Kidney Week

Abstract: FR-OR036

Induced Endothelial Expression of Podocyte Specific Retinoic Acid Receptor Responder 1 (Rarres1) in Glomerular Nephritis (GN) Accelerates Renal Injury

Session Information

• Cellular Crosstalk in Glomerular Diseases
  October 26, 2018 | Location: 25A, San Diego Convention Center
  Abstract Time: 06:06 PM - 06:18 PM

Category: Glomerular Diseases

• 1201 Glomerular Diseases: Fibrosis and Extracellular Matrix

Authors

• Möller-Hackbarth, Katja, Karolinska Institutet, Sweden, Huddinge, Sweden

Katja Möller-Hackbarth, PhD



since 03/2018 Assistant Professor at the Karolinska Institutet, Stockholm, Sweden Subject: Identification and establishment of novel therapeutic targets and biomarkers for diabetic kidney disease  10/2014-03/2018 Postdoctoral researcher at Karolinska Institutet in the Integrated Cardio Metabolic Centre (ICMC) in the group of Jaakko Patrakka 09/2013 PhD in Biology Research topic: “Cytokines, Receptors and Metalloproteases“ Institute of Biochemistry of the Christian-Albrechts-Universität zu Kiel, Germany

• Dabaghie, Dina, Karolinska Institutet, Sweden, Huddinge, Sweden

Dina Dabaghie,

• Charrin, Emmanuelle, Karolinska Institutet, Sweden, Huddinge, Sweden

Emmanuelle Charrin,

• Patrakka, Jaakko, Karolinska Institutet, Sweden, Huddinge, Sweden

Jaakko Patrakka,

Background

Glomerular damage, including endothelial dysfunction and podocyte loss, plays an important role in the pathogenesis of diabetic nephropathy (DN). Pathogenesis of microvascular damage in the disease is still poorly understood. High throughput molecular profiling (RNA seq.) identified Rarres1 as a highly podocyte specific protein, that is consistently up-regulated in kidney tissue of DN patients.

Methods

To identify cellular localization of Rarres1, we analysed the expression in human healthy and DN kidneys using immunohistochemical methods and RNA in situ hybridization. In vitro, we over/underexpress Rarres1 in human podocytes to investigate its functional role. In vivo, we generated two novel transgenic mouse lines, enabling cell-specific inactivation and overexpression of Rarres1. We induced crescentic GN model by anti-glomerular basement membrane (anti-GBM) antibodies in podocyte specific knock-out (KO) and endothelial cell (EC) specific knock-in (KI) mice for Rarres1.

Results

In healthy kidney, Rarres1 is specifically expressed by podocytes and not by other glomerular cells. In DN patients, Rarres1 expression is induced in microvascular endothelial cells. In vitro, Rarres1 overexpression leads to elevated expression of EMT related genes and activation of NF-kB signaling by interaction with Receptor Tyrosin Kinase Axl. In vivo, EC specific Rarres1 KI animals were more prone to anti-GBM-induced damage as they developed higher albuminuria than control animals and showed an accelerated immune response as well as increased levels of fibrotic makers. In contrast to this, podocyte-specific KO animals showed no obvious abnormalities.

Conclusion

In summary, these results suggest that the activation of Rarres1 expression plays a pathogenic role in renal endothelial dysfunction during disease progression by promoting fibrosis and inflammation in vitro and in vivo.