title: Inhibition of glucosylceramide accumulation results in effective blockade of polycystic kidney disease in mouse models.
abstract: Polycystic kidney disease (PKD) represents a family of genetic disorders characterized by renal cystic growth and progression to kidney failure. No treatment is currently available for people with PKD, although possible therapeutic interventions are emerging. Despite genetic and clinical heterogeneity, PKDs have in common defects of cystic epithelia, including increased proliferation, apoptosis and activation of growth regulatory pathways. Sphingolipids and glycosphingolipids are emerging as major regulators of these cellular processes. We sought to evaluate the therapeutic potential for glycosphingolipid modulation as a new approach to treat PKD. Here we demonstrate that kidney glucosylceramide (GlcCer) and ganglioside GM3 levels are higher in human and mouse PKD tissue as compared to normal tissue, regardless of the causative mutation. Blockade of GlcCer accumulation with the GlcCer synthase inhibitor Genz-123346 effectively inhibits cystogenesis in mouse models orthologous to human autosomal dominant PKD (Pkd1 conditional knockout mice) and nephronophthisis (jck and pcy mice). Molecular analysis in vitro and in vivo indicates that Genz-123346 acts through inhibition of the two key pathways dysregulated in PKD: Akt protein kinase-mammalian target of rapamycin signaling and cell cycle machinery. Taken together, our data suggest that inhibition of GlcCer synthesis represents a new and effective treatment option for PKD.
authors.affiliation: Department of Cell Biology, Genzyme Corporation, Framingham, Massachusetts, USA.
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Natoli
authors.forename: Laurie A
authors.initials: LA
authors.lastname: Smith
authors.forename: Kelly A
authors.initials: KA
authors.lastname: Rogers
authors.forename: Bing
authors.initials: B
authors.lastname: Wang
authors.forename: Svetlana
authors.initials: S
authors.lastname: Komarnitsky
authors.forename: Yeva
authors.initials: Y
authors.lastname: Budman
authors.forename: Alexei
authors.initials: A
authors.lastname: Belenky
authors.forename: Nikolay O
authors.initials: NO
authors.lastname: Bukanov
authors.forename: William R
authors.initials: WR
authors.lastname: Dackowski
authors.forename: Hervé
authors.initials: H
authors.lastname: Husson
authors.forename: Ryan J
authors.initials: RJ
authors.lastname: Russo
authors.forename: James A
authors.initials: JA
authors.lastname: Shayman
authors.forename: Steven R
authors.initials: SR
authors.lastname: Ledbetter
authors.forename: John P
authors.initials: JP
authors.lastname: Leonard
authors.forename: Oxana
authors.initials: O
authors.lastname: Ibraghimov-Beskrovnaya
mesh_terms: D000818:Animals; D002453:Cell Cycle; D004146:Dioxanes / Q000494:pharmacology*; D004195:Disease Models, Animal; D005679:G(M3) Ganglioside / Q000378:metabolism; D005963:Glucosylceramides / Q000096:biosynthesis*; D005964:Glucosyltransferases / Q000037:antagonists & inhibitors; D006028:Glycosphingolipids / Q000378:metabolism; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D007690:Polycystic Kidney Diseases / Q000188:drug therapy / Q000378:metabolism*; D011759:Pyrrolidines / Q000494:pharmacology*; D051381:Rats
chemical_list: C520404:(2-(2',3'-dihydrobenzo(1,4)dioxin-6'-yl)-2-hydroxy-1-pyrrolidin-1-ylmethylethyl)nonanoic acid amide; D004146:Dioxanes; D005679:G(M3) Ganglioside; D005963:Glucosylceramides; D006028:Glycosphingolipids; D011759:Pyrrolidines; D005964:Glucosyltransferases; C023246:ceramide glucosyltransferase