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      EGF Receptor Inhibition Alleviates Hyperuricemic Nephropathy

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          Abstract

          Hyperuricemia is an independent risk factor for CKD and contributes to kidney fibrosis. In this study, we investigated the effect of EGF receptor (EGFR) inhibition on the development of hyperuricemic nephropathy (HN) and the mechanisms involved. In a rat model of HN induced by feeding a mixture of adenine and potassium oxonate, increased EGFR phosphorylation and severe glomerular sclerosis and renal interstitial fibrosis were evident, accompanied by renal dysfunction and increased urine microalbumin excretion. Administration of gefitinib, a highly selective EGFR inhibitor, prevented renal dysfunction, reduced urine microalbumin, and inhibited activation of renal interstitial fibroblasts and expression of extracellular proteins. Gefitinib treatment also inhibited hyperuricemia-induced activation of the TGF- β1 and NF- κB signaling pathways and expression of multiple profibrogenic cytokines/chemokines in the kidney. Furthermore, gefitinib treatment suppressed xanthine oxidase activity, which mediates uric acid production, and preserved expression of organic anion transporters 1 and 3, which promotes uric acid excretion in the kidney of hyperuricemic rats. Thus, blocking EGFR can attenuate development of HN via suppression of TGF- β1 signaling and inflammation and promotion of the molecular processes that reduce uric acid accumulation in the body.

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          Author and article information

          Journal
          J Am Soc Nephrol
          J. Am. Soc. Nephrol
          jnephrol
          jnephrol
          ASN
          Journal of the American Society of Nephrology : JASN
          American Society of Nephrology
          1046-6673
          1533-3450
          November 2015
          18 March 2015
          : 26
          : 11
          : 2716-2729
          Affiliations
          [* ]Department of Nephrology and
          []Research Center for Translational Medicine Center, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China;
          []Department of Medicine, Rhode Island Hospital and Brown University School of Medicine, Providence, Rhode Island;
          [§ ]Institute of Health Sciences, Chinese Academy of Sciences, Shanghai, China;
          []Department of Pediatrics, Women & Infants Hospital, Warren Alpert Medical School of Brown University, Providence, Rhode Island; and
          []School of Life Science and Technology, Advanced Institute of Translational Medicine, Tongji University, Shanghai, China
          Author notes

          N.L. and L.W. contributed equally to this work.

          Correspondence: Dr. Shougang Zhuang, Brown University School of Medicine, Rhode Island Hospital, Middle House 301, 593 Eddy Street, Providence, RI 02903, or Dr. Na Liu, Department of Nephrology, Tongji University School of Medicine, 150 Jimo Road, Pudong New District, Shanghai 200120, China. Email: szhuang@ 123456lifespan.org or naliubrown@ 123456hotmail.com
          Article
          PMC4625671 PMC4625671 4625671 2014080793
          10.1681/ASN.2014080793
          4625671
          25788532
          Copyright © 2015 by the American Society of Nephrology
          Page count
          Pages: 14
          Categories
          Basic Research
          Custom metadata
          November 2015

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