title: The Role of MicroRNAs and Human Epidermal Growth Factor Receptor 2 in Proliferative Lupus Nephritis.
abstract: OBJECTIVE
  To understand the roles of microRNAs (miRNAs) in proliferative lupus nephritis (LN).
  
  
  METHODS
  A high-throughput analysis of the miRNA pattern of the kidneys of LN patients and controls was performed by molecular digital detection. Urinary miRNAs were measured by quantitative reverse transcription-polymerase chain reaction (qRT-PCR). Target gene expression in human mesangial cells was evaluated by arrays and qRT-PCR. Human epidermal growth factor receptor 2 (HER-2) was analyzed by immunohistochemistry in kidney samples from LN patients and in a murine model of lupus. Urinary levels of HER-2, monocyte chemotactic protein 1 (MCP-1), and vascular cell adhesion molecule 1 (VCAM-1) were measured by enzyme-linked immunosorbent assay.
  
  
  RESULTS
  Levels of the miRNAs miR-26a and miR-30b were decreased in the kidneys and urine of LN patients. In vitro these miRNAs controlled mesangial cell proliferation, and their expression was regulated by HER-2. HER-2 was overexpressed in lupus-prone NZM2410 mice and in the kidneys of patients with LN, but not in other mesangioproliferative glomerulonephritides. HER-2 was found to be up-regulated by interferon-α and interferon regulatory factor 1. Urinary HER-2 was increased in LN and reflected disease activity, and its levels correlated with those of 2 other recognized LN biomarkers, MCP-1 and VCAM-1.
  
  
  CONCLUSIONS
  The kidney miRNA pattern is broadly altered in LN, which contributes to uncontrolled cell proliferation. Levels of the miRNAs miR-26a and miR-30b are decreased in the kidneys and urine of LN patients, and they directly regulate the cell cycle in mesangial cells. The levels of these miRNAs are controlled by HER-2, which is overexpressed in NZM2410 mice and in the kidneys and urine of LN patients. HER-2, miR-26a, and miR-30b are thus potential LN biomarkers, and blocking HER-2 may be a promising new strategy to decrease cell proliferation and damage in this disease.
authors.affiliation: The Children's Hospital of Philadelphia and University of Pennsylvania Perelman School of Medicine, Philadelphia, and University of Lisbon, Lisbon, Portugal.
authors.forename: Patrícia
authors.initials: P
authors.lastname: Costa-Reis
authors.affiliation: The Children's Hospital of Philadelphia and University of Pennsylvania Perelman School of Medicine, Philadelphia.
authors.forename: Pierre A
authors.initials: PA
authors.lastname: Russo
authors.affiliation: The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.
authors.forename: Zhe
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.
authors.forename: Lucrezia
authors.initials: L
authors.lastname: Colonna
authors.affiliation: The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.
authors.forename: Kelly
authors.initials: K
authors.lastname: Maurer
authors.affiliation: The Children's Hospital of Philadelphia and Temple University, Philadelphia, Pennsylvania.
authors.forename: Stefania
authors.initials: S
authors.lastname: Gallucci
authors.affiliation: Hospital of the University of Pennsylvania, Philadelphia.
authors.forename: Steffan W
authors.initials: SW
authors.lastname: Schulz
authors.affiliation: Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Adnan N
authors.initials: AN
authors.lastname: Kiani
authors.affiliation: Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Michelle
authors.initials: M
authors.lastname: Petri
authors.affiliation: The Children's Hospital of Philadelphia and University of Pennsylvania Perelman School of Medicine, Philadelphia.
authors.forename: Kathleen E
authors.initials: KE
authors.lastname: Sullivan
mesh_terms: D000293:Adolescent; D000818:Animals; D018932:Chemokine CCL2 / Q000652:urine*; D002648:Child; D004195:Disease Models, Animal; D005260:Female; D015432:Glomerulonephritis, Membranoproliferative / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007668:Kidney / Q000378:metabolism*; D008181:Lupus Nephritis / Q000235:genetics*; D008297:Male; D050527:Mesangial Cells / Q000378:metabolism*; D051379:Mice; D035683:MicroRNAs / Q000378:metabolism* / Q000652:urine; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism* / Q000652:urine; D020133:Reverse Transcriptase Polymerase Chain Reaction; D019010:Vascular Cell Adhesion Molecule-1 / Q000652:urine*
chemical_list: D018932:Chemokine CCL2; D035683:MicroRNAs; D018719:Erb-b2 Receptor Tyrosine Kinases; D019010:Vascular Cell Adhesion Molecule-1; C528163:MIRN26 microRNA, human; C546086:MIRN30b microRNA, human; C508053:ERBB2 protein, human