title: The lipid 5-phoshatase SHIP2 controls renal brush border ultrastructure and function by regulating the activation of ERM proteins.
abstract: The microvillus brush border on the renal proximal tubule epithelium allows the controlled reabsorption of solutes that are filtered through the glomerulus and thus participates in general body homeostasis. Here, using the lipid 5-phosphatase Ship2 global knockout mice, proximal tubule-specific Ship2 knockout mice, and a proximal tubule cell model in which SHIP2 is inactivated, we show that SHIP2 is a negative regulator of microvilli formation, thereby controlling solute reabsorption by the proximal tubule. We found increased PtdIns(4,5)P2 substrate and decreased PtdIns4P product when SHIP2 was inactivated, associated with hyperactivated ezrin/radixin/moesin proteins and increased Rho-GTP. Thus, inactivation of SHIP2 leads to increased microvilli formation and solute reabsorption by the renal proximal tubule. This may represent an innovative therapeutic target for renal Fanconi syndrome characterized by decreased reabsorption of solutes by this nephron segment.
authors.affiliation: Laboratoire de Génétique Fonctionnelle, GIGA-B34, Université de Liège, Liège, Belgium.
authors.forename: Sufyan G
authors.initials: SG
authors.lastname: Sayyed
authors.affiliation: Experimental Surgery, GIGA Cardiovascular Sciences, Université de Liège, Liège, Belgium.
authors.forename: François
authors.initials: F
authors.lastname: Jouret
authors.affiliation: Center for Microscopy and Molecular Imaging (CMMI), Université Libre de Bruxelles, Gosselies, Belgium.
authors.forename: Marjorie
authors.initials: M
authors.lastname: Vermeersch
authors.affiliation: Center for Microscopy and Molecular Imaging (CMMI), Université Libre de Bruxelles, Gosselies, Belgium; Laboratoire de Parasitologie Moléculaire, Institut de Biologie et de Médecine Moléculaires (IBMM), Université Libre de Bruxelles, Gosselies, Belgium.
authors.forename: David
authors.initials: D
authors.lastname: Pérez-Morga
authors.affiliation: Laboratoire de Génétique Fonctionnelle, GIGA-B34, Université de Liège, Liège, Belgium. Electronic address: sschurmans@ulg.ac.be.
authors.forename: Stéphane
authors.initials: S
authors.lastname: Schurmans
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D003598:Cytoskeletal Proteins / Q000378:metabolism*; D004847:Epithelial Cells / Q000201:enzymology* / Q000648:ultrastructure; D005260:Female; D005838:Genotype; D006029:Glycosuria / Q000378:metabolism; D007687:Kidney Tubules, Proximal / Q000201:enzymology* / Q000648:ultrastructure; D018374:LLC-PK1 Cells; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism*; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008840:Microfilament Proteins / Q000378:metabolism*; D008871:Microvilli / Q000201:enzymology; D046912:Multiprotein Complexes; D010641:Phenotype; D019269:Phosphatidylinositol 4,5-Diphosphate / Q000378:metabolism; D018129:Phosphatidylinositol Phosphates / Q000378:metabolism; D000072183:Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D065608:Renal Reabsorption; D013552:Swine; D013997:Time Factors; D020741:rho GTP-Binding Proteins / Q000378:metabolism; D000099149:Ezrin
chemical_list: D001786:Blood Glucose; D003598:Cytoskeletal Proteins; D008565:Membrane Proteins; D008840:Microfilament Proteins; D046912:Multiprotein Complexes; D019269:Phosphatidylinositol 4,5-Diphosphate; D018129:Phosphatidylinositol Phosphates; D000072183:Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases; D020741:rho GTP-Binding Proteins; D000099149:Ezrin; C037178:phosphatidylinositol 4-phosphate; C071058:moesin; C071776:radixin; C000606435:Inppl1 protein, mouse
keywords: Fanconi syndrome; Ship2/Inppl1; microvilli; phosphoinositide; proximal tubule; renal brush border