title: Tubular Cytoplasmic Expression of Zinc Finger Protein SNAI1 in Renal Transplant Biopsies: A Sign of Diseased Epithelial Phenotype?
abstract: The aim of the present study was to analyze in vivo the role of zinc finger protein SNAI1 (SNAI1) on renal fibrosis. Unilateral ureteral obstruction injury was induced in Snai1 knockout mice. Snai1 gene deletion was, however, only partial and could therefore not be correlated to reduced fibrosis. Expression of SNAI1 protein and epithelial-mesenchymal transformation markers was then assessed in human chronic allograft nephropathy biopsy specimens. Significant up-regulation of SNAI1 protein was detected within cytoplasm of proximal tubules localized, for some of them, near foci of fibrosis and tubular atrophy. No concomitant epithelial-mesenchymal transformation could, however, be demonstrated analyzing the expression of the fibroblast markers vimentin, α-smooth muscle actin, and S100A4. SNAI1 cytoplasmic up-regulation was particularly evident in biopsy specimens obtained from calcineurin inhibitor-treated patients, which might be because of, as suggested by in vitro experiments, a decrease of the proteasome chimotrypsin activity. Deeper analysis on chronic allograft nephropathy biopsy specimens suggested that SNAI1 cytoplasmic up-regulation was preceded by a transient increase of phosphorylated heat shock protein 27, p38 mitogen-activated protein kinase, and glycogen synthase kinase 3β. Concomitant down-regulation of the polyubuquitinylated conjugates was detected in SNAI1+tubules. Altogether, these results might suggest that calcineurin inhibitor-induced tubular SNAI1 protein cytoplasmic accumulation, possibly because of impaired SNAI1 proteasomal degradation and nuclear translocation, might be a sign of a diseased profibrotic epithelial phenotype.
authors.affiliation: Discovery Technologies, Roche Innovation Center Basel, Roche Pharma Research and Early Development, Basel, Switzerland. Electronic address: marco.prunotto@roche.com.
authors.forename: Marco
authors.initials: M
authors.lastname: Prunotto
authors.affiliation: Clinics for Cardiovascular Surgery, Zurich University Hospital, Zurich, Switzerland.
authors.forename: Lyubov
authors.initials: L
authors.lastname: Chaykovska
authors.affiliation: Division of Clinical Pathology, Department of Pathology and Immunology, University Hospital Geneva, Geneva, Switzerland.
authors.forename: Massimo
authors.initials: M
authors.lastname: Bongiovanni
authors.affiliation: Institute of Pathology, Locarno, Switzerland.
authors.forename: Milo
authors.initials: M
authors.lastname: Frattini
authors.affiliation: Division of Clinical Pathology, Department of Pathology and Immunology, University Hospital Geneva, Geneva, Switzerland.
authors.forename: Thomas
authors.initials: T
authors.lastname: Cagarelli
authors.affiliation: Discovery Technologies, Roche Innovation Center Basel, Roche Pharma Research and Early Development, Basel, Switzerland.
authors.forename: Franziska
authors.initials: F
authors.lastname: Weibel
authors.affiliation: Laboratory of Uremia Pathophysiology, Giannina Gaslini Hospital, Genova, Italy.
authors.forename: Maurizio
authors.initials: M
authors.lastname: Bruschi
authors.affiliation: Hospital del Mar Medical Research Institute, Barcelona Biomedical Research Park, Barcelona, Spain.
authors.forename: Antonio Garcia
authors.initials: AG
authors.lastname: de Herreros
authors.affiliation: Division of Clinical Pathology, Department of Pathology and Immunology, University Hospital Geneva, Geneva, Switzerland; Institute of Clinical Pathology, University Hospital Lausanne, Lausanne, Switzerland.
authors.forename: Solange
authors.initials: S
authors.lastname: Moll
mesh_terms: D064591:Allografts / Q000187:drug effects; D000818:Animals; D001706:Biopsy; D065095:Calcineurin Inhibitors / Q000494:pharmacology; D002908:Chronic Disease; D003593:Cytoplasm / Q000378:metabolism*; D004285:Dogs; D004847:Epithelial Cells / Q000378:metabolism*; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects; D005260:Female; D005355:Fibrosis; D000071679:Glycogen Synthase Kinase 3 beta / Q000378:metabolism; D055551:HSP27 Heat-Shock Proteins / Q000378:metabolism; D016030:Kidney Transplantation / Q000009:adverse effects; D007684:Kidney Tubules / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D061985:Madin Darby Canine Kidney Cells; D008297:Male; D018345:Mice, Knockout; D010641:Phenotype; D010766:Phosphorylation / Q000187:drug effects; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D000071250:Snail Family Transcription Factors / Q000378:metabolism*; D015854:Up-Regulation / Q000187:drug effects; D014517:Ureteral Obstruction / Q000473:pathology; D016335:Zinc Fingers; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D065095:Calcineurin Inhibitors; D055551:HSP27 Heat-Shock Proteins; C000604407:SNAI1 protein, human; C000604429:Snai1 protein, mouse; D000071250:Snail Family Transcription Factors; D000071679:Glycogen Synthase Kinase 3 beta; D048051:p38 Mitogen-Activated Protein Kinases; D046988:Proteasome Endopeptidase Complex