title: Targeted Lipidomic and Transcriptomic Analysis Identifies Dysregulated Renal Ceramide Metabolism in a Mouse Model of Diabetic Kidney Disease.
abstract: Both type 1 and type 2 diabetes are associated with altered lipid metabolism, which might in part contribute to debilitating complications such as diabetic kidney disease (DKD). Ceramides are bioactive sphingolipids that have been implicated in a variety of diseases as they can regulate cellular responses to stress and invoke a myriad of downstream signaling responses. To investigate a potential role of altered ceramide metabolism in DKD, we utilized a highly sensitive and specific mass spectrometry (MS) method to quantitatively measure species in plasma and kidney cortex from the C57BLKSdb/dbmouse model of DKD and littermate controls. Long-chain ceramides (C14:0, C16:0, C18:0, C20:0) and a glucosylceramide (Glu-Cer C18:0) were increased in diabetic mouse plasma, while long-chain (C14:0, C16:0, C18:0) and very-long-chain (C24:0, C24:1) ceramides and a glucosylceramide (Glu-Cer C16:0) were decreased in diabetic mouse kidney tissue. Kidney and plasma ceramide levels correlated to functional and histopathological features of DKD. Transcriptomic analysis of mouse kidney tissue revealed expression changes indicative of decreased ceramide synthesis (Degs2, Smpd2) and increased conversion to sphingosine (Acer2) and downstream sphingosine-1-phosphate signaling. Correlation analysis identified a negative relationship between plasma and kidney tissue levels of ceramide C16:0 and ceramide C24:1. Overall, the findings suggest a previously unrecognized role for ceramide metabolism in DKD.
authors.affiliation: Division of Nephrology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA.
authors.forename: Kelli M
authors.initials: KM
authors.lastname: Sas
authors.affiliation: Division of Nephrology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA; Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI, USA.
authors.forename: Viji
authors.initials: V
authors.lastname: Nair
authors.affiliation: Division of Nephrology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA.
authors.forename: Jaeman
authors.initials: J
authors.lastname: Byun
authors.affiliation: Division of Nephrology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA.
authors.forename: Pradeep
authors.initials: P
authors.lastname: Kayampilly
authors.affiliation: Division of Nephrology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA.
authors.forename: Hongyu
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Division of Nephrology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA.
authors.forename: Jharna
authors.initials: J
authors.lastname: Saha
authors.affiliation: Division of Nephrology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA.
authors.forename: Frank C
authors.initials: FC
authors.lastname: Brosius
authors.affiliation: Division of Nephrology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA; Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI, USA.
authors.forename: Matthias
authors.initials: M
authors.lastname: Kretzler
authors.affiliation: Division of Nephrology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA; Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI, USA.
authors.forename: Subramaniam
authors.initials: S
authors.lastname: Pennathur
keywords: Ceramide; Diabetes; Diabetic kidney disease; Diabetic nephropathy; Glucosylceramide; Kidney; Lipidomics; Mass spectrometry