Remodeling of Intramyocardial Arteries and Myocardium as a Target of Early Chronic Kidney Disease-Mineral and Bone Disorder: an Experimental Study
E. O. Bogdanova,
A. M. Sadykov,
G. T. Ivanova,
I. M. Zubina,
O. N. Beresneva,
O. V. Galkina,
V. V. Sharoyko,
V. A. Dobronravov https://doi.org/10.24884/1682-6655-2025-24-4-48-58
Abstract
Introduction. Chronic kidney disease–mineral and bone disorder (CKD-MBD) plays a significant role in causing cardiovascular morbidity and mortality related to CKD. CKD-MBD has been studied during advanced stages when changes in inorganic phosphate (Pi) and its hormonal regulation are obvious. The initial phases of myocardial remodeling (MR) in early CKD-MBD remain poorly understood. Aim. To investigate the molecular and structural alterations in the myocardium and intramyocardial arteries in early-stage CKD-MBD model. Materials and methods. CKD-MBD was modeled using 3/4 nephrectomy in spontaneously hypertensive rats (SHR). Sham-operated rats served as a control. After 2 or 6 months, we assessed renal function, inorganic phosphate (Pi) metabolism, bone, myocardial and vascular histology and histomorphometry and gene profiles for Pi-dependent, pro-hypertrophic and pro-fibrotic signaling pathways in the myocardium. Results. The chronic kidney injury in the applied models corresponded to human CKD grade 1–2 and was accompanied by lower bone turnover with no increase in fibroblast growth factor 23 and parathyroid hormone levels. Myocardial remodeling was characterized by interstitial and perivascular fibrosis, thickening of the intramyocardial artery media, cardiomyocyte hypertrophy and tissue retention of phosphorus. The differences in the expression profiles included genes related to cell differentiation (Lgr4, Dkk1, Sfrp2), vascularization (Jag1, Fzd2, Ptch1, Bmp4) and fibrosis (Hes1, Jag1, Mapk1/3, Ctnnb1), hypertrophy (Mapk1/3, Hes1, Jag1, Ctnnb1, Ppp3ca) and Pi balance (Ankh, Mapk1/3, Ppp3ca). Conclusion. The early stages of myocardial and vascular remodeling in CKD-MBD are associated with lower bone turnover and myocardial phosphorus accumulation concurrently with altered myocardial gene expression of pathways related to Pi metabolism, vascularization, fibrosis and hypertrophy.
Keywords
chronic kidney disease,
myocardial remodeling,
intramyocardial arteries,
inorganic phosphate,
ERK1/2,
PiT-2,
Ankh,
Jagged1,
Hes1,
Lgr4
Supporting agencies: The study was supported by the State Assignment No. 121061700145-2, titled: «Development of a predictive diagnostic method for mineral and bone disorders in patients with chronic kidney disease to use in healthcare systems and designing preventive strategies aimed at reducing adverse outcome risks».
About the Authors
E. O. Bogdanova
Pavlov University
Russian Federation
Russian Federation
Bogdanova Evdokia O. – Candidate (PhD) in Biological Sciences, Researcher, Laboratory of Biochemical Homeostasis, Research Institute of Nephrology
6-8, L’va Tolstogo str., Saint Petersburg, 197022
SPIN: 8426-8033
A. M. Sadykov
Pavlov University
Russian Federation
Russian Federation
Sadykov Airat M. – Biologist, Raisa Gorbacheva Memorial Research Institute for Pediatric Oncology, Hematology and Transplantation
6-8, L’va Tolstogo str., Saint Petersburg, 197022
SPIN: 4295-6103
G. T. Ivanova
Pavlov Institute of Physiology of the Russian Academy of Sciences
Russian Federation
Russian Federation
Ivanova Galina T. – Candidate (PhD) in Biological Sciences, Leading, Laboratory of Cardiovascular and Lymphatic Systems
6, Makarova embankment, Saint Petersburg, 199034
SPIN: 5398-7584
I. M. Zubina
Pavlov University
Russian Federation
