title: Loss of GM3 synthase gene, but not sphingosine kinase 1, is protective against murine nephronophthisis-related polycystic kidney disease.
abstract: Genetic forms of polycystic kidney diseases (PKDs), including nephronophthisis, are characterized by formation of fluid-filled cysts in the kidneys and progression to end-stage renal disease. No therapies are currently available to treat cystic diseases, making it imperative to dissect molecular mechanisms in search of therapeutic targets. Accumulating evidence suggests a pathogenic role for glucosylceramide (GlcCer) in multiple forms of PKD. It is not known, however, whether other structural glycosphingolipids (GSLs) or bioactive signaling sphingolipids (SLs) modulate cystogenesis. Therefore, we set out to address the role of a specific GSL (ganglioside GM3) and signaling SL (sphingosine-1-phosphate, S1P) in PKD progression, using the jck mouse model of nephronopthisis. To define the role of GM3 accumulation in cystogenesis, we crossed jck mice with mice carrying a targeted mutation in the GM3 synthase (St3gal5) gene. GM3-deficient jck mice displayed milder PKD, revealing a pivotal role for ganglioside GM3. Mechanistic changes in regulation of the cell-cycle machinery and Akt-mTOR signaling were consistent with reduced cystogenesis. Dramatic overexpression of sphingosine kinase 1 (Sphk1) mRNA in jck kidneys suggested a pathogenic role for S1P. Surprisingly, genetic loss of Sphk1 exacerbated cystogenesis and was associated with increased levels of GlcCer and GM3. On the other hand, increasing S1P accumulation through pharmacologic inhibition of S1P lyase had no effect on the progression of cystogenesis or kidney GSL levels. Together, these data suggest that genes involved in the SL metabolism may be modifiers of cystogenesis, and suggest GM3 synthase as a new anti-cystic therapeutic target.
authors.affiliation: Department of Cell Biology, Genzyme Corporation, Framingham, MA 01701, USA.
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Natoli
authors.forename: Hervé
authors.initials: H
authors.lastname: Husson
authors.forename: Kelly A
authors.initials: KA
authors.lastname: Rogers
authors.forename: Laurie A
authors.initials: LA
authors.lastname: Smith
authors.forename: Bing
authors.initials: B
authors.lastname: Wang
authors.forename: Yeva
authors.initials: Y
authors.lastname: Budman
authors.forename: Nikolay O
authors.initials: NO
authors.lastname: Bukanov
authors.forename: Steven R
authors.initials: SR
authors.lastname: Ledbetter
authors.forename: Katherine W
authors.initials: KW
authors.lastname: Klinger
authors.forename: John P
authors.initials: JP
authors.lastname: Leonard
authors.forename: Oxana
authors.initials: O
authors.lastname: Ibraghimov-Beskrovnaya
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D005963:Glucosylceramides / Q000378:metabolism; D006028:Glycosphingolipids / Q000378:metabolism; D051379:Mice; D051058:Oncogene Protein v-akt / Q000235:genetics / Q000378:metabolism; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000235:genetics* / Q000378:metabolism; D007690:Polycystic Kidney Diseases / Q000201:enzymology / Q000235:genetics*; D012799:Sialyltransferases / Q000235:genetics* / Q000378:metabolism; D013110:Sphingosine / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D000099157:Sphingosine Kinase
chemical_list: D005963:Glucosylceramides; D006028:Glycosphingolipids; D051058:Oncogene Protein v-akt; D017853:Phosphotransferases (Alcohol Group Acceptor); D012799:Sialyltransferases; D013110:Sphingosine; D058570:TOR Serine-Threonine Kinases; D000099157:Sphingosine Kinase; C021343:haematoside synthetase