title: 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.affiliation: State Key Laboratory of Kidney Diseases (2011DAV00088), Department of Nephrology, Chinese PLA Institute of Nephrology, National Clinical Research Center for Kidney Disease (2013BAI09B05), Chinese PLA General Hospital, 28 Fuxing Road, Beijing, 100853, People's Republic of China.
authors.forename: Dapeng
authors.initials: D
authors.lastname: Chen
authors.forename: Ying
authors.initials: Y
authors.lastname: Li
authors.forename: Yan
authors.initials: Y
authors.lastname: Mei
authors.forename: Wenjia
authors.initials: W
authors.lastname: Geng
authors.forename: Jurong
authors.initials: J
authors.lastname: Yang
authors.forename: Quan
authors.initials: Q
authors.lastname: Hong
authors.forename: Zhe
authors.initials: Z
authors.lastname: Feng
authors.forename: Guangyan
authors.initials: G
authors.lastname: Cai
authors.forename: Hanyu
authors.initials: H
authors.lastname: Zhu
authors.forename: Suozhu
authors.initials: S
authors.lastname: Shi
authors.forename: Xue-Yuan
authors.initials: XY
authors.lastname: Bai
authors.forename: Xiangmei
authors.initials: X
authors.lastname: Chen
mesh_terms: D020413:3' Untranslated Regions; D000818:Animals; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D049109:Cell Proliferation; D016193:G1 Phase; D005921:Glomerulonephritis / Q000378:metabolism / Q000473:pathology; D007518:Isoantibodies / Q000276:immunology; D050527:Mesangial Cells / Q000166:cytology / Q000378:metabolism*; D035683:MicroRNAs / Q000378:metabolism*; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism*; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D018631:ras Proteins / Q000378:metabolism*
chemical_list: D020413:3' Untranslated Regions; D018797:Cell Cycle Proteins; D007518:Isoantibodies; C560944:MIRN34 microRNA, rat; D035683:MicroRNAs; D034741:RNA, Small Interfering; C035678:anti-Thy antibody; D020797:Receptor, Platelet-Derived Growth Factor beta; D020929:Mitogen-Activated Protein Kinase Kinases; D018631:ras Proteins