Russian Federation
Zubina Irina M. – Candidate (PhD) in Biological Sciences, Assistant Professor, Senior Researcher, Laboratory of Biochemical Homeostasis, Research Institute of Nephrology
6-8, L’va Tolstogo str., Saint Petersburg, 197022
SPIN: 9355-0705
O. N. Beresneva
Pavlov University
Russian Federation
Russian Federation
Beresneva Olga N. – Candidate (PhD) in Biological Sciences, Senior Researcher, Laboratory of Clinical Renal Physiology, Research Institute of Nephrology
6-8, L’va Tolstogo str., Saint Petersburg, 197022
SPIN: 2131-2450
O. V. Galkina
Pavlov University
Russian Federation
Russian Federation
Galkina Olga V. – Candidate (PhD) in Biological Sciences, Assistant Professor, Head, Laboratory of Biochemical Homeostasis, Research Institute of Nephrology
6-8, L’va Tolstogo str., Saint Petersburg, 197022
SPIN: 4251-6056
V. V. Sharoyko
Pavlov University
Russian Federation
Russian Federation
Sharoyko Vladimir V. – Doctor of Biological Sciences, Professor, Department of General and Bioorganic Chemistry
6-8, L’va Tolstogo str., Saint Petersburg, 197022
SPIN-код: 6671-4680
V. A. Dobronravov
Pavlov University
Russian Federation
Russian Federation
Dobronravov Vladimir A. – Doctor of Medical Sciences, Professor, Director, Research Institute of Nephrology
6-8, L’va Tolstogo str., Saint Petersburg, 197022
SPIN: 4293-0789
References
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 Sep 23;351(13):1296-1305. https://doi.org/10.1056/NEJMoa041031. Erratum in: N Engl J Med. 2008;18(4):4. PMID: 15385656.
2. Jankowski J, Floege J, Fliser D, et al. Cardiovascular Disease in Chronic Kidney Disease: Pathophysiological Insights and Therapeutic Options. Circulation. 2021 Mar 16;143(11):1157-1172. https://doi.org/10.1161/CIRCULATIONAHA.120.050686. Epub 2021 Mar 15. PMID: 33720773; PMCID: PMC7969169.
3. Blecker S, Matsushita K, Köttgen A, et al. High-normal albuminuria and risk of heart failure in the community. Am J Kidney Dis. 2011 Jul;58(1):47-55. https://doi.org/10.1053/j.ajkd.2011.02.391. Epub 2011 May 6. PMID: 21549463; PMCID: PMC3119712.
4. Buckalew VM Jr, Berg RL, Wang SR, et al. Prevalence of hypertension in 1,795 subjects with chronic renal disease: the modification of diet in renal disease study baseline cohort. Modification of Diet in Renal Disease Study Group. Am J Kidney Dis. 1996 Dec;28(6):811-821. https://doi.org/10.1016/s0272-6386(96)90380-7. PMID: 8957032.
5. Silberberg JS, Barre PE, Prichard SS, Sniderman AD. Impact of left ventricular hypertrophy on survival in end-stage renal disease. Kidney Int. 1989 Aug;36(2):286-290. https://doi.org/10.1038/ki.1989.192. PMID: 2528654.
6. London GM. Left ventricular alterations and end-stage renal disease. Nephrol Dial Transplant. 2002;17 Suppl 1:29-36. https://doi.org/10.1093/ndt/17.suppl_1.29. PMID: 11812909.
7. Williams MJ, White SC, Joseph Z, Hruska KA. Updates in the chronic kidney disease-mineral bone disorder show the role of osteocytic proteins, a potential mechanism of the bone-Vascular paradox, a therapeutic target, and a biomarker. Front Physiol. 2023 Jan 26;14:1120308. https://doi.org/10.3389/fphys.2023.1120308. PMID: 36776982; PMCID: PMC9909112.
8. Drüeke TB, Massy ZA. Changing bone patterns with progression of chronic kidney disease. Kidney Int. 2016 Feb;89(2):289-302. https://doi.org/10.1016/j.kint.2015.12.004. PMID: 26806832.
9. Ferreira JC, Ferrari GO, Neves KR, et al. Effects of dietary phosphate on adynamic bone disease in rats with chronic kidney disease-role of sclerostin? PLoS One. 2013 Nov 13;8(11):e79721. https://doi.org/10.1371/journal.pone.0079721. PMID: 24236156; PMCID: PMC3827459.
