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.

Abstract

Loss-of-function mutations in the OCRL gene, which encodes the phosphatidylinositol [PI] 4,5-bisphosphate [PI(4,5)P2] 5-phosphatase OCRL, cause defective endocytosis and proximal tubule dysfunction in Lowe syndrome and Dent disease 2. The defect is due to increased levels of PI(4,5)P2 and aberrant actin polymerization, blocking endosomal trafficking. PI 3-phosphate [PI(3)P] has been recently identified as a coactivator with PI(4,5)P2 in the actin pathway. Here, we tested the hypothesis that phosphoinositide 3-kinase (PI3K) inhibitors may rescue the endocytic defect imparted by OCRL loss, by rebalancing phosphoinositide signals to the actin machinery. The broad-range PI3K inhibitor copanlisib and class IA p110α PI3K inhibitor alpelisib reduced aberrant actin polymerization in OCRL-deficient human kidney cells in vitro. Levels of PI 3,4,5-trisphosphate, PI(4,5)P2 and PI(3)P were all reduced with alpelisib treatment, and siRNA knockdown of the PI3K catalytic subunit p110α phenocopied the actin phenotype. In a humanized OcrlY/- 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.

• Authors: Marine Berquez, Jonathan R Gadsby, Beatrice Paola Festa, Richard Butler, Stephen P Jackson, Valeria Berno, Alessandro Luciani, Olivier Devuyst, Jennifer L Gallop
• Journal: Kidney international (Kidney Int) Vol. 98 Issue 4 Pg. 883-896 (10 2020) ISSN: 1523-1755 [Electronic] United States
• PMID: 32919786 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: Copyright © 2020 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.

Chemical References

• Actins
• Phosphatidylinositol Phosphates
• Phosphoinositide-3 Kinase Inhibitors
• Thiazoles
• phosphatidylinositol 3-phosphate
• Alpelisib
• Phosphoric Monoester Hydrolases

Topics

• Actins
• Dent Disease
• Humans
• Mice
• Oculocerebrorenal Syndrome (genetics)
• Phosphatidylinositol 3-Kinases
• Phosphatidylinositol Phosphates
• Phosphoinositide-3 Kinase Inhibitors
• Phosphoric Monoester Hydrolases (genetics)
• Thiazoles