Tubular Cytoplasmic Expression of Zinc Finger Protein SNAI1 in Renal Transplant Biopsies: A Sign of Diseased Epithelial Phenotype?

Marco Prunotto, Lyubov Chaykovska, Massimo Bongiovanni, Milo Frattini, Thomas Cagarelli, Franziska Weibel, Maurizio Bruschi, Antonio Garcia de Herreros, Solange Moll

The American journal of pathology 2017 Jan

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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 acti n, 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. Copyright © 2017 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

Citation

Marco Prunotto, Lyubov Chaykovska, Massimo Bongiovanni, Milo Frattini, Thomas Cagarelli, Franziska Weibel, Maurizio Bruschi, Antonio Garcia de Herreros, Solange Moll. Tubular Cytoplasmic Expression of Zinc Finger Protein SNAI1 in Renal Transplant Biopsies: A Sign of Diseased Epithelial Phenotype? The American journal of pathology. 2017 Jan;187(1):55-69