Влияние активаторов рецепторов витамина D на сывороточный уровень белка Клото у пациентов с хронической болезнью почек: проспективное рандомизированное исследование

Милованова Л.Ю., Бекетов В.Д., Милованова С.Ю., Таранова М.В., Козлов В.В., Пасечник А.И., Решетников В.А., Андросова Т.В., Калашников М.В. Влияние активаторов рецепторов витамина D на сывороточный уровень белка Клото у пациентов с хронической болезнью почек: проспективное рандомизированное исследование. Терапевтический архив. 2021; 93 (6): 679–684. DOI: 10.26442/00403660.2021.06.000854

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Milovanova LYu, Beketov VD, Milovanova SYu, Taranova MV, Kozlov VV, Pasechnik AI, Reshetnikov VA, Androsova TV. Effect of vitamin D receptor activators on serum Klotho levels in 3b–4 stages chronic кidney disease patients: a prospective randomized study. Terapevticheskii Arkhiv (Ter. Arkh.). 2021; 93 (6): 679–684.
DOI: 10.26442/00403660.2021.06.000854

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Аннотация

Обоснование. Высокий риск сердечно-сосудистых событий остается одной из ведущих причин смертности у пациентов с хронической болезнью почек (ХБП). В то же время установлено, что циркулирующая форма белка Клото обладает выраженными кардио- и нефропротективными свойствами.
Цель. Оценить влияние активаторов рецепторов витамина D (АРВД) на сывороточный уровень Клото у пациентов с ХБП стадии 3b–4.
Материалы и методы. В исследование включены 90 пациентов с ХБП стадии 3b–4, имеющих на момент скрининга повышенный уровень паратиреоидного гормона (ПТГ). Из них 47 пациентов (1-я группа) начали лечение селективным АРВД (Земплар 1 мкг/сут), а 43 пациента (2-я группа) – неселективным АРВД (альфакальцидол 0,25 мкг/сут). Исходно и через 12 мес, в дополнение к обычному обследованию при ХБП, изучали уровни Клото в сыворотке крови и провели расширенное сердечно-сосудистое обследование.
Результаты. Пациенты, которым удалось достичь и поддерживать целевой уровень ПТГ, имели более высокие уровни Клото в сыворотке крови (p=0,037). Пациенты группы 1 значительно чаще достигали целевого уровня ПТГ (p=0,032), имели более высокие уровни Клото (p=0,037) и расчетной скорости клубочковой фильтрации (p=0,048), чем пациенты группы 2. Кроме того, у пациентов, получавших альфакальцидол более 6 мес, чаще наблюдались гиперкальциемия (p=0,047) и гиперфосфатемия (p=0,035), а также кальцификация клапанов сердца (p=0,048), увеличение скорости пульсовой волны (p=0,024), индекса массы миокарда левого желудочка (p=0,033) и частоты развития гипертрофии левого желудочка (p=0,048).
Заключение. У пациентов с ХБП, которым удалось достичь и поддерживать целевой уровень ПТГ в крови, наблюдались более высокие уровни Клото. Использование селективных АРВД связано как с более высокой частотой достижения целевых уровней ПТГ в сыворотке, так и с более высокими уровнями Клото, чем использование неселективных АРВД.

Ключевые слова: хроническая болезнь почек, Клото, активаторы рецепторов витамина D

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Background. High risk of cardiovascular events is among leading problems in chronic kidney disease (CKD). Serum Klotho is supposed to be cardio- and nephroprotective; modification of its levels may be important in CKD.
Aim. To evaluate the impact of vitamin D receptor activators (VDRA) on Klotho serum levels in CKD 3b–4 stages patients.
Materials and methods. Study included 90 CKD 3b–4 stages patients who had elevated serum levels of parathyroid hormone (PTH). From them, 47 patients (group 1) started to treat with the selective VDRA (zemplar 1 mcg/day), and 43 patients (group 2) started to treat with non-selective VDRA (alfacalcidol 0.25 mcg/day). At baseline and after 12 months we conducted routine examination, serum Klotho measurement, and broad cardiovascular examination.
Results. The patients who managed to maintain a target serum PTH level, had higher Klotho serum level (p=0.037) at the end of the study. Patients who used selective VDRA significantly more often reached the target PTH level (p=0.032), had higher serum Klotho levels (p=0.037), and glomerular filtration rate (eGFR) level (p=0.048) than patients who used non-selective VDRA. In addition, patients treated with alfacalcidol more than 6 months, more often had hypercalcemia (p=0.047) and hyperphosphatemia (p=0.035). Group 2 showed higher: pulse wave velocity (p=0.051), left ventricular myocardial mass index (p=0.033), and more advanced heart valve calcification (p=0.038).
Conclusion. Successful parathyroid hormone level control with vitamin D receptor activators was associated with higher serum Klotho, selective agents having shown greater effect. Long-term treatment with selective vitamin D receptor activators may contribute to cardiovascular calcification prevention by modifying Klotho levels.