10. Fang Y, Ginsberg C, Seifert M, et al. CKD-induced wingless/integration1 inhibitors and phosphorus cause the CKD-mineral and bone disorder. J Am Soc Nephrol. 2014 Aug;25(8):1760-1773. https://doi.org/10.1681/ASN.2013080818. Epub 2014 Feb 27. PMID: 24578135; PMCID: PMC4116062.
11. Raggi P, Bellasi A, Bushinsky D, et al. Slowing Progression of Cardiovascular Calcification With SNF472 in Patients on Hemodialysis: Results of a Randomized Phase 2b Study. Circulation. 2020 Mar 3;141(9):728-739. https://doi.org/10.1161/CIRCULATIONAHA.119.044195. Epub 2019 Nov 11. PMID: 31707860.
12. Malluche HH, Mawad HW, Monier-Faugere MC. Renal osteodystrophy in the first decade of the new millennium: analysis of 630 bone biopsies in black and white patients. J Bone Miner Res. 2011 Jun;26(6):1368-1376. https://doi.org/10.1002/jbmr.309. Erratum in: J Bone Miner Res. 2011 Nov;26(11):2793. PMID: 21611975; PMCID: PMC3312761.
13. Sprague SM, Bellorin-Font E, Jorgetti V, et al. Diagnostic Accuracy of Bone Turnover Markers and Bone Histology in Patients With CKD Treated by Dialysis. Am J Kidney Dis. 2016 Apr;67(4):559-566. https://doi.org/10.1053/j.ajkd.2015.06.023. Epub 2015 Aug 25. PMID: 26321176.
14. El-Husseini A, Abdalbary M, Lima F, et al. Low Turnover Renal Osteodystrophy With Abnormal Bone Quality and Vascular Calcification in Patients With Mild-to-Moderate CKD. Kidney Int Rep. 2022 Mar 6;7(5):1016-1026. https://doi.org/10.1016/j.ekir.2022.02.022. PMID: 35570986; PMCID: PMC9091581.
15. Smogorzewski M, Zayed M, Zhang YB, et al. Parathyroid hormone increases cytosolic calcium concentration in adult rat cardiac myocytes. Am J Physiol. 1993 Jun;264(6 Pt 2):H1998-2006. https://doi.org/10.1152/ajpheart.1993.264.6.H1998. PMID: 8322930.
16. Maulik SK, Mishra S. Hypertrophy to failure: what goes wrong with the fibers of the heart? Indian Heart J. 2015 JanFeb;67(1):66-69. https://doi.org/10.1016/j.ihj.2015.02.012. Epub 2015 Mar 14. PMID: 25820056; PMCID: PMC4382541.
17. Intengan HD, Schiffrin EL. Vascular remodeling in hypertension: roles of apoptosis, inflammation, and fibrosis. Hypertension. 2001 Sep;38(3 Pt 2):581-587. https://doi.org/10.1161/hy09t1.096249. PMID: 11566935.
18. Korsgaard N, Mulvany MJ. Cellular hypertrophy in mesenteric resistance vessels from renal hypertensive rats. Hypertension. 1988 Aug;12(2):162-167. https://doi.org/10.1161/01.hyp.12.2.162. PMID: 3410524.
19. Fleischer H, Vorberg E, Thurow K, et al. Determination of Calcium and Phosphor in Bones Using Microwave Digestion and ICP-MS. In Imeko Tc19 Symp, 5th ed.; International Measurement Confederation (IMEKO): Lecce, Italy, 2014.
20. Erben RG, Glösmann M. Histomorphometry in Rodents. Methods Mol Biol. 2019;1914:411-435. https://doi.org/10.1007/978-1-4939-8997-3_24. PMID: 30729480.
21. Dempster DW, Compston JE, Drezner MK, et al. Standardized nomenclature, symbols, and units for bone histomorphometry: a 2012 update of the report of the ASBMR Histomorphometry Nomenclature Committee. J Bone Miner Res. 2013 Jan;28(1):2-17. https://doi.org/10.1002/jbmr.1805. PMID: 23197339; PMCID: PMC3672237.
22. Parfrey PS, Harnett JD, Griffiths SM, et al. The clinical course of left ventricular hypertrophy in dialysis patients. Nephron. 1990;55(2):114-120. https://doi.org/10.1159/000185937. PMID: 2141918.
