCS2 display an excessive growth phenotype characterized by a 30-50% increase in mature body size. Here we show that the SOCS2-/- phenotype is dependent upon the presence of endogenous growth hormone (GH) and that treatment with exogenous GH induced excessive growth in mice lacking both endogenous GH and SOCS2. This was reflected in terms of overall body weight, body and bone lengths, and the weight of internal organs and tissues. A heightened response to GH was also measured by examining GH-responsive genes expressed in the liver after exogenous GH administration. To further understand the link between SOCS2 and the GH-signaling cascade, we investigated the nature of these interactions using structure/function and biochemical interaction studies. Analysis of the 3 structural motifs of the SOCS2 molecule revealed that each plays a crucial role in SOCS2 function, with the conserved SOCS-box motif being essential for all inhibitory function. SOCS2 was found to bind 2 phosphorylated tyrosines on the GH receptor, and mutational analysis of these amino acids showed that both were essential for SOCS2 function. Together, the data provide clear evidence that SOCS2 is a negative regulator of GH signaling.
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              Lack of Socs2 expression causes the high-growth phenotype in mice.

               S Horvat,  J V Medrano (2001)
              Characterizing causal molecular defects in mouse models of overgrowth or dwarfism helps to identify the key genes and pathways that regulate the growth process. We report here the molecular basis for high growth (hg), a spontaneous mutation that causes a 30-50% increase in postnatal growth. We conclude that hg is an allele of the suppressor of cytokine signaling 2 (Socs2), a member of a family of regulators of cytokine signal transduction. We demonstrate mapping of Socs2 to the hg region, lack of Socs2 mRNA expression, a disruption of the Socs2 locus in high-growth (HG) mice, and a similarity of phenotypes of HG mice and Socs2(-/-) mice generated by gene targeting. Characteristics of the HG phenotype suggest that Socs2 deficiency affects growth prenatally and postnatally most likely through deregulating the growth hormone (GH)/insulin-like growth factor I (IGF1). These results demonstrate a critical role for Socs2 in controlling growth. Copyright 2001 Academic Press.
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                Author and article information

                Journal
                AJN
                Am J Nephrol
                10.1159/issn.0250-8095
                American Journal of Nephrology
                S. Karger AG
                0250-8095
                1421-9670
                2020
                July 2020
                15 June 2020
                : 51
                : 7
                : 520-526
                Affiliations
                aSchneider Children’s Medical Center, Institute of Nephrology, Petach Tikva, Israel
                bSackler School of Medicine, Faculty of Health Sciences, Tel Aviv, Israel
                cShraga Segal Department of Microbiology and Immunology, Ben Gurion University of the Negev, Beer Sheva, Israel
                dDepartment of Medicine/Nephrology, Stanford University, Stanford, California, USA
                eResearch Service, Veterans Affairs Health Care System, Palo Alto, California, USA
                Author notes
                *Prof. Daniel Landau, Head, Department of Nephrology, Schneider Children’s Medical Center of Israel, 14 Kaplan St., Petach Tikva 4920235 (Israel), danny_L@clalit.org.il
                Article
                508224 Am J Nephrol 2020;51:520–526
                10.1159/000508224
                32541140
                © 2020 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: 3, Tables: 1, Pages: 7
                Categories
                Patient-Oriented, Translational Research: Research Article

                Cardiovascular Medicine, Nephrology

                SOCS2, STAT3, Growth hormone, Short stature, SOCS3, Chronic kidney disease

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