Inhibition of glucosylceramide accumulation results in effective blockade of polycystic kidney disease in mouse models.
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.
Natoli
Thomas A
TA
Department of Cell Biology, Genzyme Corporation, Framingham, Massachusetts, USA.
Smith
Laurie A
LA
Rogers
Kelly A
KA
Wang
Bing
B
Komarnitsky
Svetlana
S
Budman
Yeva
Y
Belenky
Alexei
A
Bukanov
Nikolay O
NO
Dackowski
William R
WR
Husson
Hervé
H
Russo
Ryan J
RJ
Shayman
James A
JA
Ledbetter
Steven R
SR
Leonard
John P
JP
Ibraghimov-Beskrovnaya
Oxana
O
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
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