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Original Research ARTICLE Provisionally accepted The full-text will be published soon. Notify me

Front. Physiol. | doi: 10.3389/fphys.2019.00880

Receptor for Advanced Glycation End products (RAGE) antagonism blunts kidney damage in transgenic Townes sickle mice

Emmanuelle Charrin1, 2, 3, Camille ROMANET-FAES1, 2, 3, Sarah Skinner1, 2, 3,  Vincent Pialoux1, 2, 3, 4, Philippe Joly1, 2, 3, 5, Philippe Connes1, 2, 3, 4 and  Cyril Martin1, 2, 3*
  • 1EA7424 Laboratoire Interuniversitaire de Biologie de la Motricité, Université Claude Bernard Lyon 1, France
  • 2Université de Lyon, France
  • 3Laboratory of Excellence GR-Ex, France
  • 4Institut Universitaire de France, France
  • 5Laboratoire de Biologie Médicale et d’anatomie Pathologique, Hospices Civils de Lyon, Groupement Hospitalier EST, France

A large proportion of adult patients with sickle cell disease (SCD) develops kidney disease and is at a high risk of mortality. The contribution of advanced glycation end products and their receptor (AGE/RAGE) axis has been established in the pathogenesis of multiple kidney diseases. The aim of the present study was to determine the implication of RAGE in the development of SCD-related kidney complications in a mouse model of SCD, as this has never been investigated. Eight-week-old AA (normal) and SS (homozygous SCD) Townes mice were treated with a specific RAGE antagonist (RAP) or vehicle (NaCl). After 3 weeks of treatment, red blood cell count, hematocrit, and hemoglobin levels were significantly higher in RAP-treated SS mice. Reticulocyte count and sickle cell count were reduced in RAP-SS compared to their NaCl-treated littermates. The lower NADPH oxidase activity in the kidney of RAP-treated mice compared to NaCl-treated mice suggests limited ROS production. RAP-treated SS mice had decreased NF-κB protein expression and activation as well as reduced TNF-α mRNA expression in the kidney. Glomerular area, interstitial fibrosis, tubular iron deposits and KIM-1 protein expression were significantly reduced after RAP treatment. In conclusion, this study provides strong evidence supporting the pathogenic role of RAGE in kidney injuries in sickle cell mice.

Keywords: Sickle cell disease (HbSS), RAGE (receptor for advanced glycation end products), Kidney, Oxidative Stress, Inflammation

Received: 14 Jan 2019; Accepted: 24 Jun 2019.

Edited by:

Paola Bianchi, IRCCS Ca 'Granda Foundation Maggiore Policlinico Hospital, Italy

Reviewed by:

Anna Rita Migliaccio, Icahn School of Medicine at Mount Sinai, United States
RAFFAELLA COLOMBATTI, University Hospital of Padua, Italy  

Copyright: © 2019 Charrin, ROMANET-FAES, Skinner, Pialoux, Joly, Connes and Martin. 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.

* Correspondence: PhD. Cyril Martin, Université de Lyon, Lyon, 69361, Rhône-Alpes, France, cyril.martin@univ-lyon1.fr