Long Non-coding RNAs Rian and Miat Mediate Myofibroblast Formation in Kidney Fibrosis
| العنوان: | Long Non-coding RNAs Rian and Miat Mediate Myofibroblast Formation in Kidney Fibrosis |
|---|---|
| المؤلفون: | Jacques M.G.J. Duijs, Ton J. Rabelink, Angela Koudijs, Anton Jan van Zonneveld, Ellen Lievers, Roel Bijkerk, Wendy Stam, Yu Wah Au |
| المصدر: | Frontiers in Pharmacology, 10. FRONTIERS MEDIA SA Frontiers in Pharmacology, Vol 10 (2019) Frontiers in Pharmacology |
| بيانات النشر: | FRONTIERS MEDIA SA, 2019. |
| سنة النشر: | 2019 |
| مصطلحات موضوعية: | 0301 basic medicine, Stromal cell, kidney fibrosis, Biology, Miat, 03 medical and health sciences, 0302 clinical medicine, pericyte, microRNA, Renal fibrosis, medicine, Gene silencing, Pharmacology (medical), Original Research, Pharmacology, Kidney, long non-coding RNA, urogenital system, lcsh:RM1-950, RNA therapeutics, Long non-coding RNA, myofibroblast, 030104 developmental biology, medicine.anatomical_structure, lcsh:Therapeutics. Pharmacology, 030220 oncology & carcinogenesis, Rian, Cancer research, Pericyte, Myofibroblast |
| الوصف: | There is an increasing prevalence of chronic kidney disease (CKD), which associates with the development of interstitial fibrosis. Pericytes (perivascular fibroblasts) provide a major source of alpha-SMA-positive myofibroblasts that are responsible for the excessive deposition of extracellular matrix. In order to identify pericyte long non-coding RNAs (lncRNAs) that could serve as a target to decrease myofibroblast formation and counteract the progression of kidney fibrosis we employed two models of experimental kidney injury, one focused on kidney fibrosis (unilateral ureteral obstruction; UUO), and one focused on acute kidney injury that yields kidney fibrosis in the longer term (unilateral ischemia-reperfusion injury; IRI). This was performed in FoxD1-GC;tdTomato stromal cell reporter mice that allowed pericyte fate tracing. Tomato red-positive FoxD1-derivative cells of control and injured kidneys were FACS-sorted and used for lncRNA and mRNA profiling yielding a distinctive transcriptional signature of pericytes and myofibroblasts with 244 and 586 differentially expressed lncRNAs (> twofold, P < 0.05), in the UUO and IRI models, respectively. Next, we selected two differentially expressed and conserved lncRNAs, Rian (RNA imprinted and accumulated in nucleus) and Miat (Myocardial infarction associated transcript), and explored their potential regulatory role in myofibroblast formation through knockdown of their function with gapmers. While Miat was upregulated in myofibroblasts of UUO and IRI in mice, gapmer silencing of Miat attenuated myofibroblast formation as evidenced by decreased expression of alpha-SMA, col1 alpha 1, SMAD2, and SMAD3, as well as decreased alpha-SMA and pro-collagen-1 alpha 1 protein levels. In contrast, silencing Rian, which was found to be downregulated in kidney myofibroblast after IRI and UUO, resulted in increased myofibroblast formation. In addition, we found microRNAs that were previously linked to Miat (miR-150) and Rian (14q32 miRNA cluster), to be dysregulated in the FoxD1-derivative cells, suggesting a possible interaction between miRNAs and these lncRNAs in myofibroblast formation. Taken together, lncRNAs play a regulatory role in myofibroblast formation, possibly through interacting with miRNA regulation, implicating that understanding their biology and their modulation may have the potential to counteract the development of renal fibrosis. |
| اللغة: | English |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::1d57ed4c77f8634cde432045b7136b5d https://hdl.handle.net/1887/122903 |
| Rights: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....1d57ed4c77f8634cde432045b7136b5d |
| قاعدة البيانات: | OpenAIRE |
| الوصف غير متاح. |