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 C57BLKS db/db mouse 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.
Highlights
Dyslipidemia is a common feature of both prediabetes and overt diabetes mellitus
diabetic kidney disease (DKD) is a frequent complication of both T1DM and T2DM, the physiological processes associated with DKD development are incompletely understood
Abnormal lipid metabolism has been implicated in the pathogenesis of DKD and, in the case of kidney disease, ceramides are known to be important in the response to cellular stress by promoting apoptosis and inflammation [15,29]
Summary
Dyslipidemia is a common feature of both prediabetes and overt diabetes mellitus Both lack of insulin as occurring in type 1 diabetes (T1DM) and insulin resistance, which typifies type 2 diabetes (T2DM), result in altered plasma lipids in humans. Few studies have reported ceramide levels in diabetic microvascular complication-prone tissues, and most reports in DKD are extrapolated from plasma levels [12,14]. Given the conflicting literature on ceramides in kidney disease, a relative lack of information on the relationship between plasma and tissue levels, and the recent understanding that individual ceramide species are crucial to function, we investigated individual ceramide species in plasma and kidney tissue in a mouse model of DKD
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