RT Journal Article
SR Electronic
T1 Cyclophilins A and B Oppositely Regulate Renal Tubular Epithelial Phenotype
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 288886
DO 10.1101/288886
A1 Eduard Sarró
A1 Mónica Durán
A1 Ana Rico
A1 Anthony J. Croatt
A1 Karl A. Nath
A1 Salcedo Maria Teresa
A1 Justin H. Gundelach
A1 Daniel Batlle
A1 Richard J. Bram
A1 Anna Meseguer
YR 2018
UL http://biorxiv.org/content/early/2018/03/26/288886.abstract
AB Cyclophilins (Cyp) are peptidil-prolyl-isomerases and the intracellular receptors for the immunosuppressant Cyclosporine-A (CsA), which produces epithelial-mesenchymal-transition (EMT) and renal tubule-interstitial fibrosis. Since CsA inhibits Cyp enzymatic activity, we hypothesized that Cyp could be involved in EMT and fibrosis. Here, we demonstrate that CypB is a critical regulator of tubule epithelial cell plasticity on the basis that: i) CypB silencing caused epithelial differentiation in proximal tubule-derived HK-2 cells, ii) CypB silencing prevented TGFβ-induced EMT in HK-2, and iii) CypB knockdown mice exhibited reduced UUO-induced inflammation and kidney fibrosis. By contrast, silencing of CypA induces a more undifferentiated phenotype and favors TGFβ effects. EMT mediators Slug and Snail were up-regulated in CypA-silenced cells, while in CypB silencing, Slug, but not Snail, was down-regulated; thus, reinforcing the role of Slug in kidney fibrosis. CypA regulates Slug through its PPIase activity whereas CypB depends on its ER location, where interacts with calreticulin, a calcium modulator which is involved in TGFβ signaling. In conclusion, this work uncovers new roles for CypA and CypB in modulating proximal tubular cell plasticity.