The phosphoinositide 3-kinase inhibitor alpelisib restores actin organization and improves proximal tubule dysfunction in vitro and in a mouse model of Lowe syndrome and Dent disease
Marine Berquez, Jonathan R Gadsby, Beatrice Paola Festa, Richard Butler, Stephen P. Jackson, Valeria Berno, Alessandro Luciani, Olivier Devuyst, Jennifer L. Gallop
Abstract
mouse model, alpelisib reduced endosomal actin staining while restoring stress fiber architecture and levels of megalin at the plasma membrane of proximal tubule cells, reflected by improved endocytic uptake of low molecular weight proteins in vivo. Thus, our findings support the link between phosphoinositide lipids, actin polymerization and endocytic trafficking in the proximal tubule and represent a proof-of-concept for repurposing alpelisib in Lowe syndrome/Dent disease 2.
Topics & Concepts
In vitroKinaseRho kinase inhibitorPhosphoinositide 3-kinaseDiseaseMedicinePharmacologyCell biologyEndocrinologyBiologyInternal medicineChemistryRho-associated protein kinaseBiochemistryPI3K/AKT/mTOR pathwaySignal transductionOral and gingival health researchCellular transport and secretionCoagulation, Bradykinin, Polyphosphates, and Angioedema