Features of microvasculature regulation in patients with chronic kidney disease on peritoneal dialysis

Introduction and aim. Chronic kidney disease (CKD) is one of the most common non-infectious diseases, in which arterial hypertension (AH) is progressing. The mechanisms of AH in CKD are complex and understudied. This research was conducted with the objective to investigate the mechanisms of microvascular tonus increase in the group of patients with the 5th stage of CKD who were treated with peritoneal dialysis. Materials and methods. Patients from dialysis department were included in the study (76 people). Blood flow in microvessels was measured by laser Doppler flowmetry (LDF). Results of LDF used for the calculation of neurogenic (HT), myogenic (MT) and endothelium-dependent tonus (EDT) microvessels. Cardiotonic steroid concentration in plasma was measured by competitive immunofluorescence using antibodies to ouabain and marinobufagenin. The activity of Na/K-ATPase was measured by spectrophotometry. Results and discussion. HT microvessels in patients with CKD was increased by 21.4±3,88 %, MT - 33.4±5,62 %, EDT 17.1±3.14 % compared with the control group. Endogenous ouabain (EO) concentration in plasma of patients with CKD was on average 0.311±0.032 nM/L, in the control - 0.296±0.031 nM/L. Marinobufagenin (MBG) concentration in the plasma of patients with CKD was 2.10; 0.89; 3.07 nM/L (median, 25th and 75th percentile), and in control - 0.347; 0.103; 0.427 nM/L. The activity of Na/K-ATPase in patients with CKD was 1.54±0.18 μmol Pi/mL/hr, vs. 3.07±0.44 μmol Pi/mL/h in the control. The correlation between the value of MT of microvascular and MBG concentration in blood plasma of patients with CKD was found (rs = 0.736). Conclusions. Our results show that high NT of microvessels of patients with CKD and is connected with increased activity of the central structures of the sympathetic nervous system, while increase of EDT is connected with endothelial dysfunction and increase of MT is connected with increasing concentration of MBG (not EO) in blood plasma. We believe that the MBG causes contraction of smooth muscle cells of blood vessels by activating signaling function of Na/K-ATPase.

микроциркуляторное русло, сосуды, тонус, маринобуфагенин, оуабаин, Na/K-АТФаза, microsculature, vessels, tonus, marinobufagenin, ouabain, Na/K-ATPase

1. Крупаткин А. И., Сидоров В. В. Функциональная диагностика состояния микроциркуляторно-тканевых систем: рук-во для врачей. М.: Либроком, 2013. 496 с.

2. Лобов Г. И., Гурков А. С., Дворецкий Д. П. Микроциркуляторный кровоток в коже кисти у пациентов с артериовенозной фистулой, находящихся на лечении программным гемодиализом // Регионарное кровообращение и микроциркуляция. 2012. № 1(41). С. 35-44.

3. Лобов Г. И., Гурков А. С. Модуляция кровотока в микроциркуляторном русле пальцев кисти после формирования радиоцефалической артериовенозной фистулы // Нефрол. и диализ. 2014. Т. 16. № 3. С. 364-371.

4. Bagrov A. Y., Fedorova O. V. Effects of two putative endogenous digitalis-like factors, marinobufagenin and ouabain, on the Na+,K+-pump in human mesenteric arteries // J. Hypertens. 1998. Vol. 16. № 12 (Pt 2). P 1953-1958.

5. Bagrov A. Y., Shapiro J. I., Fedorova O. V. Endogenous Cardiotonic Steroids: Physiology, Pharmacology, and Novel Therapeutic Targets // Pharmacol. Rev. 2009. Vol. 61. № 1. P. 9-38.

6. Blaustein M. P Physiological effects of endogenous ouabain: control of intracellular Ca2+ stores and cell responsiveness // Am. J. Physiol. 1993. Vol. 264. № 6 (Pt 1). P. C1367-C1387.

7. Bernjak A., Deitrick G. A., Bauman W. A. et al. Basal sympathetic activity to the microcirculation in tetraplegic man revealed by wavelet transform of laser Doppler flowmetry // Microvasc. Res. 2011. Vol. 81. № 3. P. 313-318. doi: 10.1016/j. mvr.2011.01.005.

8. Bracic M. A., Stefanovska A. Wavelet based analysis of human blood flow dynamics // Bull. Math. Biol. 1998. Vol. 60. № 5. P. 919-935.

9. Collins A. J., Foley R. N., Chavers B. et al., United States Renal Data System 2011 Annual Data Report: Atlas of chronic kidney disease & end-stage renal disease in the United States // Am. J. Kidney Dis. 2012. Vol. 59. № 1 (Suppl. 1). P. e1-e420.

