Cyclophilins A and B oppositely regulate renal tubular epithelial cell phenotype
作者机构：Renal Physiopathology GroupCIBBIM-NanomedicineVall d’Hebron Research Institute08035 BarcelonaSpain Cardiovascular Diseases GroupVall d’Hebron Research Institute08035 BarcelonaSpain Biomimetic Systems for Cell Engineering LaboratoryInstitute for Bioengineering of Catalonia(IBEC)The Barcelona Institute of Science and Technology(BIST)08028 BarcelonaSpain Division of Nephrology and Hypertension and Department of MedicineMayo ClinicRochesterMN 55905USA Department of PathologyHospital Universitari Vall d’Hebron08035 BarcelonaSpain Department of Pediatric and Adolescent MedicineCollege of MedicineMayo ClinicRochesterMN 55905USA Department of Biochemistry and Molecular BiologyCollege of MedicineMayo ClinicRochesterMN 55905USA Division of Nephrology and HypertensionNorthwestern University Feinberg School of MedicineChicagoIL 60611USA Department of ImmunologyCollege of MedicineMayo ClinicRochesterMN 55905USA Departament de Bioquímica i Biologia MolecularUnitat de Bioquímica de MedicinaUniversitat Autònoma de Barcelona08193 BellaterraSpain Red de Investigación Renal(REDINREN)Instituto de Salud Carlos III-FEDER28040 MadridSpain
出 版 物：《Journal of Molecular Cell Biology》 (分子细胞生物学报（英文版）)
年 卷 期：2020年第12卷第7期
页 面：499-514页
核心收录：
学科分类：0710[理学-生物学] 071010[理学-生物化学与分子生物学] 081704[工学-应用化学] 07[理学] 08[工学] 0817[工学-化学工程与技术] 071003[理学-生理学]
基 金：supported in part by grants from Ministerio de Cienciae Innovacion(SAF 201459945-Rand SAF 201789989-R to A.M.) the Fundacion Senefro(SEN 2019 to A.M.),Instituto de Salud Carloslll(PIE13/00027) Red de Investigacion Renal REDinREN(12/0021/0013).KAN.is supported by Nationa Mnstitutes of Health(NIH)DK 47060.A.M.group holds the Quality Mention from the Generalitat de Catalunya(2017 SGR)
主 题：cyclophilins epithelial phenotype Slug TGFβ UUO fibrosis
摘 要：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 *** we demonstrate that in cultured TECs,CypA silencing triggers loss of epithelial features and enhances transforming growth factorβ(TGFβ)-induced EMT in association with upregulation of epithelial repressors Slug and *** pro-epithelial action of CypA relies on its PPIase *** contrast,CypB emerges as an epithelial repressor,because CypB silencing promotes epithelial differentiation,prevents TGFβ-induced EMT,and induces tubular structures in 3D *** addition,in the kidneys of CypB knockout mice subjected to unilateral ureteral obstruction,inflammatory and pro-fibrotic events were *** silencing/knockout leads to Slug,but not Snail,*** support of Slug expression depends on its endoplasmic reticulum location,where it interacts with calreticulin,a calcium-buffering chaperone related to Slug *** CypB silencing reduces ionomycin-induced calcium release and Slug upregulation,we suggest that Slug expression may rely on CypB modulation of calreticulin-dependent calcium *** 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.
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