MicroRNA‑21 and myocardial remodeling with the reduction of the nephron mass

Background and objective. Currently, the role of miRNA‑21 in the development of heart and kidney damage and their interaction remains unclear. Therefore, the aim of this work is to assess the impact of changes in the expression of microRNA‑21 in myocardial tissue in the development of cardiac remodeling with chronic reduction in the mass of active nephrons in the experiment. Design and methods. Wistar drain rats were divided into two groups. The first (control) group included nine falsely operated animals. The second (n = 9) group included rats with step-by-step resection of 5/6 renal tissue. After 4 months after surgery, blood pressure (BP) was measured, heart ultrasound (echocardiography, EchoCG) was performed and the level of relative expression of microRNA‑21 in myocardial tissue was determined. Results. The rats with an experimental decrease in the mass of functioning nephrons, showed significantly higher levels of BP, microRNA‑21 expression in the myocardium and the thickness of the interventricular septum (according to EchoCG). They also demonstrated smaller end-systolic dimension of the left ventricle and systolic motion of the mitral valve ring. Conclusions. Our data indicate the potential role of miRNA‑21 in the development of concentric left ventricular remodeling while reducing the number of functioning nephrons. This remodeling is characterized by the prevalence of myocardial hypertrophy over fibrosis. However, the specific mechanisms linking microRNA in the pathogenesis of heart remodeling require further research.

1. Zhong X, Chung AC, Chen HY, Meng XM, Lan HY. Smad3‑mediated upregulation of miR‑21 promotes renal fibrosis. J Am Soc Nephrol. 2011;22(9):1668–1681.

2. Ichii O, Horino T. MicroRNAs associated with the development of kidney diseases in humans and animals. J Toxicol Pathol. 2018;31(1):23–34. doi:10.1293/tox.2017-0051

3. Smirnov AV, Dobronravov VA, Kayukov IG. Cardiorenal continuum: pathogenetic foundations of preventive nephrology. Nefrologiya = Nephrology. 2005;9(3):7–15. In Russian.

4. Yuan J, Chen H, Ge D, Xu Y, Xu H, Yang Y et al. Mir‑21 promotes cardiac fibrosis after myocardial infarction via targeting Smad7. Cell Physiol Biochem. 2017;42(6):2207–2219. doi:10.1159/000479995

5. Lullo L, Bellasi A, Barbera V, Russo D, Russo L, Di Iorio B et al. Pathophysiology of the cardio-renal syndromes types 1–5: an up-to-date. Di Indian Heart J. 2017;69(2):255–265. doi:10.1016/j.ihj.2017.01.005

6. Kamyshova ES, Bobkova IN. MicroRNA in chronic glomerulonephritis: promising biomarkers for diagnosis and evaluation of prognosis. Ther Arch. 2017;89(6):89–96. In Russian.

7. Chuppa S, Liang M, Liu P, Liu Y, Casati M, Cowley A et al. MicroRNA‑21 regulates peroxisome proliferator-activated receptor alpha, a molecular mechanism of cardiac pathology in cardiorenal syndrome type 4. Kidney Int. 2018;93(2):375–389. doi:10.1016/j.kint.2017.05.014

8. Kamyshova ES, Bobkova IN, Kutyrina IМ. Current understanding of the role of microRNAs in diabetic nephropathy: potential biomarkers and targets for targeted therapy. Saharnyiy Diabet = Diabetes. 2017;20(1):42–50. In Russian.

9. Griffin KA, Picken M, Bidani AK. Method of renal mass reduction is a critical modulator of subsequent hypertension and glomerular injury. J Am Soc Nephrol. 1994;4(12):2023–2031.

10. Loboda A, Sobczak M, Jozkowicz A, Dulak J. TGF-β1/Smads and miR‑21 in Renal Fibrosis and Inflammation. Mediators Inflamm. 2016;2016:8319283. doi:10.1155/2016/8319283

11. Yacov N, Feldman B, Volkov A, Ishai E, Breitbart E, Mendel I. Treatment with lecinoxoids attenuates focal and segmental glomerulosclerosis development in nephrectomized rats. Basic Clin Pharmacol Toxicol. 2018. 124(2):131–143. doi:10.1111/bcpt.13114

12. Maquigussa E, Paterno JC, de Oliveira Pokorny GH, da Silva Perez M, Varela VA, da Silva Novaes A et al. Klotho and PPAR gamma activation mediate the renoprotective effect of losartan in the 5/6 nephrectomy model. Front Physiol. 2018;9:1033. doi:10.3389/fphys.2018.01033

13. Zhong X, Chung AC, Chen HY, Meng XM, Lan HY. Smad3‑mediated upregulation of miR‑21 promotes renal fibrosis. J Am Soc Nephrol. 2011;22(9):1668–1681.