10. Davis M. J., Hill M. A. Signaling mechanisms underlying the vascular myogenic response // Physiol. Rev. 1999. Vol. 79. № 2. P. 387-423.

11. Fedorova O. V., Lakatta E. G., Bagrov A. Y. Endogenous Na,K pump ligands are differentially regulated during acute NaCl loading of Dahl rats // Circulation. 2000. Vol. 102. № 24. P. 3009-3014.

12. Fisher J. P., Paton J. F. The sympathetic nervous system and blood pressure in humans: implications for hypertension // J. Hum. Hypertens. 2012. Vol. 26. № 8. P. 463-475. doi: 10.1038/jhh.2011.66.

13. Gargiulo R., Suhail F., Lerma E. V. Hypertension and chronic kidney disease // Dis. Mon. 2015. Vol. 61. № 9. P. 387-395. doi: 10.1016/j.disamonth.2015.07.00.

14. Goligorsky M. S. Pathogenesis of endothelial cell dysfunction in chronic kidney disease: a retrospective and what the future may hold // Kidney Res. Clin. Pract. 2015. Vol. 34. № 2. P. 76-82. doi: 10.1016/j.krcp.2015.05.003.

15. Haas M., Askari A., Xie Z. Involvement of Src and epidermal growth factor receptor in the signal-transducing function of Na+/K+-ATPase // J. Biol. Chem. 2000. Vol. 275. № 36. P. 27832-27837.

16. Hauck C., Frishman W. H. Systemic hypertension: the roles of salt, vascular Na+/K+ ATPase and the endogenous glycosides, ouabain and marinobufagenin // Cardiol. Rev. 2012. Vol. 20. №3. P. 130-138. doi: 10.1097/CRD.0b013e31823c835c.

17. Holowatz L. A., Thompson-Torgerson C. S., Kenney W. L. The human cutaneous circulation as a model of generalized microvascular function // J. Appl. Physiol. 2008. Vol. 105. № 1. P. 370-372. doi: 10.1152/japplphysiol.00858.2007.

18. Judd E., Calhoun D. A. Management of hypertension in CKD: beyond the guidelines //Adv. Chronic Kidney Dis. 2015. Vol. 22. № 2. P. 116-122. doi: 10.1053/j.ackd.2014.12.001.

19. Kennedy D. J., Vetteth S., Periyasamy S. M. et al. Central role for the cardiotonic steroid marinobufagenin in the pathogenesis of experimental uremic cardiomyopathy // Hypertension. 2006. Vol. 47. № 3. P. 488-495. doi: 10.1161/01.HYP.0000202594.82271.92.

20. Kolmakova E. V., Haller S. T., Kennedy D. J. et al. Endogenous cardiotonic steroids in chronic renal failure // Nephrol. Dial. Transplant. 2011. Vol. 26. № 9. P. 2912-2919. doi: 10.1093/ndt/gfq772.

21. Kometiani P., Li J., Gnudi L. et al. Multiple signal transduction pathways link Na+/K+-ATPase to growth-related genes in cardiac myocytes: the roles of Ras and mitogen-activated protein kinases // J. Biol. Chem. 1998. Vol. 273. №N 24. P. 15249-15256.

22. Levey A., Beto J., Coronado B. et. al. Controlling the epidemic of cardiovascular disease in chronic renal disease: what do we know, what do we need to learn, where do we go from here? // Am. J. Kidney Dis. 1998. Vol. 32. № 5. P. 853-906.

23. Liu M., Ren Y., Guo C. Effect of ouabain on the pathogenesis of hypertension in rats // Chin. Med. J. 2014. Vol. 127. № 10. P. 1931-1934.

24. Rajendran P., Rengarajan T., Thangavel J. et al. The vascular endothelium and human diseases // Int. J. Biol. Sci. 2013. Vol. 9. № 9 (10). P. 1057-1069. doi: 10.7150/ijbs.7502.

25. Said S., Hernandez G.T. The link between chronic kidney disease and cardiovascular disease // J. Nephropathol. 2014. Vol. 3. № 3. P. 99-104. doi: 10.12860/jnp.2014.

26. Yannoutsos A., Levy B.I., Safar M. E. et al. Pathophysiology of hypertension: interactions between macro and microvascular alterations through endothelial dysfunction // J. Hypertens. 2014. Vol. 32. № 2. P. 216-224. doi: 10.1097/HJH.0000000000000021.