Vitamin D and fibroplastic processes in myocardium in spontaneously hypertensive rats with initial kidney dysfunction

Background. Even a moderate decrease in glomerular filtration rate leads to an increased risk of cardiovascular diseases (CVD), which is the leading cause of mortality in patients with chronic kidney disease (CKD). Left ventricular hypertrophy (LVH) underlies CVD development in renal dysfunction. The prevalence of LVH in patients with CKD stages 2–4 is 50–70 % and reaches 95 % at the beginning of dialysis, which significantly exceeds the number of cases in general population (15–21 %). Common hemodynamic factors associated with chronic kidney damage —hypertension (HTN), activation of the renin-angiotensin system, anemia, fluid and sodium retention, and others largely explain the high prevalence of LVH among patients with CKD. Nevertheless, the existence of additional non-hemodynamic mechanisms of myocardial remodeling (MR) is evident.

Objective. To investigate the associations between the MR physiological/histological characteristics and laboratory parameters of calcium-phosphate metabolism in the initial stages of experimental CKD. Design and methods. Four groups of spontaneously hypertensive rats (SHR) were studied (n = 35): 3/4 nephrectomized rats (Nx) one month exposed after surgery (Nx(1), n = 9), 5/6 Nx two months after surgery (Nx(2), n = 8), sham operated rats one month after surgery (SO(1), n = 9) and two months after surgery (SO(2), n = 9). Myocardial mass index (MMI), systolic blood pressure (BP), proteinuria, creatinine (Cr) concentration, total calcium (Ca) and inorganic phosphate (Pi), 25-OH vitamin D (25OHD) and parathyroid hormone (PTH) in serum, myocardial morphology were studied in all experimental animals.

Results. The models corresponded to the 1–3 stages CKD. There were no significant changes in serum total Ca (p = 0,066), Pi (p = 0,051) and PTH (p = 0,015) concentrations, the level of 25OHD was significantly lower in Nx(2) rats vs control (p = 0,015). MMI increased in all nephrectomized rats (p = 0,008). The cardiomyocytes (CM) thickness increased in Nx(1) and Nx(2) animals compared to the corresponding controls (p = 0,010, p = 0,002). A significant increase in interstitial (IF) and perivascular (PF) fibrosis occurred in Nx(2) rats with more damaging influence (p = 0,017, p = 0,004). CM thickness, IF and PF increased with the elevation of BP (r = 0,39, p = 0,038, r = 0,47, p = 0,026, r = 0,49, p = 0,031) and serum Cr (r = 0,68, p = 0,001, r = 0,61, p = 0,003, r = 0,69, p = 0,001), and the decrease in serum 25OHD concentration (r = –0,045, p = 0,047, r = –0,50, p = 0,020, r = –0,52, p = 0,012). Multiple linear regression analysis showed, that 25OHD is an independent predictor of myocardial fibrosis (IF: β = –0,38 ± 0,18, p = 0,047, PF: β = –0,34 ± 0,15, p = 0,032).

Conclusions. The initial stages of CKD accompanied with HTN are associated with serum 25OHD concentration decrease CM hypertrophy and myocardial fibrosis. The CM growth is an earlier event in relation to the interstitial fibrosis. The obtained data suggest a possible role of vitamin D deficiency in the development of myocardial fibrotic lesions.

1. Achinger SG, Ayus JC. The role of vitamin D in left ventricular hypertrophy and cardiac function. Kidney Int Suppl. 2005;95:37–42. doi:10.1111/j.1523-1755.2005.09506

2. Levin A, Bakris GL, Molitch M, Molitch M, Smulders M, Tian J et al. Prevalence of abnormal serum vitamin D, PTH, calcium, and phosphorus in patients with chronic kidney disease: results of the study to evaluate early kidney disease. Kidney Int. 2007;71:31–38. doi:10.1038/sj.ki.5002009

3. Sarafidis PA, Li S, Chen SCh, Collins AJ, Brown WW, Klag MJ et al. Hypertension awareness, treatment, and control in chronic kidney disease. Am J Med. 2008;121(4):332–340. doi:10.1016/j.amjmed.2007.11.025

4. Weishaar RE, Kim SN, Saunders DE, Simpson RU. Involvement of vitamin D 3 with cardiovascular function. III. Effects on physical and morphological properties. Am J Physiol. 1990;258(1Pt1):134–142. doi:10.1152/ajpendo.1990.258.1.E134

5. Xiang W, Kong J, Chen S, Cao LP, Qiao G, Zheng W et al. Cardiac hypertrophy in vitamin D receptor knockout mice: role of the systemic and cardiac renin-angiotensin systems. Am J Physiol Endocrinol Metab. 2005;288(1):125–132. doi:10.1152/ajpendo.00224.2004

6. Chen S, Sun Y, Agrawal D K. Vitamin D deficiency and essential hypertension. J Am Soc Hypertens. 2015;9(11):885–901. doi:10.1016/j.jash.2015.08.009

7. Dobnig H, Pilz S, Scharnagl H, Renner W, Seelhorst U, Wellnitz B et al. Independent association of low serum 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D levels with all-cause and cardiovascular mortality. Arch Intern Med. 2008;168(12):1340–1349. doi:10.1001/archinte.168.12.1340