23. Levin A, Singer J, Thompson CR, et al. Prevalent left ventricular hypertrophy in the predialysis population: identifying opportunities for intervention. Am J Kidney Dis. 1996 Mar;27(3):347-354. https://doi.org/10.1016/s0272-6386(96)90357-1. PMID: 8604703.
24. Xie J, Yoon J, An SW, Kuro-o M, Huang CL. Soluble Klotho Protects against Uremic Cardiomyopathy Independently of Fibroblast Growth Factor 23 and Phosphate. J Am Soc Nephrol. 2015 May;26(5):1150-1160. https://doi.org/10.1681/ASN.2014040325. Epub 2014 Dec 4. PMID: 25475745; PMCID: PMC4413766.
25. Nadruz W. Myocardial remodeling in hypertension. J Hum Hypertens. 2015 Jan;29(1):1-6. https://doi.org/10.1038/jhh.2014.36. Epub 2014 May 8. PMID: 24804791.
26. Aoki J, Ikari Y, Nakajima H, et al. Clinical and pathologic characteristics of dilated cardiomyopathy in hemodialysis patients. Kidney Int. 2005 Jan;67(1):333-340. https://doi.org/10.1111/j.1523-1755.2005.00086.x. PMID: 15610259.
27. 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 Jan;37(1):1-19. https://doi.org/10.1038/s41371-022-00751-4. Epub 2022 Sep 22. PMID: 36138105; PMCID: PMC9831930.
28. Mark PB, Johnston N, Groenning BA, et al. Redefinition of uremic cardiomyopathy by contrast-enhanced cardiac magnetic resonance imaging. Kidney Int. 2006 May;69(10):1839-1845. https://doi.org/10.1038/sj.ki.5000249. PMID: 16508657.
29. Wang M, Zhang J, Kalantar-Zadeh K, Chen J. Focusing on Phosphorus Loads: From Healthy People to Chronic Kidney Disease. Nutrients. 2023 Feb 28;15(5):1236. https://doi.org/10.3390/nu15051236. PMID: 36904234; PMCID: PMC10004810.
30. Bevington A, Mundy KI, Yates AJ, et al. A study of intracellular orthophosphate concentration in human muscle and erythrocytes by 31P nuclear magnetic resonance spectroscopy and selective chemical assay. Clin Sci (Lond). 1986 Dec;71(6):729-735. https://doi.org/10.1042/cs0710729. PMID: 3024899.
31. Chazot G, Lemoine S, Kocevar G, et al. Intracellular Phosphate and ATP Depletion Measured by Magnetic Resonance Spectroscopy in Patients Receiving Maintenance Hemodialysis. J Am Soc Nephrol. 2021 Jan;32(1):229-237. https://doi.org/10.1681/ASN.2020050716. Epub 2020 Oct 22. PMID: 33093193; PMCID: PMC7894675.
32. Polovlkova OG, Makeeva OA, Lezhnev AA, et al. Expression profile of calcineurin pathway genes in myocardium tissues in relation to ischemic heart remodeling in humans. Mol Biol (Mosk). 2013 May-Jun;47(3):433-440. (In Russ.)]. https://doi.org/10.7868/s0026898413030117. PMID: 23888774.
33. Ha SW, Park J, Habib MM, Beck GR Jr. Nano-Hydroxyapatite Stimulation of Gene Expression Requires Fgf Receptor, Phosphate Transporter, and Erk1/2 Signaling. ACS Appl Mater Interfaces. 2017 Nov 15;9(45):39185-39196. https://doi.org/10.1021/acsami.7b12029. Epub 2017 Oct 31. PMID: 29045789; PMCID: PMC10336561.
34. Bon N, Couasnay G, Bourgine A, et al. Phosphate (Pi)-regulated heterodimerization of the high-affinity sodiumdependent Pi transporters PiT1/Slc20a1 and PiT2/Slc20a2 underlies extracellular Pi sensing independently of Pi uptake. J Biol Chem. 2018 Feb 9;293(6):2102-2114. https://doi.org/10.1074/jbc.M117.807339. Epub 2017 Dec 12. PMID: 29233890; PMCID: PMC5808770.
35. Szeri F, Niaziorimi F, Donnelly S, et al. The Mineralization Regulator ANKH Mediates Cellular Efflux of ATP, Not Pyrophosphate. J Bone Miner Res. 2022 May;37(5):1024-1031. https://doi.org/10.1002/jbmr.4528. Epub 2022 Feb 28. PMID: 35147247; PMCID: PMC9098669.
