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Transcriptomics Reveal Altered Metabolic and Signaling Pathways in Podocytes Exposed to C16 Ceramide-Enriched Lipoproteins

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Department of Regenerative Medicine and Cell Biology, Medical University of South Carolina, Charleston, SC 29425, USA
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Division of Nephrology, Department of Medicine, Medical University of South Carolina, Charleston, SC 29425, USA
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Division of Endocrinology, Metabolism, and Medical Genetics, Department of Medicine, Medical University of South Carolina, Charleston, SC 29425, USA
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Research Service, Ralph H. Johnson Department of Veterans Affairs Medical Center, Charleston, SC 29401, USA
*
Author to whom correspondence should be addressed.
Genes 2020, 11(2), 178; https://doi.org/10.3390/genes11020178
Received: 23 January 2020 / Revised: 3 February 2020 / Accepted: 4 February 2020 / Published: 7 February 2020
(This article belongs to the Section Human Genomics and Genetic Diseases)
Sphingolipids are bioactive lipids associated with cellular membranes and plasma lipoproteins, and their synthesis and degradation are tightly regulated. We have previously determined that low plasma concentrations of certain ceramide species predict the development of nephropathy in diabetes patients with normal albumin excretion rates at baseline. Herein, we tested the hypothesis that altering the sphingolipid content of circulating lipoproteins can alter the metabolic and signaling pathways in podocytes, whose dysfunction leads to an impairment of glomerular filtration. Cultured human podocytes were treated with lipoproteins from healthy subjects enriched in vitro with C16 ceramide, or D-erythro 2-hydroxy C16 ceramide, a ceramide naturally found in skin. The RNA-Seq data demonstrated differential expression of genes regulating sphingolipid metabolism, sphingolipid signaling, and mTOR signaling pathways. A multiplex analysis of mTOR signaling pathway intermediates showed that the majority (eight) of the pathway phosphorylated proteins measured (eleven) were significantly downregulated in response to C16 ceramide-enriched HDL2 compared to HDL2 alone and hydroxy ceramide-enriched HDL2. In contrast, C16 ceramide-enriched HDL3 upregulated the phosphorylation of four intermediates in the mTOR pathway. These findings highlight a possible role for lipoprotein-associated sphingolipids in regulating metabolic and signaling pathways in podocytes and could lead to novel therapeutic targets in glomerular kidney diseases. View Full-Text
Keywords: RNA-Seq; podocyte; ceramide; lipoprotein; sphingolipids; mTOR RNA-Seq; podocyte; ceramide; lipoprotein; sphingolipids; mTOR
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Hammad, S.M.; Twal, W.O.; Arif, E.; Semler, A.J.; Klein, R.L.; Nihalani, D. Transcriptomics Reveal Altered Metabolic and Signaling Pathways in Podocytes Exposed to C16 Ceramide-Enriched Lipoproteins. Genes 2020, 11, 178.

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