Cyclophilins A and B oppositely regulate renal tubular epithelial cell phenotype
Sarró, Eduard (Hospital Universitari Vall d'Hebron)
Durán, Mónica (Vall d'Hebron Institut de Recerca (VHIR))
Rico, Ana (Vall d'Hebron Institut de Recerca (VHIR))
Bou-Teen, Diana (Cardiovascular Diseases Group)
Fernández-Majada, Vanesa (Biomimetic Systems for Cell Engineering Laboratory)
Croatt, Anthony J. (Mayo Clinic (Rochester, Estats Units d'Amèrica))
Nath, Karl A. (Mayo Clinic (Rochester, Estats Units d'Amèrica))
Salcedo, Maria-Teresa (Vall d'Hebron Institut de Recerca (VHIR))
Gundelach, Justin H. (Mayo Clinic (Rochester, Estats Units d'Amèrica))
Batlle, Daniel (Northwestern University Feinberg School of Medicine (Chicago, Estats Units d'Amèrica))
Bram, Richard J. (Mayo Clinic (Rochester, Estats Units d'Amèrica))
Meseguer Navarro, Anna (Universitat Autònoma de Barcelona. Departament de Bioquímica i de Biologia Molecular)

Fecha:	2020
Resumen:	Restoration of kidney tubular epithelium following sublethal injury sequentially involves partial epithelial-mesenchymal transition (pEMT), proliferation, and further redifferentiation into specialized tubule epithelial cells (TECs). Because the immunosuppressant cyclosporine-A produces pEMT in TECs and inhibits the peptidyl-prolyl isomerase (PPIase) activity of cyclophilin (Cyp) proteins, we hypothesized that cyclophilins could regulate TEC phenotype. Here we demonstrate that in cultured TECs, CypA silencing triggers loss of epithelial features and enhances transforming growth factor β (TGF β)-induced EMT in association with upregulation of epithelial repressors Slug and Snail. This pro-epithelial action of CypA relies on its PPIase activity. By contrast, CypB emerges as an epithelial repressor, because CypB silencing promotes epithelial differentiation, prevents TGF β -induced EMT, and induces tubular structures in 3D cultures. In addition, in the kidneys of CypB knockout mice subjected to unilateral ureteral obstruction, inflammatory and pro-fibrotic events were attenuated. CypB silencing/knockout leads to Slug, but not Snail, downregulation. CypB support of Slug expression depends on its endoplasmic reticulum location, where it interacts with calreticulin, a calcium-buffering chaperone related to Slug expression. As CypB silencing reduces ionomycin-induced calcium release and Slug upregulation, we suggest that Slug expression may rely on CypB modulation of calreticulin-dependent calcium signaling. In conclusion, this work uncovers new roles for CypA and CypB in modulating TEC plasticity and identifies CypB as a druggable target potentially relevant in promoting kidney repair.
Ayudas:	Instituto de Salud Carlos III PIE13-00027 Ministerio de Ciencia e Innovación SAF201789989-R Ministerio de Ciencia e Innovación SAF201459945-R
Nota:	Altres ajuts: E.S. and M.D. were supported by the generous contribution of Asdent Patients Association. This work was supported in part by grants from Ministerio de Ciencia e Innovación, the Fundación Senefro (SEN2019 to A.M.), and Red de Investigación Renal REDinREN (12/0021/0013). K.A.N. is supported by National Institutes of Health (NIH) DK 47060. A.M. group holds the Quality Mention from the Generalitat de Catalunya.
Derechos:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, sempre que no sigui amb finalitats comercials, i sempre que es reconegui l'autoria de l'obra original.
Lengua:	Anglès
Documento:	Article ; recerca ; Versió publicada
Materia:	Cyclophilins ; Epithelial phenotype ; Slug ; TGFβ ; UUO ; Fibrosis
Publicado en:	Journal of Molecular Cell Biology, Vol. 12 (march 2020) , p. 499-514, ISSN 1759-4685

DOI: 10.1093/jmcb/mjaa005
PMID: 32162654

16 p, 2.9 MB

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