ArticleHuman molecular genetics2012
Loss of GM3 synthase gene, but not sphingosine kinase 1, is protective against murine nephronophthisis-related polycystic kidney disease.
Article in Human molecular genetics, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 19 papers.
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Who cites it
19 citing papers in PubMed, 35 citations in OpenAlex.
- Pharmacokinetics, Pharmacodynamics, Safety, and Tolerability of Oral Venglustat in Healthy Volunteers.Clinical pharmacology in drug development · 2021Trial
- Loss of PKD1/polycystin-1 impairs lysosomal activity in a CAPN (calpain)-dependent manner.Autophagy · 2021Article
- The role of neuraminidase in TLR4-MAPK signalling and the release of cytokines by lupus serum-stimulated mesangial cells.Immunology · 2021Article
- Renal Ciliopathies: Sorting Out Therapeutic Approaches for Nephronophthisis.Frontiers in cell and developmental biology · 2021Review
- Gangliosides in Podocyte Biology and Disease.International journal of molecular sciences · 2020Review
- Article
- Correction of cilia structure and function alleviates multi-organ pathology in Bardet-Biedl syndrome mice.Human molecular genetics · 2020Article
- ADPKD current management and ongoing trials.Journal of nephrology · 2020Review
- Targeting glycosphingolipid metabolism as a potential therapeutic approach for treating disease in female MRL/lpr lupus mice.PloS one · 2020Article
- Lipid mediators of insulin signaling in diabetic kidney disease.American journal of physiology. Renal physiology · 2019Review
- Emerging targeted strategies for the treatment of autosomal dominant polycystic kidney disease.Clinical kidney journal · 2018Review
- Inhibition of pannexin-1 channel activity by adiponectin in podocytes: Role of acid ceramidase activation.Biochimica et biophysica acta. Molecular and cell biology of lipids · 2018Article
- Targeting Glucosylceramide Synthesis in the Treatment of Rare and Common Renal Disease.Seminars in nephrology · 2018Review
- Article
- High-resolution genetic localization of a modifying locus affecting disease severity in the juvenile cystic kidneys (jck) mouse model of polycystic kidney disease.Mammalian genome : official journal of the International Mammalian Genome Society · 2016Article
- Reduction of ciliary length through pharmacologic or genetic inhibition of CDK5 attenuates polycystic kidney disease in a model of nephronophthisis.Human molecular genetics · 2016Article
- Simplifying complexity: genetically resculpting glycosphingolipid synthesis pathways in mice to reveal function.Glycoconjugate journal · 2014Review
- MALDI imaging MS reveals candidate lipid markers of polycystic kidney disease.Journal of lipid research · 2013Article
- New treatments for autosomal dominant polycystic kidney disease.British journal of clinical pharmacology · 2013Review
Corrections and comments
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Authors and funding
11 authors at 2 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
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.
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