Keywords: chronic kidney disease, Klotho, vitamin D, receptor activator

Список литературы

1. Go AS, Chertow GM, Fan D, et al. Chronic kidney disease and the risks of death, cardiovascular events, and hospitalization. N Engl J Med. 2004;351:1296-305. DOI: 10.1056/NEJMoa041031
2. Couser WG, Remuzzi G, Mendis S, Tonelli M. The contribution of chronic kidney disease to the global burden of major noncommunicable diseases. Kidney Int. 2011;80(12):1258-70. DOI:10.1038/ki.2011.368
3. Grabner A, Faul C. The Role of FGF23 and Klotho in Uremic Cardiomyopathy. Curr Opin Nephrol Hypertens. 2016;25:314-24. DOI:10.1097/MNH.0000000000000231..5
4. Neyra JA, Hu MC. Potential application of Klotho in human chronic kidney disease. Bone. 2017;100:41-9. DOI:10.1016/j.bone.2017.01.017
5. Xie J, Yoon J, An SW, et al. Soluble Klotho Protects against Uremic Cardiomyopathy Independently of Fibroblast Growth Factor 23 and Phosphate. J Am Soc Nephrol. 2015;26:1150-60. DOI:10.1681/ASN.2014040325
6. Kuro-o M. Klotho and chronic kidney disease – Whats new? Nephrol Dial Transplant. 2009;24(6):1705-8. DOI:10.1093/ndt/gfp069
7. Carracedo J, Alique M, Vida C, et al. Mechanisms of Cardiovascular Disorders in Patients With Chronic Kidney Disease: A Process Related to Accelerated Senescence. Front Cell Dev Biol. 2020;8:185. DOI:10.3389/fcell.2020.00185
8. Hu MC, Shiizaki K, Kuro-o M, Moe OW. Fibroblast growth factor 23 and Klotho: Physiology and pathophysiology of an endocrine network of mineral metabolism. Annu Rev Physiol. 2013;75:503-33. DOI:10.1146/annurev-physiol-030212-183727
9. Seifert ME, De Las Fuentes L, Ginsberg C, et al. Left ventricular mass progression despite stable blood pressure and kidney function in stage 3 chronic kidney disease. Am J Nephrol. 2014;39:392-9. DOI:10.1159/000362251
10. Memmos E, Sarafidis P, Pateinakis P, et al. Soluble Klotho is associated with mortality and cardiovascular events in hemodialysis. BMC Nephrol. 2019;11:217. DOI:10.1186/s12882-019-1391-1
11. Kim HJ, Kang E, Oh YK, et al. The association between soluble Klotho and cardiovascular parameters in chronic kidney disease: Results from the KNOW-CKD study. BMC Nephrol. 2018;5:51. DOI:10.1186/s12882-018-0851-3
12. Li F, Yao Q, Ao L, et al. Klotho suppresses high phosphate-induced osteogenic responses in human aortic valve interstitial cells through inhibition of Sox9.
J Mol Med. 2017;95:739-51. DOI:10.1007/s00109-017-1527-3
13. Hu MC, Shi M, Gillings N, et al. Recombinant α-Klotho may be prophylactic and therapeutic for acute to chronic kidney disease progression and uremic cardiomyopathy. Kidney Int. 2017;91:1104-14. DOI:10.1016/j.kint.2016.10.034
14. Levin A, Stevens PE, Bilous RW, et al. Kidney disease: Improving global outcomes (KDIGO) CKD work group. KDIGO. 2012 clinical practice guide-line for the evaluation and management of chronic kidney disease. Kidney Int Suppl. 2013;3:1-150. DOI: 10.1038/kisup.2012.73
15. Mancia G, Fagard R, Narkiewicz K, et al. The task force for the management of arterial hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC). Eur Heart J. 2013;34(28):2159-219. DOI:10.1093/eurheartj/eht151
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18. Lau WL, LeafEM, Hu MC, et al. Vitamin D receptor agonists increase Klotho and osteopontin while decreasing aortic calcification in mice with chronic kidney disease fed a high phosphate diet. Kidney Int. 2012;82(12):1261-70. DOI:10.1038/ki.2012.322
19. Naves-Díaz M, Alvarez-Hernández D, Passlick-Deetjen J, et al. Oral active vitamin D is associated with improved survival in hemodialysis patients. Kidney Int. 2008;74:1070-8. DOI: 10.1038/ki.2008.343
20. Becker LE, Koleganova N, Piecha G, et al. Effect of paricalcitol and calcitriol on aortic wall remodeling in uninephrectomized ApoE knockout mice. Am J Physiol Renal Physiol. 2011;300:F772-82. DOI: 10.1152/ajprenal.00042.2010
21. Lopez I, Mendoza FJ, Aguilera-Tejero E, et al. The effect of calcitriol, paricalcitol, and a calcimimetic on extraosseous calcifications in uremic rats. Kidney Int. 2008;73:300-7. DOI: 10.1038/sj.ki.5002675
