title: Micro-RNA analysis of renal biopsies in human lupus nephritis demonstrates up-regulated miR-422a driving reduction of kallikrein-related peptidase 4.
abstract: Aberrancies in gene expression in immune effector cells and in end-organs are implicated in lupus pathogenesis. To gain insights into the mechanisms of tissue injury, we profiled the expression of micro-RNAs in inflammatory kidney lesions of human lupus nephritis (LN).
  
  
  
  Kidney specimens were from patients with active proliferative, membranous or mixed LN and unaffected control tissue. Micro-RNAs were quantified by TaqMan Low Density Arrays. Bioinformatics was employed to predict gene targets, gene networks and perturbed signaling pathways. Results were validated by transfection studies (luciferase assay, real-time PCR) and in murine LN. Protein expression was determined by immunoblotting and immunohistochemistry.
  
  
  
  Twenty-four micro-RNAs were dysregulated (9 up-regulated, 15 down-regulated) in human LN compared with control renal tissue. Their predicted gene targets participated in pathways associated with TGF-β, kinases, NF-κB, HNF4A, Wnt/β-catenin, STAT3 and IL-4. miR-422a showed the highest upregulation (17-fold) in active LN and correlated with fibrinoid necrosis lesions (β = 0.63, P = 0.002). In transfection studies, miR-422a was found to directly target kallikrein-related peptidase 4 (KLK4) mRNA. Concordantly, KLK4 mRNA was significantly reduced in the kidneys of human and murine LN and correlated inversely with miR-422a levels. Immunohistochemistry confirmed reduced KLK4 protein expression in renal mesangial and tubular epithelial cells in human and murine LN.
  
  
  
  KLK4, a serine esterase with putative renoprotective properties, is down-regulated by miR-422a in LN kidney suggesting that, in addition to immune activation, local factors may be implicated in the disease.
authors.affiliation: Laboratory of Autoimmunity and Inflammation, Institute of Molecular Biology-Biotechnology, FORTH, Iraklio, Greece.
authors.forename: Eleni
authors.initials: E
authors.lastname: Krasoudaki
authors.affiliation: Laboratory of Autoimmunity and Inflammation, Institute of Molecular Biology-Biotechnology, FORTH, Iraklio, Greece Biomedical Research Foundation of the Academy of Athens, Iraklio, Greece.
authors.forename: Aggelos
authors.initials: A
authors.lastname: Banos
authors.affiliation: Laboratory of Autoimmunity and Inflammation, Institute of Molecular Biology-Biotechnology, FORTH, Iraklio, Greece.
authors.forename: Elias
authors.initials: E
authors.lastname: Stagakis
authors.affiliation: Hospital for Special Surgery, Weill Cornell Medical College, New York, NY, USA.
authors.forename: Konstantinos
authors.initials: K
authors.lastname: Loupasakis
authors.affiliation: Department of Pathology, University of Crete Medical School, Iraklio, Greece.
authors.forename: Elias
authors.initials: E
authors.lastname: Drakos
authors.affiliation: Department of Pathology, University of Crete Medical School, Iraklio, Greece.
authors.forename: Vaios
authors.initials: V
authors.lastname: Sinatkas
authors.affiliation: Laboratory of Autoimmunity and Inflammation, Institute of Molecular Biology-Biotechnology, FORTH, Iraklio, Greece.
authors.forename: Amalia
authors.initials: A
authors.lastname: Zampoulaki
authors.affiliation: Department of Nephrology, Aristotle University of Thessaloniki Medical School, Thessaloniki, Greece.
authors.forename: Aikaterini
authors.initials: A
authors.lastname: Papagianni
authors.affiliation: Center for Systems Biomedicine, Division of Digestive Diseases, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA, USA.
authors.forename: Dimitrios
authors.initials: D
authors.lastname: Iliopoulos
authors.affiliation: Laboratory of Autoimmunity and Inflammation, Institute of Molecular Biology-Biotechnology, FORTH, Iraklio, Greece Biomedical Research Foundation of the Academy of Athens, Iraklio, Greece 4th Department of Medicine, Attikon University Hospital, University of Athens Medical School, Athens, Greece.
authors.forename: Dimitrios T
authors.initials: DT
authors.lastname: Boumpas
authors.affiliation: Laboratory of Autoimmunity and Inflammation, Institute of Molecular Biology-Biotechnology, FORTH, Iraklio, Greece Rheumatology, Clinical Immunology and Allergy, University of Crete Medical School, Iraklio, Greece.
authors.forename: George K
authors.initials: GK
authors.lastname: Bertsias
mesh_terms: D000818:Animals; D001706:Biopsy; D016022:Case-Control Studies; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D006801:Humans; D007610:Kallikreins / Q000235:genetics / Q000378:metabolism*; D007668:Kidney / Q000378:metabolism* / Q000473:pathology; D008181:Lupus Nephritis / Q000235:genetics* / Q000378:metabolism / Q000473:pathology / Q000601:surgery; D051379:Mice; D035683:MicroRNAs / Q000235:genetics*; D015398:Signal Transduction; D015854:Up-Regulation
chemical_list: C574206:MIRN422 microRNA, human; D035683:MicroRNAs; D007610:Kallikreins; C120801:kallikrein 4
keywords: autoimmune; epigenetic; glomerulonephritis; inflammation; tissue injury