Abstract: TH-PO962
DNM3OS Non-Coding RNA as a New Therapeutic Target in the Context of Renal Fibrosis
Session Information
- Pathology and Lab Medicine: Basic
October 25, 2018 | Location: Exhibit Hall, San Diego Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Pathology and Lab Medicine
- 1501 Pathology and Lab Medicine: Basic
Authors
- Cauffiez, Christelle, University of Lille EA4483, Lille, France
- Savary, Grégoire, University of Lille EA4483, Lille, France
- Dewaeles, Edmone, University of Lille EA4483, Lille, France
- Lemaire, Julie, University of Lille EA4483, Lille, France
- Glowacki, Francois, CHRU de Lille, Lille, France
- Pottier, Nicolas, University of Lille EA4483, Lille, France
Background
The study of miRNAs in fibroproliferative diseases, and in particular in kidney fibrosis, has underscored their involvement in the key mechanisms of fibrogenesis. In the context of pulmonary fibrosis, the polycistronic RNA DNM3OS, producing the three fibromiRs, miR-199a-5p, miR-199a-3p and miR-214-3p, has recently been described as a regulator of the process fibrosis. Indeed, these three miRNAs participate in TGF-β pathway regulation and in the differentiation of fibroblasts into myofibroblasts. The aim of this study was to evaluate in kidney the anti-fibrotic potential of targeting the non-coding DNM3OS RNA by different oligonucleotide approaches directed against DNM3OS or miR- 199a-5p.
Methods
In a first step, the oligonucleotides were selected according to their anti-fibrotic efficacy in the 3T3 fibroblast cell line.
The study then relies mainly on the use of a murine model of renal fibrosis induced by unilateral ureteral obstruction. After evaluating their safety (acute or chronic administration), oligonucleotides formulated for in vivo administration and directed against either miR-199a-5p or DNM3OS (Gapmer) were systemically injected before and after the induction of renal fibrosis. Fibrotic lesions was evaluated by studying the renal expression of fibronectin 1 (FN1) and Collagen 1a1 (COL1A1) genes as well as by the histological analysis of kidney sections by immunohistochemistry and Sirius Red staining.
Results
Our results showed that the administration of oligonucleotides directed against miR-199a-5p or DNM3OS allows a significant reduction in renal fibrosis lesions induced by ureteral obstruction. In particular, we observed a decrease in the expression of extracellular matrix compounds such as FN1 and COL1A1. In addition, tolerance studies (single or chronic) of anti-miR-199a-5p did not reveal any renal or hepatic toxicity of the oligonucleotide in mice.
Conclusion
Overall, in the context of fibroproliferative pathologies, our results underline the interest of the therapeutic targeting of polycistronic RNA DNM3OS based on the modulation of the expression of this non-coding RNA or of one of the miRNAs that it produces using synthetic oligonucleotides. The clinical development of such molecules could eventually limit the progression of fibrosis.