22. Cardús A, Panizo S, Parisi E, et al. Differential effects of vitamin D analogs on vascular calcification. J Bone Miner Res. 2007;22:860-6. DOI: 10.1359/jbmr.070305
23. Jono S, Nishizawa Y, Shioi A, et al. 1,25-Dihydroxyvitamin D3 increases in vitro vascular calcification by modulating secretion of endogenous parathyroid hormone-related peptide. Circulation. 1998;98:1302-6. DOI: 10.1161/01.cir.98.13.1302
24. Li X, Speer MY, Yang H, et al. Vitamin D receptor activators induce an anticalcific paracrine program in macrophages: requirement of osteopontin. Arterioscler Thromb Vasc Biol. 2010;30:321-6. DOI: 10.1161/ATVBAHA.109.196576
25. Wu-Wong JR, Noonan W, Ma J, et al. Role of phosphorus and vitamin D analogs in the pathogenesis of vascular calcification. J Pharmacol Exp Ther. 2006;318:90-8. DOI: 10.1124/jpet.106.101261
26. Brown AJ, Finch J, Slatopolsky E. Differential effects of 19-nor-1,25-dihydroxyvitamin D(2) and 1,25-dihydroxyvitamin D(3) on intestinal calcium and phosphate transport. J Lab Clin Med. 2002;139:279-84. DOI: 10.1111/j.1523-1755.2002.kid573.x
27. Teng M, Wolf M, Lowrie E, et al. Survival of patients undergoing hemodialysis with paricalcitol or calcitriol therapy. N Engl J Med. 2003;349:446-56. DOI: 10.1056/NEJMoa022536
28. Mathew S, Lund RJ, Chaudhary LR, et al. Vitamin D receptor activators can protect against vascular calcification. J Am Soc Nephrol. 2008;19:1509-19. DOI: 10.1681/ASN
29. Mizobuchi M, Finch JL, Martin DR, et al. Differential effects of vitamin D receptor activators on vascular calcification in uremic rats. Kidney Int. 2007;72:709-15. DOI: 10.1038/sj.ki.5002406
30. Kumar V, Yadav AK, Singhal M, et al. Vascular function and cholecalciferol supplementation in CKD: A self-controlled case series. J Steroid Biochem Mol Biol. 2018;180:19-22. DOI:10.1016/j.jsbmb.2018.01.001
31. Chitalia N, Ismail T, Tooth L, et al. Impact of Vitamin D supplementation on arterial vasomotion, stiffness and endothelial biomarkers in chronic kidney disease patients. PLoS ONE. 2014;9:e91363. DOI:10.1371/journal.pone.0091363
32. Lundwall K, Jacobson SH, Jörneskog G, Spaak J. Treating endothelial dysfunction with Vitamin D in chronic kidney disease: A metaanalysis. BMC Nephrol. 2018;19:247. DOI:10.1186/s12882-018-1042-y
33. Chen S, Law CS, Grigsby CL, et al. Cardiomyocyte-specific deletion of the Vitamin D receptor gene results in cardiac hypertrophy. Circulation. 2011;124:1838-47. DOI:10.1161/CIRCULATIONAHA.111.032680
34. Olejnik A, Franczak A, Krzywonos-Zawadzka A, et al. The Biological Role of Klotho Protein in the Development of Cardiovascular Diseases. Biomed Res Int. 2018;2018:5171945. DOI:10.1155/2018/5171945
35. Buchanan S, Combet E, Stenvinkel P, Shiels PG. Klotho, Aging, and the Failing Kidney. Front Endocrinol (Lausanne). 2020;11:560. DOI:10.3389/fendo.2020.00560
36. Weishaar RE, Simpson RU. Vitamin D3 and cardiovascular function in rats. J Clin Investig. 1987;79:1706-12. DOI:10.1172/JCI113010
37. Gluba-Brzózka A, Franczyk B, Ciałkowska-Rysz A, et al. Impact of Vitamin D on the Cardiovascular System in Advanced Chronic Kidney Disease (CKD) and Dialysis Patients Nutrients. 2018;10(6):709. DOI:10.3390/nu10060709
38. Levin A, Li YC. Vitamin D and its analogues: Do they protect against cardiovascular disease in patients with kidney disease? Kidney Int. 2005;68:1973-81. DOI:10.1111/j.1523-1755.2005.00651.x
39. Li YC, Kong J, Wei M, et al. 1,25-Dihydroxyvitamin D(3) is a negative endocrine regulator of the renin-angiotensin system. J Clin Investig. 2002;110:229-38. DOI:10.1172/JCI0215219
40. Li YC. Vitamin D regulation of the renin-angiotensin system. J Cell Biochem. 2003;88:327-31. DOI:10.1002/jcb.10343
41. Xiang W, Kong J, Chen S, 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:E125-32.DOI:10.1152/ajpendo.00224.2004
42. Zhou L, Mo H, Miao J, et al. Klotho Ameliorates Kidney Injury and Fibrosis and Normalizes Blood Pressure by Targeting the Renin-Angiotensin System. Am J Pathol. 2015;185(12):3211-23.DOI:10.1016/j.ajpath.2015.08.004

