Cyclophilins A and B Oppositely Regulate Renal Tubular Epithelial Phenotype

Sarro, E.; Duran, M.; Rico, A.; Croatt, A. J.; Nath, K. A.; Salcedo, M. T.; Gundelach, J. H.; Batlle, D.; Bram, R. J.; Meseguer, A.

doi:10.1101/288886

bioRxiv · 10.1101/288886

Cyclophilins A and B Oppositely Regulate Renal Tubular Epithelial Phenotype

Sarro, E.·Duran, M.·Rico, A.·Croatt, A. J.·Nath, K. A.·Salcedo, M. T.·Gundelach, J. H.·Batlle, D.·Bram, R. J.·Meseguer, A.

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Abstract

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 TGF{beta}-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 TGF{beta} 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 TGF{beta} signaling. In conclusion, this work uncovers new roles for CypA and CypB in modulating proximal tubular cell plasticity.

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Sarro, E., Duran, M., Rico, A., Croatt, A. J., Nath, K. A., Salcedo, M. T., Gundelach, J. H., Batlle, D., Bram, R. J., Meseguer, A.. 2018-03-26. Cyclophilins A and B Oppositely Regulate Renal Tubular Epithelial Phenotype. https://doi.org/10.1101/288886

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