The Role of MicroRNA-21 in Venous Neointimal Hyperplasia: Implications for Targeting miR-21 for VNH Treatment.

Abstract

The molecular mechanism of hemodialysis access arteriovenous fistula (AVF) failure due to venous neointimal hyperplasia (VNH) is not known. The role of microRNA-21 (miR-21) in VNH associated with AVF failure was investigated by performing in vivo and in vitro experiments. In situ hybridization results revealed that miR-21 expression increased and was associated with fibroblasts in failed AVFs from patients. In a murine AVF model, qRT-PCR gene expression results showed a significant increase in miR-21 and a decrease in miR-21 target genes in graft veins (GVs) compared to contralateral veins in mouse AVF. miR-21 knockdown in GVs was performed using a lentivirus-mediated small hairpin RNA (shRNA), and this improved AVF patency with a decrease in neointima compared to control GVs. Moreover, loss of miR-21 in GVs significantly decreased the Tgfβ1, Col-Ia, and Col-Iva genes. Immunohistochemistry demonstrated a significant decrease in myofibroblasts and proliferation with an increase in terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) staining in miR-21-knockdown vessels, along with a decrease in hypoxia-inducible factor-1 alpha (HIF-1α) and phospho-SMAD2 (pSMAD-2) and phospho-SMAD3 (pSMAD-3) and an increase in phosphatase and tensin homolog (PTEN) staining. Hypoxic fibroblast knockdown for miR-21 showed a significant decrease in Tgfβ-1 expression and pSMAD-2 and -3 levels and a decrease in myofibroblasts. These results indicate that miR-21 upregulation causes VNH formation by fibroblast-to-myofibroblast differentiation.

• Authors: Sreenivasulu Kilari, Chuanqi Cai, Chenglei Zhao, Amit Sharma, Ekaterina Chernogubova, Michael Simeon, Chin-Cheng Wu, Hsiang-Lin Song, Lars Maegdefessel, Sanjay Misra
• Journal: Molecular therapy : the journal of the American Society of Gene Therapy (Mol Ther) Vol. 27 Issue 9 Pg. 1681-1693 (09 04 2019) ISSN: 1525-0024 [Electronic] United States
• PMID: 31326400 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.

Chemical References

• Biomarkers
• MIRN21 microRNA, human
• MicroRNAs
• RNA, Small Interfering

Topics

• Animals
• Apoptosis (genetics)
• Arteriovenous Fistula (genetics, pathology)
• Biomarkers
• Cell Differentiation (genetics)
• Cell Proliferation
• Disease Models, Animal
• Fibroblasts (metabolism)
• Fibrosis (genetics)
• Gene Expression
• Gene Knockdown Techniques
• Humans
• Hyperplasia
• Hypoxia (genetics, metabolism)
• Immunohistochemistry
• Lentivirus (genetics)
• Male
• Mice
• MicroRNAs (genetics)
• Myofibroblasts (metabolism)
• Neointima (genetics, pathology, therapy)
• RNA Interference
• RNA, Small Interfering (genetics)
• Transduction, Genetic
• Veins (metabolism, pathology)