Condition of the cardiovascular system in Wistar rats with experimental renal dysfunction

The aim: to evaluate functional and structural changes in blood vessels and myocardium in Wistar rats at different stages of the formation of experimental kidney dysfunction.

Materials and Methods. Four groups of animals were studied. The first two groups consisted of rats subjected to 5/6 nephrectomy (NE). The period after NE is 2 or 4 months. The third and fourth groups included sham-operated (SO) animals of a similar observation period. After the end of the experiment, blood pressure was measured in rats, the left ventricular mass index (LVMI) was calculated, a biochemical blood test, histological, immunohistochemical and electron microscopic examination of the myocardium were performed, and the contractile activity of the portal vein was recorded for a period of 2 months (in vitro).

Results. 2 months after NE, an increase in blood pressure, LVMI, and a decrease in the autorhythmic contractile activity of the portal vein were detected in rats. At the histological level, thickening of cardiomyocytes and arterial vessel walls and the presence of perivascular fibrosis were noted. After 4 months, in rats with NE, the increase in blood pressure, cardiomyocyte hypertrophy and perivascular fibrosis progressed. The thickness of cardiomyocytes was 14.1±3.11 μm, which was significantly greater than in the group with NE for 2 months (12.5±1.5 μm; p=0.008). At this period of observation, electron microscopic examination revealed deintegration of myofibrils, disruption of myofibril stacking and z-disk structure, and changes in the shape of mitochondria. 2 months after NE, an increase in the area of open capillaries was detected in rats (1902.8±202.9 μm²) compared to the corresponding LO animals (730.4±58.2 μm²; p=0.000). As renal dysfunction develops, the capillary area tends to increase (2139.1±396.5 μm²; p =0.120).

Conclusion. In Wistar rats with renal dysfunction, changes were detected not only in the level of blood pressure, but also in the functional activity of the intravenous fluid, as well as in the structural components of the myocardium – cardiomyocytes, stroma and blood vessels. The increase in myocardial mass at the histological level was manifested by a significant increase in the thickness of cardiomyocytes, the volume of connective tissue, and the thickness of the wall of arterial vessels, reaching a maximum value at a longer period after NE.

1. Matsushita K, Ballew SH, Wang AY et al. Epidemiology and risk of cardiovascular disease in populations with chronic kidney disease. Nat Rev Nephrol 2022; 18(11):696–707. doi: 10.1038/s41581-022-00616-6

2. Ozdemir M, Asoglu R, Dogan Z et al. The association of glomerular filtration rate with echocardiographic parameters in chronic kidney disease. J Clin Med Res 2021; 13(2):121–129. doi: 10.14740/jocmr4439

3. Nitta K, Iimuro S, Enyu Imai E et al. Risk factors for increased left ventricular hypertrophy in patients with chronic kidney disease: findings from the CKD-JAC study. Clin Exp Nephrol 2019; 23(1): 85–98. doi: 10.1007/s10157-018-1605-z

4. Law JP, Pickup L, Pavlovic D et al. Hypertension and cardiomyopathy associated with chronic kidney disease: epidemiology, pathogenesis and treatment considerations. J Hum Hypertens 2023; 37(1): 1–19. doi:10.1038/s41371-022-00751-4

5. Thobani A, Jacobson TA. Dyslipidemia in patients with kidney disease. Cardiol Clin 2021; 39(3):353–363. doi: 10.1016/j.ccl.2021.04.008

6. Taguchi K, Elias BC, Brooks CR et al. Uremic Toxin-Targeting as a Therapeutic Strategy for Preventing Cardiorenal Syndrome. Circ J 2019; 84(1):2–8. doi: 10.1253/circj.CJ-19-0872

7. Burnier M, Damianaki A. Hypertension as Cardiovascular Risk Factor in Chronic Kidney Disease. Circ Res 2023; 132(8):1050–1063. doi: 10.1161/CIRCRESAHA.122.321762

8. Oe Y, Mitsui S, Sato E et al. Lack of Endothelial Nitric Oxide Synthase Accelerates Ectopic Calcification in Uremic Mice Fed an Adenine and High Phosphorus Diet. Am J Pathol 2021; 191(2): 283–293. doi: 10.1016/j.ajpath.2020.10.012

9. Ivanova GT, Lobov GI, Beresneva ON, Parastaeva MM. Changes in the reactivity of vessels of rats with an experimental decrease in the mass of functioning nephrons. Nephrology (SaintPetersburg) 2019; 23(4): 88–95 (in Russ.) doi: 10.24884/1561-6274-2019-23-4-88-95