14. Lu J, Liu X, Liao Y, Wang D, Chen J, Li S. Jian-Pi-Yi-Shen formula regulates inflammatory cytokines production in 5/6 nephrectomized rats via suppression of NF-κB activation. Evid Based Complement Alternat Med. 2018;2018:7203547. doi:10.1155/2018/7203547.eCollection 2018

15. Smirnov AV, Dobronravov VA, Kayukov IG. Cardiorenal continuum: pathogenetic foundations of preventive nephrology. Nefrologiya = Nephrology. 2005;9(3):7–15. In Russian.

16. Karabaeva AZh, Yesayan AM, Kayukov IG, Parastaeva MM, Beresneva ON, Kotenko LV et al. Effect of spironolactone on left ventricular myocardial hypertrophy in Wistar rats with experimental uremia. Bulleten Eksperimentalnoy Biologii i Mediciny = Bulletin of Experimental Biology and Medicine. 2008;145(6):659–662. In Russian.

17. Lullo L, Bellasi A, Barbera V, Russo D, Russo L, Di Iorio B et al. Pathophysiology of the cardio-renal syndromes types 1–5: an up-to-date. Di Indian Heart J. 2017;69(2):255–265. doi:10.1016/j.ihj.2017.01.005

18. Beresneva ON, Parastaeva MM, Ivanova GT, Zubina IM, Kucher AG, Kayukov IG. Assessment of cardioprotective action low protein a soybean diet and level of inorganic anions of blood serum at spontaneous-hypertensive rats with a nephrectomy. Nefrologiya = Nephrology. 2007;11(3):70–76. In Russian.

19. Chuppa S, Liang M, Liu P, Liu Y, Casati M, Cowley A et al. MicroRNA‑21 regulates peroxisome proliferator-activated receptor alpha, a molecular mechanism of cardiac pathology in cardiorenal syndrome type 4. Kidney Int. 2018;93(2):375–389. doi:10.1016/j.kint.2017.05.014

20. Shobeiri N, Adams MA, Holden RM. Vascular calcification in animal models of CKD: A review. Am J Nephrol. 2010;31(6): 471–481. doi:10.1159/000299794

21. Griffin KA, Picken M, Bidani AK. Method of renal mass reduction is a critical modulator of subsequent hypertension and glomerular injury. J Am Soc Nephrol. 1994;4(12):2023–2031.

22. Claramunt D, Gil-Peña H, Fuente R, Hernández-Frías O, Santos F. Animal models of pediatric chronic kidney disease. Is adenine intake an appropriate model? Nefrologia. 2015;35(6):517–522. doi:10.1016/j.nefro.2015.08.004

23. Yacov N, Feldman B, Volkov A, Ishai E, Breitbart E, Mendel I. Treatment with lecinoxoids attenuates focal and segmental glomerulosclerosis development in nephrectomized rats. Basic Clin Pharmacol Toxicol. 2018. 124(2):131–143. doi:10.1111/bcpt.13114

24. Beresneva ON, Parastaeva MM, Shved NV, Ivanova GT, Kucher AG, Kayukov IG et al. Combined effect of age and reduction in the mass of active nephrons on myocardial remodeling in rats. Nefrologiya = Nephrology. 2015;19(4):100–107. In Russian.

25. Maquigussa E, Paterno JC, de Oliveira Pokorny GH, da Silva Perez M, Varela VA, da Silva Novaes A et al. Klotho and PPAR gamma activation mediate the renoprotective effect of losartan in the 5/6 nephrectomy model. Front Physiol. 2018;9:1033. doi:10.3389/fphys.2018.01033

26. Kayukov IG, Beresneva ON, Parastaeva MM, Shved NV, Ivanova GT, Kucher AG. Influence of age and reduction of the weight of active nephrons on the state of the myocardium and coronary bed in young rats. Regionarnoe Krovoobraschenie i Mikrotsirkulyatsiya = Regional Blood Circulation and Microcirculation. 2015;14(4):66–73. In Russian.

27. Lu J, Liu X, Liao Y, Wang D, Chen J, Li S. Jian-Pi-Yi-Shen formula regulates inflammatory cytokines production in 5/6 nephrectomized rats via suppression of NF-κB activation. Evid Based Complement Alternat Med. 2018;2018:7203547. doi:10.1155/2018/7203547.eCollection 2018

28. Dionísio LM, Luvizoto MJ, Gribner C, Carneiro D, Carvalho V, Robes F et al. Biomarkers of cardiorenal syndrome in uremic myocardiopathy animal model. J Bras Nefrol. 2018;40 (2):105–111. doi:10.1590/2175-8239‑JBN‑3878

29. Karabaeva AZh, Yesayan AM, Kayukov IG, Parastaeva MM, Beresneva ON, Kotenko LV et al. Effect of spironolactone on left ventricular myocardial hypertrophy in Wistar rats with experimental uremia. Bulleten Eksperimentalnoy Biologii i Mediciny = Bulletin of Experimental Biology and Medicine. 2008;145(6):659–662. In Russian.

