INFLUENCE OF EMPAGLIFLOZIN ON THE KIDNEYS IN NORMOGLYCEMIC RATS WITH HEART FAILURE

THE AIM. To evaluate the effect of the sodium-glucose cotransporter SGLT-2 inhibitor - empagliflozin on the kidney in nondiabetic Wistar rats with experimental heart failure (HF). MATERIAL AND METHODS. Cronic heart failure (CHF) was induced by ligation the left coronary artery. Animals with CHF in the first group (n=11) received empagliflozin (Jardiance®, Boehringer Ingelheim) orally (1 mg / kg/day) for 1 month. In the second group of rats with CHF (n = 10) the drug is not administered. Systolic blood pressure, heart rate, concentrations and daily urinary excretion of glucose, albumin, creatinine, urea and essential ions were measured. The relative level of microRNA-21 urinary expression was established. RESULTS. Empagliflozin administration led to an increase in glycosuria, albuminuria, and the expression of microRNA-21 in urine. However in this conditions inorganic phosphorus excretion decreased. Empagliflozin did not influence on blood pressure, heart rate or levels of investigated substances excretion including sodium. CONCLUSION. The findings suggest that the SGLT-2 inhibitors may have some negative direct effects on the kidneys. However, in diabetes, such effects of these drugs can be masked by powerful nephroprotective actions associated with the ability of SGLT-2 inhibitors to counteract hyperglycemia and glomerular hyperfiltration.

1. Aziz Z, Absetz P, Oldroyd J et al. A systematic review of real-world diabetes prevention programs: learnings from the last 15 years. Implement Sci 2015;10, article 172 doi: 10.1186/ s13012-015-0354-6

2. Смирнов АВ, Добронравов ВА, Кисина АА и др. Клинические рекомендации по диагностике и лечению диабетической нефропатии. Нефрология 2015;19(1): 67-77 [Smirnov AV, Dobronravov VA, Kisina AA i dr. Klinicheskie rekomendacii po diagnostike i lecheniyu diabeticheskoj nefropatii. Nefrologiya 2015;19(1): 67-77]

3. Mima A. Diabetic nephropathy: protective factors and a new therapeutic paradigm. J Diabetes Complications 2013;27(5):526–530

4. Hoshino J, Mise K, Ueno T et al. A pathological scoring system to predict renal outcome in diabetic nephropathy. Am J Nephrol 2015;41(4-5):337–344

5. Patschan D, Muller GA. Acute kidney Injury in diabetes mellitus. Int J Nephrol 2016; 2016:6232909

6. Tang SC, Chan GC, Lai KN. Recent advances in managing and understanding diabetic nephropathy. F1000Res. 2016 May 31;5. pii: F1000 Faculty Rev-1044. doi: 10.12688/f1000research. 7693.1

7. Vallianou NG, Geladari E, Kazazis CE. SGLT-2 inhibitors: Their pleiotropic properties. Diabetes Metab Syndr 2016; pii: S1871-4021(16)30226-0. doi: 10.1016/j.dsx.2016.12.003. [Epub ahead of print]

8. Vallon V, Thomson SC. Targeting renal glucose reabsorption to treat hyperglycaemia: the pleiotropic effects of SGLT2 inhibition. Diabetologia 2017; 60(2):215-225

9. Бабенко АЮ, Байрашева ВК. Диабетическая нефропатия. Зависит ли ренопротекция от выбора сахароснижающей терапии. Мед совет 2015; (7): 32-43 [Babenko AYU, Bajrasheva VK. Diabeticheskaya nefropatiya. Zavisit li renoprotekciya ot vybora saharosnizhayushchej terapii. Medicinskij sovet 2015; (7): 32-43]

10. Kalra S, Singh V, Nagrale D. Sodium-Glucose Cotransporter2 Inhibition and the Glomerulus: A Review. Adv Ther 2016; 33(9):1502-1518

11. Карпов АА, Ивкин ДЮ, Драчева АВ и др. Моделирование постинфарктной сердечной недостаточности путем окклюзии левой коронарной артерии у крыс: техника и методы морфофункциональной оценки. Биомедицина 2014; (3):32-48 [Karpov AA, Ivkin DYU, Dracheva AV i dr. Modelirovanie postinfarktnoj serdechnoj nedostatochnosti putem okklyuzii levoj koronarnoj arterii u krys: tekhnika i metody morfofunkcional’noj ocenki. Biomedicina 2014; (3):32-48]