8. Lavie CJ, Lee JH, Milani RV. Vitamin D and cardiovascular disease will it live up to its hype? J Am Coll Cardiol. 2011;58(15): 1547–1556. doi:10.1016/j.jacc.2011.07.008

9. Khalili H, Talasaz AH, Salarifar M. Serum vitamin D concentration status and its correlation with early biomarkers of remodeling following acute myocardial infarction. Clin Res Cardiol. 2012;101(5):321–327. doi:10.1007/s00392-011-0394-0

10. Gunta SS, Thadhani RI, Mak RH. The effect of vitamin D status on risk factors for cardiovascular disease. Nat Rev Nephrol. 2013;9(6):337–347. doi:10.1038/nrneph.2013.74

11. Helvig CF, Cuerrier D, Hosfield CM, Ireland B, Kharebov AZ. Dysregulation of renal vitamin D metabolism in the uremic rat. Kidney Int. 2010;78(5):463–472. doi:10.1038/ki.2010.168

12. Meredith A, Boroomand S, Carthy J, Luo Zh, McManus B. 1,25 Dihydroxyvitamin D 3 inhibits TGFβ1-Mediated primary human cardiac myofibroblast activation. PLoS One. 2015;10(6): e0128655. doi:10.1371/journal.pone.0128655

13. Yuan W, Pan W, Kong J, Zheng W, Szeto FL, Wong KE et al. 1,25-dihydroxyvitamin D 3 suppresses renin gene transcription by blocking the activity of the cyclic AMP response element in the renin gene promoter. J Biol Chem. 2007;282(41):29821–29830. doi:10.1074/jbc.M705495200

14. O’Connell TD, Berry JE, Jarvis AK, Somerman MJ, Simpson RU. 1,25-Dihydroxyvitamin D 3 regulation of cardiac myocyte proliferation and hypertrophy. Am J Physiol. 1997;272(4Pt2): H1751–H1758. doi:10.1152/ajpheart.1997.272.4.H1751

15. Koleganova N, Piecha G, Ritz E, Gross ML. Calcitriol ameliorates capillary deficit and fibrosis of the heart in subtotally nephrectomized rats. Nephrol Dial Transplant. 2009;24(3):778–787. doi:10.1093/ndt/gfn549

16. Simpson RU. Selective knockout of the vitamin D receptor in heart results in cardiac hypertrophy: is the heart a drugable target for vitamin D receptor agonists? Circulation. 2012;124(17):1808–1810. doi:10.1161/circulationaha.111.061234

17. Dobronravov VA, Bogdanova EO, Semenova NYu, Beresneva OV, Parastaeva MM, Galkina OV et al. Renal expression of αKlotho protein, fibroblast growth factor 23 and parathyroid hormone in experimental modeling of early stages of chronic kidney damage. Nefrologiya = Nephrology. 2014;18(2):72–78. In Russian.

18. 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.

19. Pietrzyk B, Smertka M, Chudek J. Sclerostin: Intracellular mechanisms of action and its role in the pathogenesis of skeletal and vascular disorders. Adv Clin Exp Med. 2017;26(8):1283–1291. doi:10.17219/acem/68739

20. 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 spontaneoushypertensive rats with a nephrectomy. Nefrologiya = Nephrology. 2007;11(3):70–76. In Russian.

21. Ormrod D, Miller T. Experimental uremia. Description of a model producing varying degrees of stable uremia. Nephron. 1980;26(5):249–254.

22. Kamishnikova LA, Efremova OA, Pivivar RS. The features of cardio renal interaction in patients with chronic kidney disease. Current state of the problem. Nauchnie Vedomosti Belgorodskogo Gosudarstvennogo Universiteta. Seriya Meditsina Farmacia. 2017;5(254):13–21. In Russian.

23. Rasin VA, Gimaev RH. Miocardial fibrosis in arterial hypertension. Ul’yanovskiy Medicobiologicheskiy Jurnal. 2013;3:7–14. In Russian.

24. Barrio-Vázquez S, Naves-Díaz M, Carrillo-López N, Rodríguez I, Fernández-Vázquez A, Valdivielso JM et al. Vitamin D receptor activation, left ventricular hypertrophy and myocardial fibrosis. Nephrol Dial Transplant. 2013;28(11):2735–2744. doi:10.1093/ndt/gft268

25. Panizo S, Carrillo-López N, Naves-Díaz M, Solache-Berrocal G, Martínez-Arias L, Rodrigues-Díez RR et al. Regulation of miR-29b and miR-30c by vitamin D receptor activators contributes to attenuate uraemia-induced cardiac fibrosis. Nephrol Dial Transplant. 2017;32(11):1831–1840. doi:10.1093/ndt/gfx060

26. Li JW, Xu C, Fan Y, Wang Y, Xiao YB. Can serum levels of alkaline phosphatase and phosphate predict cardiovascular diseases and total mortality in individuals with preserved renal function? A systemic review and meta-analysis. PLoS One. 2014;9(7): e102276. doi:10.1371/journal.pone.0102276