30. Chen C, Lu C, Qian Y, Li H, Tan Y, Cai L et al. Urinary miR‑21 as a potential biomarker of hypertensive kidney injury and fibrosis. Sci Rep. 2017;7(1):17737. doi:10.1038/s41598-017-18175-3

31. Beresneva ON, Parastaeva MM, Ivanova GT, Zubina IM, Kucher AG, Kayukov IG. Assessment of cardioprotective action low protein a soybean diet and level of inorganic anions of blood serum at spontaneous-hypertensive rats with a nephrectomy. Nefrologiya = Nephrology. 2007;11(3):70–76. In Russian.

32. Zhou TB, Jiang ZP. Role of miR‑21 and its signaling pathways in renal diseases. J Recept Signal Transduct Res. 2014;34 (5):335–337. doi:10.3109/10799893.2014.896382

33. Shobeiri N, Adams MA, Holden RM. Vascular calcification in animal models of CKD: A review. Am J Nephrol. 2010;31(6): 471–481. doi:10.1159/000299794

34. Chung AC, Lan HY. MicroRNAs in renal fibrosis. Front Physiol. 2015;6:50. doi:10.3389/fphys.2015.00050

35. Claramunt D, Gil-Peña H, Fuente R, Hernández-Frías O, Santos F. Animal models of pediatric chronic kidney disease. Is adenine intake an appropriate model? Nefrologia. 2015;35(6):517–522. doi:10.1016/j.nefro.2015.08.004

36. Lv W, Fan F, Wang Y, Gonzalez-Fernandez E, Wang C, Yang L et al. Therapeutic potential of microRNAs for the treatment of renal fibrosis and CKD. Physiol Genomics. 2018;50(1):20–34. doi:10.1152/physiolgenomics.00039

37. Beresneva ON, Parastaeva MM, Shved NV, Ivanova GT, Kucher AG, Kayukov IG et al. Combined effect of age and reduction in the mass of active nephrons on myocardial remodeling in rats. Nefrologiya = Nephrology. 2015;19(4):100–107. In Russian.

38. Cao W, Shi P, Ge JJ. miR‑21 enhances cardiac fibrotic remodeling and fibroblast proliferation via CADM1/STAT3 pathway. BMC Cardiovasc Disord. 2017;17 (1):88. doi:10.1186/s12872-017-0520-7

39. Kayukov IG, Beresneva ON, Parastaeva MM, Shved NV, Ivanova GT, Kucher AG. Influence of age and reduction of the weight of active nephrons on the state of the myocardium and coronary bed in young rats. Regionarnoe Krovoobraschenie i Mikrotsirkulyatsiya = Regional Blood Circulation and Microcirculation. 2015;14(4):66–73. In Russian.

40. Topkara VK, Mann DL. Role of microRNAs in cardiac remodeling and heart failure. Cardiovasc Drugs Ther. 2011;25 (2):171–182. doi:10.1007/s10557-011-6289-5

41. Dionísio LM, Luvizoto MJ, Gribner C, Carneiro D, Carvalho V, Robes F et al. Biomarkers of cardiorenal syndrome in uremic myocardiopathy animal model. J Bras Nefrol. 2018;40 (2):105–111. doi:10.1590/2175-8239‑JBN‑3878

42. Chen C, Lu C, Qian Y, Li H, Tan Y, Cai L et al. Urinary miR‑21 as a potential biomarker of hypertensive kidney injury and fibrosis. Sci Rep. 2017;7(1):17737. doi:10.1038/s41598-017-18175-3

43. Zhou TB, Jiang ZP. Role of miR‑21 and its signaling pathways in renal diseases. J Recept Signal Transduct Res. 2014;34 (5):335–337. doi:10.3109/10799893.2014.896382

44. Chung AC, Lan HY. MicroRNAs in renal fibrosis. Front Physiol. 2015;6:50. doi:10.3389/fphys.2015.00050

45. Lv W, Fan F, Wang Y, Gonzalez-Fernandez E, Wang C, Yang L et al. Therapeutic potential of microRNAs for the treatment of renal fibrosis and CKD. Physiol Genomics. 2018;50(1):20–34. doi:10.1152/physiolgenomics.00039

46. Cao W, Shi P, Ge JJ. miR‑21 enhances cardiac fibrotic remodeling and fibroblast proliferation via CADM1/STAT3 pathway. BMC Cardiovasc Disord. 2017;17 (1):88. doi:10.1186/s12872-017-0520-7

47. Topkara VK, Mann DL. Role of microRNAs in cardiac remodeling and heart failure. Cardiovasc Drugs Ther. 2011;25 (2):171–182. doi:10.1007/s10557-011-6289-5