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Receptor for Advanced Glycation End Products Antagonism Blunts Kidney Damage in Transgenic Townes Sickle Mice
Emmanuelle Charrin1,2, Camille Faes1,2, Amandine Sotiaux1,2
1Interuniversity Laboratory of Human Movement Biology, University Claude Bernard Lyon 1, University of Lyon, Lyon, France.
Abstract:
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. 8-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 evidence supporting the pathogenic role of RAGE in kidney injuries in sickle cell mice.
Insights
Blocking the receptor for advanced glycation end products (RAGE) improved blood counts and reduced kidney damage in a mouse model of sickle cell disease (SCD). This suggests RAGE is a key factor in SCD-related kidney complications.
Area of Science:
- Nephrology
- Hematology
- Molecular Biology
Background:
- Sickle cell disease (SCD) frequently leads to kidney disease and mortality in adults.
- The advanced glycation end products and their receptor (AGE/RAGE) axis is implicated in various kidney diseases.
Purpose of the Study:
- To investigate the role of the RAGE axis in the development of kidney complications associated with SCD.
- To evaluate the therapeutic potential of a RAGE antagonist in a mouse model of SCD.
Main Methods:
- Adult normal (AA) and sickle cell disease (SS) Townes mice were treated with a RAGE antagonist (RAP) or vehicle.
- Hematological parameters, oxidative stress markers, inflammatory markers, and kidney injury indicators were assessed.
Main Results:
- RAGE antagonist treatment improved red blood cell count, hematocrit, and hemoglobin levels in SS mice.
- Treatment reduced reticulocyte and sickle cell counts, NADPH oxidase activity, and ROS production.
- RAGE inhibition decreased NF-κB activation, TNF-α expression, and markers of kidney damage like glomerular area, fibrosis, and KIM-1.
Conclusions:
- The study demonstrates a pathogenic role for RAGE in sickle cell kidney disease.
- Targeting the RAGE axis with antagonists may offer a therapeutic strategy for SCD-related kidney complications.
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