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1. Go AS, Chertow GM, Fan D, et al. Chronic kidney disease and the risks of death, cardiovascular events, and hospitalization. N Engl J Med. 2004;351:1296-305. DOI: 10.1056/NEJMoa041031
2. Couser WG, Remuzzi G, Mendis S, Tonelli M. The contribution of chronic kidney disease to the global burden of major noncommunicable diseases. Kidney Int. 2011;80(12):1258-70. DOI:10.1038/ki.2011.368
3. Grabner A, Faul C. The Role of FGF23 and Klotho in Uremic Cardiomyopathy. Curr Opin Nephrol Hypertens. 2016;25:314-24. DOI:10.1097/MNH.0000000000000231..5
4. Neyra JA, Hu MC. Potential application of Klotho in human chronic kidney disease. Bone. 2017;100:41-9. DOI:10.1016/j.bone.2017.01.017
5. Xie J, Yoon J, An SW, et al. Soluble Klotho Protects against Uremic Cardiomyopathy Independently of Fibroblast Growth Factor 23 and Phosphate. J Am Soc Nephrol. 2015;26:1150-60. DOI:10.1681/ASN.2014040325
6. Kuro-o M. Klotho and chronic kidney disease – Whats new? Nephrol Dial Transplant. 2009;24(6):1705-8. DOI:10.1093/ndt/gfp069
7. Carracedo J, Alique M, Vida C, et al. Mechanisms of Cardiovascular Disorders in Patients With Chronic Kidney Disease: A Process Related to Accelerated Senescence. Front Cell Dev Biol. 2020;8:185. DOI:10.3389/fcell.2020.00185
8. Hu MC, Shiizaki K, Kuro-o M, Moe OW. Fibroblast growth factor 23 and Klotho: Physiology and pathophysiology of an endocrine network of mineral metabolism. Annu Rev Physiol. 2013;75:503-33. DOI:10.1146/annurev-physiol-030212-183727
9. Seifert ME, De Las Fuentes L, Ginsberg C, et al. Left ventricular mass progression despite stable blood pressure and kidney function in stage 3 chronic kidney disease. Am J Nephrol. 2014;39:392-9. DOI:10.1159/000362251
10. Memmos E, Sarafidis P, Pateinakis P, et al. Soluble Klotho is associated with mortality and cardiovascular events in hemodialysis. BMC Nephrol. 2019;11:217. DOI:10.1186/s12882-019-1391-1
11. Kim HJ, Kang E, Oh YK, et al. The association between soluble Klotho and cardiovascular parameters in chronic kidney disease: Results from the KNOW-CKD study. BMC Nephrol. 2018;5:51. DOI:10.1186/s12882-018-0851-3
12. Li F, Yao Q, Ao L, et al. Klotho suppresses high phosphate-induced osteogenic responses in human aortic valve interstitial cells through inhibition of Sox9.
J Mol Med. 2017;95:739-51. DOI:10.1007/s00109-017-1527-3
13. Hu MC, Shi M, Gillings N, et al. Recombinant α-Klotho may be prophylactic and therapeutic for acute to chronic kidney disease progression and uremic cardiomyopathy. Kidney Int. 2017;91:1104-14. DOI:10.1016/j.kint.2016.10.034
14. Levin A, Stevens PE, Bilous RW, et al. Kidney disease: Improving global outcomes (KDIGO) CKD work group. KDIGO. 2012 clinical practice guide-line for the evaluation and management of chronic kidney disease. Kidney Int Suppl. 2013;3:1-150. DOI: 10.1038/kisup.2012.73
15. Mancia G, Fagard R, Narkiewicz K, et al. The task force for the management of arterial hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC). Eur Heart J. 2013;34(28):2159-219. DOI:10.1093/eurheartj/eht151
