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

Sreenivasulu Kilari, Chuanqi Cai, Chenglei Zhao, Amit Sharma, Ekaterina Chernogubova, Michael Simeon, Chin Cheng Wu, Hsiang Lin Song, Lars Maegdefessel, Sanjay Misra

Research output: Contribution to journalArticle

2 Scopus citations

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. About 50% of hemodialysis arteriovenous fistula (AVF) will fail within a year of placement. Novel strategies that can improve fistula patency are needed. The present study demonstrated a significant role of microRNA-21 in AVF failure, and its knockdown in outflow veins of AVF improved the AVF function and durability.

Original languageEnglish (US)
Pages (from-to)1681-1693
Number of pages13
JournalMolecular Therapy
Volume27
Issue number9
DOIs
StatePublished - Sep 4 2019

Keywords

  • TGF-β
  • animal models
  • arteriovenous fistula
  • chronic kidney disease
  • miR-21
  • vascular remodeling

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Genetics
  • Pharmacology
  • Drug Discovery

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  • Cite this

    Kilari, S., Cai, C., Zhao, C., Sharma, A., Chernogubova, E., Simeon, M., Wu, C. C., Song, H. L., Maegdefessel, L., & Misra, S. (2019). The Role of MicroRNA-21 in Venous Neointimal Hyperplasia: Implications for Targeting miR-21 for VNH Treatment. Molecular Therapy, 27(9), 1681-1693. https://doi.org/10.1016/j.ymthe.2019.06.011