Effect of Empagliflozin on Sphingolipid Catabolism in Diabetic and Hypertensive Rats

Overview

Journal Int J Mol Sci

Publisher MDPI

Specialties Biochemistry
Chemistry
Molecular Biology

Date 2022 Mar 10

PMID 35270028

Authors

Roxana Perez-Villavicencio

Javier Flores-Estrada

Martha Franco

Bruno Escalante

Oscar Perez-Mendez

Adriana Mercado

Rocio Bautista-Perez

Affiliations

Soon will be listed here.

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.

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References

Deutschman D, Carstens J, Klepper R, Smith W, Page M, Young T . Predicting obstructive coronary artery disease with serum sphingosine-1-phosphate. Am Heart J. 2003; 146(1):62-8. DOI: 10.1016/S0002-8703(03)00118-2. View

Coroneos E, Martinez M, McKenna S, Kester M . Differential regulation of sphingomyelinase and ceramidase activities by growth factors and cytokines. Implications for cellular proliferation and differentiation. J Biol Chem. 1995; 270(40):23305-9. DOI: 10.1074/jbc.270.40.23305. View

Bautista-Perez R, Arellano A, Franco M, Osorio H, Coronel I . Sphingosine-1-phosphate induced vasoconstriction is increased in the isolated perfused kidneys of diabetic rats. Diabetes Res Clin Pract. 2011; 94(1):e8-11. DOI: 10.1016/j.diabres.2011.06.023. View

Casasampere M, Camacho L, Cingolani F, Casas J, Egido-Gabas M, Abad J . Activity of neutral and alkaline ceramidases on fluorogenic N-acylated coumarin-containing aminodiols. J Lipid Res. 2015; 56(10):2019-28. PMC: 4583077. DOI: 10.1194/jlr.D061564. View

Mitsnefes M, Scherer P, Friedman L, Gordillo R, Furth S, Warady B . Ceramides and cardiac function in children with chronic kidney disease. Pediatr Nephrol. 2014; 29(3):415-22. PMC: 4068150. DOI: 10.1007/s00467-013-2642-1. View

Becker K, Kitatani K, Idkowiak-Baldys J, Bielawski J, Hannun Y . Selective inhibition of juxtanuclear translocation of protein kinase C betaII by a negative feedback mechanism involving ceramide formed from the salvage pathway. J Biol Chem. 2004; 280(4):2606-12. DOI: 10.1074/jbc.M409066200. View

Ruiz-Ortega M, Ruperez M, Lorenzo O, Esteban V, Blanco J, Mezzano S . Angiotensin II regulates the synthesis of proinflammatory cytokines and chemokines in the kidney. Kidney Int Suppl. 2002; (82):S12-22. DOI: 10.1046/j.1523-1755.62.s82.4.x. View

Inoue T, Okino N, Kakuta Y, Hijikata A, Okano H, Goda H . Mechanistic insights into the hydrolysis and synthesis of ceramide by neutral ceramidase. J Biol Chem. 2008; 284(14):9566-77. PMC: 2666609. DOI: 10.1074/jbc.M808232200. View

Pan W, Yu J, Shi R, Yan L, Yang T, Li Y . Elevation of ceramide and activation of secretory acid sphingomyelinase in patients with acute coronary syndromes. Coron Artery Dis. 2014; 25(3):230-5. DOI: 10.1097/MCA.0000000000000079. View

10.

Heise T, Seman L, Macha S, Jones P, Marquart A, Pinnetti S . Safety, tolerability, pharmacokinetics, and pharmacodynamics of multiple rising doses of empagliflozin in patients with type 2 diabetes mellitus. Diabetes Ther. 2013; 4(2):331-45. PMC: 3889329. DOI: 10.1007/s13300-013-0030-2. View

11.

Wiegmann K, Schutze S, Machleidt T, Witte D, Kronke M . Functional dichotomy of neutral and acidic sphingomyelinases in tumor necrosis factor signaling. Cell. 1994; 78(6):1005-15. DOI: 10.1016/0092-8674(94)90275-5. View

12.

Sobczak A, Pitt S, Smith T, Ajjan R, Stewart A . Lipidomic profiling of plasma free fatty acids in type-1 diabetes highlights specific changes in lipid metabolism. Biochim Biophys Acta Mol Cell Biol Lipids. 2020; 1866(1):158823. PMC: 7695620. DOI: 10.1016/j.bbalip.2020.158823. View

13.

Bautista-Perez R, Del Valle-Mondragon L, Cano-Martinez A, Perez-Mendez O, Escalante B, Franco M . Involvement of neutral sphingomyelinase in the angiotensin II signaling pathway. Am J Physiol Renal Physiol. 2014; 308(10):F1178-87. DOI: 10.1152/ajprenal.00079.2014. View

14.

Liu J, Zhang H, Li Z, Hailemariam T, Chakraborty M, Jiang K . Sphingomyelin synthase 2 is one of the determinants for plasma and liver sphingomyelin levels in mice. Arterioscler Thromb Vasc Biol. 2009; 29(6):850-6. PMC: 2763553. DOI: 10.1161/ATVBAHA.109.185223. View

15.

Blachnio-Zabielska A, Koutsari C, Tchkonia T, Jensen M . Sphingolipid content of human adipose tissue: relationship to adiponectin and insulin resistance. Obesity (Silver Spring). 2012; 20(12):2341-7. PMC: 3443533. DOI: 10.1038/oby.2012.126. View

16.

Klein R, Hammad S, Baker N, Hunt K, Al Gadban M, Cleary P . Decreased plasma levels of select very long chain ceramide species are associated with the development of nephropathy in type 1 diabetes. Metabolism. 2014; 63(10):1287-95. PMC: 5894336. DOI: 10.1016/j.metabol.2014.07.001. View

17.

Zhuo J . Monocyte chemoattractant protein-1: a key mediator of angiotensin II-induced target organ damage in hypertensive heart disease?. J Hypertens. 2004; 22(3):451-4. PMC: 2277522. DOI: 10.1097/01.hjh.0000098211.37783.e7. View

18.

Hofmeister R, Wiegmann K, Korherr C, Bernardo K, Kronke M, Falk W . Activation of acid sphingomyelinase by interleukin-1 (IL-1) requires the IL-1 receptor accessory protein. J Biol Chem. 1997; 272(44):27730-6. DOI: 10.1074/jbc.272.44.27730. View

19.

Spijkers L, van den Akker R, Janssen B, Debets J, De Mey J, Stroes E . Hypertension is associated with marked alterations in sphingolipid biology: a potential role for ceramide. PLoS One. 2011; 6(7):e21817. PMC: 3139577. DOI: 10.1371/journal.pone.0021817. View

20.

Aragon-Herrera A, Feijoo-Bandin S, Otero Santiago M, Barral L, Campos-Toimil M, Gil-Longo J . Empagliflozin reduces the levels of CD36 and cardiotoxic lipids while improving autophagy in the hearts of Zucker diabetic fatty rats. Biochem Pharmacol. 2019; 170:113677. DOI: 10.1016/j.bcp.2019.113677. View