10. Goodman WG, Goldin J, Kuizon BD et al. Coronary-artery calcification in young adults with end-stage renal disease who are undergoing dialysis. N Engl J Med 2000; 342(20):1478–1483. doi: 10.1056/NEJM200005183422003

11. Hutcheson JD, Goettsch C. Cardiovascular Calcification Heterogeneity in Chronic Kidney Disease. Circ Res 2023; 132(8):993–1012. doi: 10.1161/CIRCRESAHA.123.321760

12. Ren S-C, Mao N, Yi S et al. Vascular Calcification in Chronic Kidney Disease: An Update and Perspective. Aging Dis 2022; 13(3):673–697. doi: 10.14336/AD.2021.1024

13. Perkovic V, Verdon C, Ninomiya T et al. The relationship between proteinuria and coronary risk: a systematic review and meta-analysis. PLoS Med 2008; 5:e207. doi: 10.1371/journal.pmed.0050207

14. Düsing P, Zietzer A, Goody PR et al. Vascular pathologies in chronic kidney disease: pathophysiological mechanisms and novel therapeutic approaches. J Mol Med (Berl) 2021; 99: 335–348. doi: 10.1007/s00109-021-02037-7

15. Beresneva ON, Zaraisky MI, Kulikov AN et al. MicroRNA-21 and myocardial remodeling with a reduction in the mass of active nephrons. Arterial hypertension 2019; 25(2): 191–199 (in Russ.) doi: 10.18705/1607-419X-2019-25-2

16. Ivanova GT, Kucher AG, Beresneva ON et al. Experimental evaluation of the nephroprotective and cardioprotective effects of long-term use of a low-protein diet including ketosteril. Nephrology (Saint-Petersburg) 2011; 15(4): 45–50 (In Russ.). doi: 10.24884/1561-6274-2011-15-4-45-50

17. Martinez-Arias L, Panizo-Garcia S, Martin-Virgala J et al. Contribution of phosphorus and PTH to the development of cardiac hypertrophy and fibrosis in an experimental model of chronic renal failure. Nefrologia (Engl Ed) 2021; 41(6): 640–651. doi: 10.1016/j.nefroe.2021.12.004

18. Gerdes J, Lemke H, Baisch H et al. Cell cycle analysis of a cell proliferation-associated human nuclear antigen defined by the monoclonal antibody Ki-67. J Immunol 1984; 133(4):1710–1715

19. Wang AY, Wang M, Lam C et al. Left ventricular filling pressure by Doppler echocardiography in patients with end-stage renal disease. Hypertension 2008; 52(1):107–114. doi: 10.1161/HYPERTENSIONAHA.108.112334

20. Patel N, Yaqoob MM, Aksentijevic D. Cardiac metabolic remodelling in chronic kidney disease. Nat Rev Nephrol 2022;18(8): 524–537. https://doi.org/10.1038/s41581-022-00576-x

21. Beresneva ON, Parastaeva MM, Ivanova GT at al. Myocardial effects of a low-protein diet in experimental kidney dysfunction. Nephrology (Saint-Petersburg) 2022; 26(4):110–118 (In Russ.). doi: 10.36485/1561-6274-2022-26-4-110-118

22. . 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

23. Yuan J, Chen H, Ge D 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

24. Chuppa S, Liang M, Liu P 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

25. 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

26. Xu L, Han S, Chen Z. Increase of Oxidative Stress by Deficiency of The ALDH2/UCP2/Nrf2 Axis Exacerbates Cardiac Dysfunction in Chronic Kidney Disease. Rev. Cardiovasc Med 2022; 23(4): 127. https://doi.org/10.31083/j.rcm2304127

27. He Q, Wang C, Qin J et al. Effect of miR-203 expression on myocardial fibrosis. Eur Rev Med Pharmacol Sci 2017; 21:837–842

28. Taïbi F, Metzinger-Le Meuth V, M’Baya-Moutoula E et al. Possible involvement of microRNAs in vascular damage in experimental chronic kidney disease. Biochim Biophys Acta 2014; 1842(1): 88–98. https://doi.org/10.1016/j.bbadis.2013.10.005

29. Piko N, Bevc S, Hojs R, Ekart R. Atherosclerosis and epigenetic modifications in chronic kidney disease. Nephron 2023; 147 (11): 655–659. https://doi.org/10.1159/000531292