12. Kusaka H, Koibuchi N, Hasegawa Y et al. Empagliflozin lessened cardiac injury and reduced visceral adipocyte hypertrophy in prediabetic rats with metabolic syndrome. Cardiovasc Diabetol 2016;15(1):157-171

13. Heise T, Jordan J, Wanner C, Heer M et al. Pharmacodynamic effects of single and multiple doses of empagliflozin in patients with type 2 diabetes. Clin Ther 2016; Sep 28. pii: S01492918(16)30716-0. doi: 10.1016/j.clinthera.2016.09.001

14. Neal B, Perkovic V, de Zeeuw D et al. Efficacy and safety of canagliflozin, an inhibitor of sodium-glucose cotransporter 2, when used in conjunction with insulin therapy in patients with type 2 diabetes. Diabetes Care 2015;38(3):403–411

15. Kohan DE, Fioretto P, Tang W, List JF. Long-term study of patients with type 2 diabetes and moderate renal impairment shows that dapagliflozin reduces weight and blood pressure but does not improve glycemic control. Kidney Int 2014; 85(4): 962–971

16. Barnett AH, Mithal A, Manassie J et al. EMPA-REG Renal Trial investigators Efficacy and safety of empagliflozin added to existing antidiabetes treatment in patients with type 2 diabetes and chronic kidney disease: a randomised, double-blind, placebocontrolled trial. Lancet Diabetes Endocrinol 2014; 2(5): 369–384

17. Yale JF, Bakris G, Cariou B et al. Efficacy and safety of canagliflozin in subjects with type 2 diabetes and chronic kidney disease. Diabetes Obes Metab 2013; 15(5): 463–473

18. De Nicola L, Gabbai FB, Liberti ME et al. Sodium/glucose cotransporter 2 inhibitors and prevention of diabetic nephropathy: targeting the renal tubule in diabetes. Am J Kidney Dis 2014; 64(1): 16–24

19. Vallon V, Richter K, Blantz RC et al. Glomerular hyperfiltration in experimental diabetes mellitus potential role of tubular reabsorption. J Am Soc Nephrol 1999; 10(12): 2569–2576

20. Terami N, Ogawa D, Tachibana H et al. Long-term treatment with the sodium glucose cotransporter 2 inhibitor, dapagliflozin, ameliorates glucose homeostasis and diabetic nephropathy in db/db mice. PLoS One 2014; 9(6): e100777. doi: 10.1371/journal.pone.0100777

21. Gembardt F, Bartaun C, Jarzebska N et al. The SGLT2 inhibitor empagliflozin ameliorates early features of diabetic nephropathy in BTBR ob/ob type 2 diabetic mice with and without hypertension. Am J Physiol Renal Physiol 2014; 307(3): F317–F325

22. Cherney DZ, Perkins BA, Soleymanlou N et al. The renal hemodynamic effect of SGLT2 inhibition in patients with type 1 diabetes. Circulation 2013:CIRCULATIONAHA. 113.005081

23. Takenaka T, Inoue T, Watanabe Y. How the kidney hyperfiltrates in diabetes: From molecules to hemodynamics. World J Diabetes 2015; 6(4): 576-582

24. Liu X, Hong Q, Wang Z et al. Transforming growth factorβ-sphingosine kinase 1/S1P signaling upregulates microRNA-21 to promote fibrosis in renal tubular epithelial cells. Exp Biol Med (Maywood) 2016; 241(3): 265-272

25. Yang Y, Xiao L, Li J et al. Urine miRNAs: potential biomarkers for monitoring progression of early stages of diabetic nephropathy. Med Hypotheses 2013; 81(2):274-278

26. Смирнов АВ, Кучер АГ, Добронравов ВА и др. Диетарный соевый протеин замедляет развитие интерстициального почечного фиброза у крыс с односторонней обструкцией мочечточника: введение в нутритивную эпигеномику. Нефрология 2012; 16(4): 75-83 [Smirnov AV, Kucher AG, Dobronravov VA i dr. Dietarnyj soevyj protein zamedlyaet razvitie intersticial‘nogo pochechnogo fibroza u krys s odnostoronnej obstrukciej mochechtochnika: vvedenie v nutritivnuyu ehpigenomiku. Nefrologiya 2012; 16(4): 75-83]

