ArticleScientific reports2022
Glucosylceramide synthase inhibition protects against cardiac hypertrophy in chronic kidney disease.
Article in Scientific reports, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 10 papers, 1 of them a synthesis that pooled it.
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Who cites it
10 citing papers in PubMed, 1 synthesis or guideline pooled it, 11 citations in OpenAlex.
- Cardiorenal Associations in Preclinical Modeling: A Systematic Review and Meta-Analysis.International journal of molecular sciences · 2026Pooled it
- Chronic kidney disease induces a distinct lipidomic signature and accelerates atherosclerosis progression in a novel minipig model.Laboratory animal research · 2026Article
- Miglustat ameliorates isoproterenol-induced cardiac fibrosis via targeting UGCG.Molecular medicine (Cambridge, Mass.) · 2025Article
- Glycosphingolipids in Cardiovascular Disease: Insights from Molecular Mechanisms and Heart Failure Models.Biomolecules · 2024Review
- Glucosylceramide flippases contribute to cellular glucosylceramide homeostasis.Journal of lipid research · 2024Article
- Phosphate in Cardiovascular Disease: From New Insights Into Molecular Mechanisms to Clinical Implications.Arteriosclerosis, thrombosis, and vascular biology · 2024Review
- Deficiency of the lipid flippase ATP10A causes diet-induced dyslipidemia in female mice.Scientific reports · 2024Article
- UGCG modulates heart hypertrophy through B4GalT5-mediated mitochondrial oxidative stress and the ERK signaling pathway.Cellular & molecular biology letters · 2023Article
- The therapeutic potential of sphingolipids for cardiovascular diseases.Frontiers in cardiovascular medicine · 2023Review
- A Nurr1 ligand C-DIM12 attenuates brain inflammation and improves functional recovery after intracerebral hemorrhage in mice.Scientific reports · 2022Article
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Authors and funding
8 authors at 2 institutions in 1 country.
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Abstract
A significant population of patients with chronic kidney disease (CKD) develops cardiac hypertrophy, which can lead to heart failure and sudden cardiac death. Soluble klotho (sKL), the shed ectodomain of the transmembrane protein klotho, protects the heart against hypertrophic growth. We have shown that sKL protects the heart by regulating the formation and function of lipid rafts by targeting the sialic acid moiety of gangliosides, GM1/GM3. Reduction in circulating sKL contributes to an increased risk of cardiac hypertrophy in mice. sKL replacement therapy has been considered but its use is limited by the inability to mass produce the protein. Therefore, alternative methods to protect the heart are proposed. Glucosylation of ceramide catalyzed by glucosylceramide synthase is the entry step for the formation of gangliosides. Here we show that oral administration of a glucosylceramide synthase inhibitor (GCSi) reduces plasma and heart tissue glycosphingolipids, including gangliosides. Administration of GCSi is protective in two mouse models of cardiac stress-induction, one with isoproterenol overstimulation and the other with 5/6 nephrectomy-induced CKD. Treatment with GCSi does not alter the severity of renal dysfunction and hypertension in CKD. These results provide proof of principle for targeting glucosylceramide synthase to decrease gangliosides as a treatment for cardiac hypertrophy. They also support the hypothesis that sKL protects the heart by targeting gangliosides.
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Registered trials
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