Abstract
The profile of sphingomyelin and its metabolites shows changes in the plasma, organs, and tissues of patients with cardiovascular, renal, and metabolic diseases. The objective of this study was to investigate the effect of empagliflozin on the levels of sphingomyelin and its metabolites, as well as on the activity of acid and neutral sphingomyelinase (aSMase and nSMase) and neutral ceramidase (nCDase) in the plasma, kidney, heart, and liver of streptozotocin-induced diabetic and Angiotensin II (Ang II)-induced hypertension rats. Empagliflozin treatment decreased hyperglycemia in diabetic rats whereas blood pressure remained elevated in hypertensive rats. In diabetic rats, empagliflozin treatment decreased sphingomyelin in the plasma and liver, ceramide in the heart, sphingosine-1-phosphate (S1P) in the kidney, and nCDase activity in the plasma, heart, and liver. In hypertensive rats, empagliflozin treatment decreased sphingomyelin in the plasma, kidney, and liver; S1P in the plasma and kidney; aSMase in the heart, and nCDase activity in the plasma, kidney, and heart. Our results suggest that empagliflozin downregulates the interaction of the de novo pathway and the catabolic pathway of sphingolipid metabolism in the diabetes, whereas in Ang II-dependent hypertension, it only downregulates the sphingolipid catabolic pathway.
Highlights
Numerous human studies have shown that, in cardiovascular, renal, and metabolic diseases, the profiles of sphingomyelin [1–4] and its metabolites ceramide [5–11], sphingosine [12], and sphingosine-1-phosphate (S1P) [13,14] are altered in the plasma, organs, and tissues
Concerning the expression at the mRNA level of the enzymes involved in the synthesis and degradation of ceramide (SMase, CDase, and sphingosine kinase (SK)-1), the levels of these enzymes were increased in intra-abdominal adipose tissue and the myocardium of obese patients with or without type 2 diabetes [16,17]
The neutral ceramidase (nCDase) activity increased in the plasma, kidney, and heart of hypertensive rats compared with the sham group but decreased with empagliflozin treatment. nCDase activity in the liver did not show changes with and without treatment (Figure 14)
Summary
Numerous human studies have shown that, in cardiovascular, renal, and metabolic diseases, the profiles of sphingomyelin [1–4] and its metabolites ceramide [5–11], sphingosine [12], and sphingosine-1-phosphate (S1P) [13,14] are altered (reduction or elevation) in the plasma, organs (liver and heart), and tissues (skeletal muscle and adipose). Most of these studies focused on the determination of ceramide in plasma. It is necessary to perform preclinical studies to determine the content of sphingomyelin and its bioactive metabolites in plasma and organs such as the brain, liver, heart, and kidney, because the sphingolipid metabolism imbalance can be affected directly or indirectly in various organs. The level of SK expression decreased in the brain of stroke-prone spontaneously hypertensive rats and S1P receptor expression was increased in the kidney of strokeresistant spontaneously hypertensive rats [18]
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