miR-34a regulates mesangial cell proliferation via the PDGFR-β/Ras-MAPK signaling pathway.

Abstract

The main pathological characteristic of glomerulonephritis is diffuse mesangial cell proliferation. MiR-34a is associated with the proliferation of various organs and cancer cells. However, the role of miR-34a in renal proliferation diseases is not clear. Therefore, this study aimed to elucidate the mechanism of miR-34a in the regulation of renal mesangial cell proliferation. The miR-34a expression level at different time points in an anti-Thy1 mesangial proliferative nephritis rat model was determined by qRT-PCR. The cell proliferation rate and cell cycle changes were measured in the in vitro cultured rat mesangial cells (RMCs). Our results suggested that miR-34a expression was negatively correlated with the degree of cell proliferation in the anti-Thy1 nephritis model. MiR-34a could extend the G0/G1 phase and block cell proliferation in RMCs. Dual-luciferase assay results showed that there were binding sites of miR-34a at 3'-UTR of platelet-derived growth factor receptor-β (PDGFR-β). MiR-34a can inhibit PDGFR-β protein expression at a post-transcriptional level, suppress Ras/MAPK signaling pathways, and down-regulate expression of cell cycle proteins at the G0/G1 phase, such as cyclin D1, CDK4/CDK6. In addition, miR-34a may also inhibit RMC proliferation by directly targeting cyclin E and CDK2. MiR-34a inhibits exogenous stimuli-induced proliferation of mesangial cells. Expression levels of phospho-PDGFR-β and phospho-MEK1 (an important downstream molecule in PDGFR-β-induced signaling pathway) were significantly increased in the anti-Thy-1 nephritis rat model. These results suggest that miR-34a may regulate RMC proliferation by directly inhibiting expressions of PDGFR-β, MEK1, and cell cycle proteins, cyclin E and CDK2.

• Authors: Dapeng Chen, Ying Li, Yan Mei, Wenjia Geng, Jurong Yang, Quan Hong, Zhe Feng, Guangyan Cai, Hanyu Zhu, Suozhu Shi, Xue-Yuan Bai, Xiangmei Chen
• Journal: Cellular and molecular life sciences : CMLS (Cell Mol Life Sci) Vol. 71 Issue 20 Pg. 4027-42 (Oct 2014) ISSN: 1420-9071 [Electronic] Switzerland
• PMID: 24638095 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 3' Untranslated Regions
• Cell Cycle Proteins
• Isoantibodies
• MIRN34 microRNA, rat
• MicroRNAs
• RNA, Small Interfering
• anti-Thy antibody
• Receptor, Platelet-Derived Growth Factor beta
• Mitogen-Activated Protein Kinase Kinases
• ras Proteins

Topics

• 3' Untranslated Regions
• Animals
• Cell Cycle Proteins (genetics, metabolism)
• Cell Line
• Cell Proliferation
• G1 Phase
• Glomerulonephritis (metabolism, pathology)
• Isoantibodies (immunology)
• Mesangial Cells (cytology, metabolism)
• MicroRNAs (metabolism)
• Mitogen-Activated Protein Kinase Kinases (metabolism)
• RNA Interference
• RNA, Small Interfering (metabolism)
• Rats
• Rats, Wistar
• Receptor, Platelet-Derived Growth Factor beta (antagonists & inhibitors, genetics, metabolism)
• Signal Transduction
• ras Proteins (metabolism)