27. Смирнов АВ, Карунная АВ, Зарайский МИ и др. Экспрессия микроРНК-21 в моче у пациентов с нефропатиями. Нефрология 2014; 18 (6): 59-63 [Smirnov AV, Karunnaya AV, Zarajskij MI i dr. Ehkspressiya mikroRNK-21 v moche u pacientov s nefropatiyami. Nefrologiya 2014; 18 (6): 59-63]

28. Wagner CA, Hernando N, Forster IC et al. The SLC34 family of sodium-dependent phosphate transporters. Pflugers Arch 2014; 466:139-153

29. Wagner CA, Rubio-Aliaga I, Biber J, Hernando N. Genetic diseases of renal phosphate handling. Nephrol Dial Transplant 2014; 29 (Suppl 4): iv45-54

30. Beck L, Karaplis AC, Amizuka N et al. Targeted inactivation of Npt2 in mice leads to severe renal phosphate wasting, hypercalciuria, and skeletal abnormalities. Proc Natl Acad Sci USA 1998;95: 5372-5377

31. Segawa H, Kaneko I, Takahashi A et al. Growth-related renal type II Na/Pi cotransporter. J Biol Chem 2002;277:19665-19672

32. Hilfiker H, Hattenhauer O, Traebert M et al. Characterization of a murine type II sodium-phosphate cotransporter expressed in mammalian small intestine. Proc Natl Acad Sci USA 1998; 95:14564-14569

33. Villa-Bellosta R, Ravera S, Sorribas V et al. The Na+-Pi cotransporter PiT-2 (SLC20A2) is expressed in the apical membrane of rat renal proximal tubules and regulated by dietary Pi. Am J Physiol Renal Physiol 2009; 296: F691-F699

34. Segawa H, Onitsuka A, Furutani J et al. Npt2a and Npt2c in mice play distinct and synergistic roles in inorganic phosphate metabolism and skeletal development. Am J Physiol Renal Physiol 2009; 297: F671-F678

35. Raskin P, Pak CY. The effect of chronic insulin therapy on phosphate metabolism in diabetes mellitus. Diabetologia 1981; 21(1): 50-53

36. Shimamoto K, Higashiura K, Nakagawa M et al. Effects of hyperinsulinemia under the euglycemic condition on calcium and phosphate metabolism in non-obese normotensive subjects. Tohoku J Exp Med 1995;177(4):271-278

37. Ishimura E, Nishizawa Y, Emoto M et al. Effect of insulin on urinary phosphate excretion in type II diabetes mellitus with or without renal insufficiency. Metabolism 1996; 45(6):782-786

38. Guntupalli J, Rogers A, Bourke E. Effect of insulin on renal phosphorus handling in the rat: interaction with PTH and nicotinamide. Am J Physiol 1985; 249(4 Pt 2):F610-618

39. Guntupalli J, Allon M, Bourke E. Effects of physiologic hyperinsulinemia on renal phosphate handling in the rat: a role for calcium. Miner Electrolyte Metab 1989;15(6):338-345

40. Nowicki M, Kokot F, Surdacki A. The influence of hyperinsulinaemia on calcium-phosphate metabolism in renal failure. Nephrol Dial Transplant 1998;13(10):2566-2571

41. Ikeda K, Matsumoto T, Morita K et al. The role of insulin in the stimulation of renal 1,25-dihydroxyvitamin D synthesis by parathyroid hormone in rats. Endocrinology 1987;121(5):1721-1726

42. Kempe DS, Siraskar G, Frohlich H et al. Regulation of renal tubular glucose reabsorption by Akt2/PKBβ. Am J Physiol Renal Physiol 2010;298(5):F1113-F1117

43. Kempe DS, Ackermann TF, Boini KM et al. Akt2/PKBbetasensitive regulation of renal phosphate transport. Acta Physiol (Oxf) 2010;200(1):75-85 44. Lizcano JM, Alessi DR. The insulin signalling pathway. Curr Biol 2002;12(7):R236-R238