36. Huang CK, Dai D, Xie H, et al. Lgr4 Governs a ProInflammatory Program in Macrophages to Antagonize PostInfarction Cardiac Repair. Circ Res. 2020 Sep 25;127(8):953-973. https://doi.org/10.1161/CIRCRESAHA.119.315807. Epub 2020 Jun 30. PMID: 32600176.
37. Shao JS, Cai J, Towler DA. Molecular mechanisms of vascular calcification: lessons learned from the aorta. Arterioscler Thromb Vasc Biol. 2006 Jul;26(7):1423-1430. https://doi.org/10.1161/01.ATV.0000220441.42041.20. Epub 2006 Apr 6. PMID: 16601233.
38. Rathinavel A, Sankar J, Mohammed Sadullah SS, Niranjali Devaraj S. Oligomeric proanthocyanidins protect myocardium by mitigating left ventricular remodeling in isoproterenolinduced postmyocardial infarction. Fundam Clin Pharmacol. 2018 Feb;32(1):51-59. https://doi.org/10.1111/fcp.12325. Epub 2017 Nov 15. PMID: 29059499.
39. Sun B, Huo R, Sheng Y, et al. Bone morphogenetic protein4 mediates cardiac hypertrophy, apoptosis, and fibrosis in experimentally pathological cardiac hypertrophy. Hypertension. 2013 Feb;61(2):352-360. https://doi.org/10.1161/HYPERTENSIONAHA.111.00562. Epub 2012 Dec 17. PMID: 23248151.
40. Dave RK, Ellis T, Toumpas MC, et al. Sonic hedgehog and notch signaling can cooperate to regulate neurogenic divisions of neocortical progenitors. PLoS One. 2011 Feb 17;6(2):e14680. https://doi.org/10.1371/journal.pone.0014680. PMID: 21379383; PMCID: PMC3040755.
41. Zhang K, Zhang YQ, Ai WB, et al. Hes1, an important gene for activation of hepatic stellate cells, is regulated by Notch1 and TGF-β/BMP signaling. World J Gastroenterol. 2015 Jan 21;21(3):878-887. https://doi.org/10.3748/wjg.v21.i3.878. PMID: 25624721; PMCID: PMC4299340.
42. Ingram WJ, McCue KI, Tran TH, et al. Sonic Hedgehog regulates Hes1 through a novel mechanism that is independent of canonical Notch pathway signalling. Oncogene. 2008 Feb 28;27(10):1489-1500. https://doi.org/10.1038/sj.onc.1210767. Epub 2007 Sep 17. PMID: 17873912.
43. Wang G, Zhang Z, Xu Z, et al. Activation of the sonic hedgehog signaling controls human pulmonary arterial smooth muscle cell proliferation in response to hypoxia. Biochim Biophys Acta. 2010 Dec;1803(12):1359-1367. https://doi.org/10.1016/j.bbamcr.2010.09.002. Epub 2010 Sep 15. PMID: 20840857; PMCID: PMC2956789.
44. Katoh M, Katoh M. NUMB is a break of WNT-Notch signaling cycle. Int J Mol Med. 2006 Sep;18(3):517-521. PMID: 16865239.
45. Ortega-Campos SM, García-Heredia JM. The Multitasker Protein: A Look at the Multiple Capabilities of NUMB. Cells. 2023 Jan 15;12(2):333. https://doi.org/10.3390/cells12020333. PMID: 36672267; PMCID: PMC9856935.
46. Shimizu I, Minamino T. Physiological and pathological cardiac hypertrophy. J Mol Cell Cardiol. 2016 Aug;97:245262. https://doi.org/10.1016/j.yjmcc.2016.06.001. Epub 2016 Jun 2. PMID: 27262674.
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Bogdanova E.O., Sadykov A.M., Ivanova G.T., Zubina I.M., Beresneva O.N., Galkina O.V., Sharoyko V.V., Dobronravov V.A. Remodeling of Intramyocardial Arteries and Myocardium as a Target of Early Chronic Kidney Disease-Mineral and Bone Disorder: an Experimental Study. Regional blood circulation and microcirculation. 2025;24(4):48-58. (In Russ.) https://doi.org/10.24884/1682-6655-2025-24-4-48-58
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