16. Kidney Disease: Improving Global Outcomes (KDIGO) CKD-MBD Work Group. KDIGO clinical practice guideline for the diagnosis, evolution, prevention, and treatment of chronic kidney disease-mineral and bone disorder (CKD-MBD). Kidney Int Suppl. 2009;76:S1-130
17. Ermolenko VM, Volgina GV, Dobronravov VA, et al. National recommendations on mineral and bone disorders in chronic kidney disease. Russian Dialysis Society (May 2010). Nephrologia i dialis. 2011;13(1):33-51 (in Russian)
18. Lau WL, LeafEM, Hu MC, et al. Vitamin D receptor agonists increase Klotho and osteopontin while decreasing aortic calcification in mice with chronic kidney disease fed a high phosphate diet. Kidney Int. 2012;82(12):1261-70. DOI:10.1038/ki.2012.322
19. Naves-Díaz M, Alvarez-Hernández D, Passlick-Deetjen J, et al. Oral active vitamin D is associated with improved survival in hemodialysis patients. Kidney Int. 2008;74:1070-8. DOI: 10.1038/ki.2008.343
20. Becker LE, Koleganova N, Piecha G, et al. Effect of paricalcitol and calcitriol on aortic wall remodeling in uninephrectomized ApoE knockout mice. Am J Physiol Renal Physiol. 2011;300:F772-82. DOI: 10.1152/ajprenal.00042.2010
21. Lopez I, Mendoza FJ, Aguilera-Tejero E, et al. The effect of calcitriol, paricalcitol, and a calcimimetic on extraosseous calcifications in uremic rats. Kidney Int. 2008;73:300-7. DOI: 10.1038/sj.ki.5002675
22. Cardús A, Panizo S, Parisi E, et al. Differential effects of vitamin D analogs on vascular calcification. J Bone Miner Res. 2007;22:860-6. DOI: 10.1359/jbmr.070305
23. Jono S, Nishizawa Y, Shioi A, et al. 1,25-Dihydroxyvitamin D3 increases in vitro vascular calcification by modulating secretion of endogenous parathyroid hormone-related peptide. Circulation. 1998;98:1302-6. DOI: 10.1161/01.cir.98.13.1302
24. Li X, Speer MY, Yang H, et al. Vitamin D receptor activators induce an anticalcific paracrine program in macrophages: requirement of osteopontin. Arterioscler Thromb Vasc Biol. 2010;30:321-6. DOI: 10.1161/ATVBAHA.109.196576
25. Wu-Wong JR, Noonan W, Ma J, et al. Role of phosphorus and vitamin D analogs in the pathogenesis of vascular calcification. J Pharmacol Exp Ther. 2006;318:90-8. DOI: 10.1124/jpet.106.101261
26. Brown AJ, Finch J, Slatopolsky E. Differential effects of 19-nor-1,25-dihydroxyvitamin D(2) and 1,25-dihydroxyvitamin D(3) on intestinal calcium and phosphate transport. J Lab Clin Med. 2002;139:279-84. DOI: 10.1111/j.1523-1755.2002.kid573.x
27. Teng M, Wolf M, Lowrie E, et al. Survival of patients undergoing hemodialysis with paricalcitol or calcitriol therapy. N Engl J Med. 2003;349:446-56. DOI: 10.1056/NEJMoa022536
28. Mathew S, Lund RJ, Chaudhary LR, et al. Vitamin D receptor activators can protect against vascular calcification. J Am Soc Nephrol. 2008;19:1509-19. DOI: 10.1681/ASN
29. Mizobuchi M, Finch JL, Martin DR, et al. Differential effects of vitamin D receptor activators on vascular calcification in uremic rats. Kidney Int. 2007;72:709-15. DOI: 10.1038/sj.ki.5002406
30. Kumar V, Yadav AK, Singhal M, et al. Vascular function and cholecalciferol supplementation in CKD: A self-controlled case series. J Steroid Biochem Mol Biol. 2018;180:19-22. DOI:10.1016/j.jsbmb.2018.01.001
