title: MiR-223 downregulation promotes glomerular endothelial cell activation by upregulating importin α4 and α5 in IgA nephropathy.
abstract: Glomerular endothelial cells (GEnCs) contribute to renal injuries in IgA nephropathy (IgAN). Here we profiled microRNAs (miRNAs) in GEnCs treated with conditioned medium from human mesangial cells in vitro. Levels of miR-223 in GEnCs decreased after incubation with the medium prepared with pIgA from patients with glomerular endothelial proliferation and were also decreased in the glomerular tissues of patients with glomerular endothelial proliferation. Mesangial-derived IL-6 caused miR-223 levels to decrease. The addition of exogenous miR-223 inhibited cell proliferation, ICAM-1 expression, and monocyte adhesion. The NF-κB and STAT3 signaling pathways collaborate during the activation process. MiR-223 mimics inhibited the nuclear localization and DNA binding of p65 and STAT3 but had no effect on the expression of upstream molecules. Instead, importin α4 and α5 (multipurpose nuclear transport receptors), validated as targets of miR-223, were responsible for the nuclear transport of p65 and STAT3. Importin α4 and α5 siRNA inhibited the nuclear localization of p65 and STAT3 and prevented cell proliferation and monocyte adhesion. The level of miR-223 in circulating endothelial cells was decreased and related to the clinical and pathological parameters. Thus, miR-223 downregulation promotes glomerular endothelial cell activation by upregulating importin α4 and α5 in IgAN. Monitoring the level of miR-223 in circulating endothelial cells may provide a noninvasive method for evaluating the severity of IgAN.
authors.affiliation: Research Institute of Nephrology, Jinling Hospital, Nanjing University School of Medicine, Nanjing, China.
authors.forename: Hao
authors.initials: H
authors.lastname: Bao
authors.affiliation: Research Institute of Nephrology, Jinling Hospital, Nanjing University School of Medicine, Nanjing, China.
authors.forename: Hao
authors.initials: H
authors.lastname: Chen
authors.affiliation: Research Institute of Nephrology, Jinling Hospital, Nanjing University School of Medicine, Nanjing, China.
authors.forename: Xiaodong
authors.initials: X
authors.lastname: Zhu
authors.affiliation: Research Institute of Nephrology, Jinling Hospital, Nanjing University School of Medicine, Nanjing, China.
authors.forename: Minchao
authors.initials: M
authors.lastname: Zhang
authors.affiliation: Research Institute of Nephrology, Jinling Hospital, Nanjing University School of Medicine, Nanjing, China.
authors.forename: Genhong
authors.initials: G
authors.lastname: Yao
authors.affiliation: Research Institute of Nephrology, Jinling Hospital, Nanjing University School of Medicine, Nanjing, China.
authors.forename: Yusheng
authors.initials: Y
authors.lastname: Yu
authors.affiliation: Research Institute of Nephrology, Jinling Hospital, Nanjing University School of Medicine, Nanjing, China.
authors.forename: Weisong
authors.initials: W
authors.lastname: Qin
authors.affiliation: Research Institute of Nephrology, Jinling Hospital, Nanjing University School of Medicine, Nanjing, China.
authors.forename: Caihong
authors.initials: C
authors.lastname: Zeng
authors.affiliation: Research Institute of Nephrology, Jinling Hospital, Nanjing University School of Medicine, Nanjing, China.
authors.forename: Ke
authors.initials: K
authors.lastname: Zen
authors.affiliation: Research Institute of Nephrology, Jinling Hospital, Nanjing University School of Medicine, Nanjing, China.
authors.forename: Zhihong
authors.initials: Z
authors.lastname: Liu
mesh_terms: D000328:Adult; D049109:Cell Proliferation; D015536:Down-Regulation; D042783:Endothelial Cells / Q000502:physiology; D005260:Female; D005922:Glomerulonephritis, IGA / Q000473:pathology*; D006801:Humans; D015850:Interleukin-6 / Q000494:pharmacology; D007678:Kidney Glomerulus / Q000473:pathology*; D008297:Male; D035683:MicroRNAs / Q000097:blood / Q000502:physiology*; D016328:NF-kappa B / Q000502:physiology; D050796:STAT3 Transcription Factor / Q000502:physiology; D015854:Up-Regulation; D028901:alpha Karyopherins / Q000502:physiology*
chemical_list: D015850:Interleukin-6; D035683:MicroRNAs; D016328:NF-kappa B; D050796:STAT3 Transcription Factor; D028901:alpha Karyopherins; C423142:KPNA1 protein, human; C106306:KPNA3 protein, human; C525067:MIR223, human; C494086:STAT3 protein, human