31. Chitalia N, Ismail T, Tooth L, et al. Impact of Vitamin D supplementation on arterial vasomotion, stiffness and endothelial biomarkers in chronic kidney disease patients. PLoS ONE. 2014;9:e91363. DOI:10.1371/journal.pone.0091363
32. Lundwall K, Jacobson SH, Jörneskog G, Spaak J. Treating endothelial dysfunction with Vitamin D in chronic kidney disease: A metaanalysis. BMC Nephrol. 2018;19:247. DOI:10.1186/s12882-018-1042-y
33. Chen S, Law CS, Grigsby CL, et al. Cardiomyocyte-specific deletion of the Vitamin D receptor gene results in cardiac hypertrophy. Circulation. 2011;124:1838-47. DOI:10.1161/CIRCULATIONAHA.111.032680
34. Olejnik A, Franczak A, Krzywonos-Zawadzka A, et al. The Biological Role of Klotho Protein in the Development of Cardiovascular Diseases. Biomed Res Int. 2018;2018:5171945. DOI:10.1155/2018/5171945
35. Buchanan S, Combet E, Stenvinkel P, Shiels PG. Klotho, Aging, and the Failing Kidney. Front Endocrinol (Lausanne). 2020;11:560. DOI:10.3389/fendo.2020.00560
36. Weishaar RE, Simpson RU. Vitamin D3 and cardiovascular function in rats. J Clin Investig. 1987;79:1706-12. DOI:10.1172/JCI113010
37. Gluba-Brzózka A, Franczyk B, Ciałkowska-Rysz A, et al. Impact of Vitamin D on the Cardiovascular System in Advanced Chronic Kidney Disease (CKD) and Dialysis Patients Nutrients. 2018;10(6):709. DOI:10.3390/nu10060709
38. Levin A, Li YC. Vitamin D and its analogues: Do they protect against cardiovascular disease in patients with kidney disease? Kidney Int. 2005;68:1973-81. DOI:10.1111/j.1523-1755.2005.00651.x
39. Li YC, Kong J, Wei M, et al. 1,25-Dihydroxyvitamin D(3) is a negative endocrine regulator of the renin-angiotensin system. J Clin Investig. 2002;110:229-38. DOI:10.1172/JCI0215219
40. Li YC. Vitamin D regulation of the renin-angiotensin system. J Cell Biochem. 2003;88:327-31. DOI:10.1002/jcb.10343
41. Xiang W, Kong J, Chen S, 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:E125-32.DOI:10.1152/ajpendo.00224.2004
42. Zhou L, Mo H, Miao J, et al. Klotho Ameliorates Kidney Injury and Fibrosis and Normalizes Blood Pressure by Targeting the Renin-Angiotensin System. Am J Pathol. 2015;185(12):3211-23.DOI:10.1016/j.ajpath.2015.08.004

Авторы

Л.Ю. Милованова*1, В.Д. Бекетов1, С.Ю. Милованова1, М.В. Таранова1, В.В. Козлов1, А.И. Пасечник2, В.А. Решетников1, Т.В. Андросова1, М.В. Калашников1

1 ФГАОУ ВО «Первый Московский государственный медицинский университет им. И.М. Сеченова» Минздрава России (Сеченовский Университет), Москва, Россия;
2 ФГБОУ ВО «Московский государственный университет им. М.В. Ломоносова», Москва, Россия
*Ludm.milovanova@gmail.com

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Ludmila Yu. Milovanova*1, Vladimir D. Beketov1, Svetlana Yu. Milovanova1, Marina V. Taranova1, Vasilii V. Kozlov1, Anastasiia I. Pasechnik2, Vladimir A. Reshetnikov1, Tatiana V. Androsova1, Mikhail V. Kalashnikov1

1 Sechenov First Moscow State Medical University (Sechenov University), Moscow, Russia;
2 Lomonosov Moscow State University, Moscow, Russia
*Ludm.milovanova@gmail.com

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