Atherosclerosis: Open Access
Open Access

Chronic kidney disease; Vascular calcification; Cells; Atherosclerosis

Introduction

Chronic kidney disease (CKD) progression is associated with a number of significant consequences, including cardiovascular events, which are the leading cause of mortality in CKD patients [1]. Cardiovascular events are frequently caused by vascular calcification (VC) and cardiac valve calcification (CVC) [2,3]. As compared to the non-CKD population, the incidence of vascular calcification or CVC in CKD is substantially greater, increasing the likelihood of sudden mortality [3,4]. In CKD patients, VC is caused by two separate but overlapping vascular pathologies: atherosclerosis and arteriosclerosis. Atherosclerosis is defined by lipid-laden plaques that are restricted to the tunica intima of the artery wall, causing vascular irritation, thickening, and calcification [5]. Arteriosclerosis, also known as medial arterial calcification, is associated with vascular fibrosis, thickness, and rigidity, all of which contribute to left ventricular hypertrophy [6]. The heart valve is made up of of valve endothelial cells (VECs) and valvular interstitial cells (VICs) (VICs). The major cause of valve calcification is endothelial dysfunction, which leads to interstitial cell loss and differentiation [7]. We cover the modulation of vascular and cardiac valvular calcification in this paper. We emphasise fundamental insights into VC and CVC processes, as well as CVC risk factors, which may provide the groundwork for innovative treatment methods to address vascular and cardiac valve calcification in CKD. FGF-23, a bonederived hormone, is localised at 12p13 in humans and contains 251 amino acids protein (molecular weight=30 kDa), and it is commonly thought to play a significant role in vascular alterations [8,9]. Klotho, a component of the klotho/FGF-receptor complex, was initially discovered by Kuro-o et al. and has since become an important factor in health and illness [10-12]. It encodes a single-pass transmembrane klotho protein associated in cardiovascular disease, including as atherosclerosis and VC, and is expressed at high levels in renal distal tubular epithelium, but not in the parathyroid gland or human vascular tissue [12,13]. The membrane klotho interacts with fibroblast growth factor receptors (particularly FGFR1) to produce a high-affinity for FGF-23 in order to maintain mineral homeostasis by promoting phosphate excretion into the urine and lowering blood 1,25 (OH)2D3 levels [14,15]. While the klotho gene is expressed in the distal tubule of the kidney, renal phosphate reabsorption occurs mostly in the proximal tubule. Hence, how the FGF-23/klotho axis reduces phosphate resorption in the proximal has to be investigated further. It has been shown that a high level of FGF-23 in vascular smooth muscle cells (VSMCs) and CKD is associated with the advancement of arterial calcification score irrespective of blood phosphorus level [16,17]. FGF23 is also linked to artery endothelial damage, particularly in CKD [18,19]. Subsequent research revealed that the anti-VC effects of active vitamin D and its analogue can be mediated by reduced FGF-23 and enhanced klotho expression independent of serum parathyroid hormone (PTH) levels [20,21]. CKD is a disease characterised by vascular klotho deficit caused by chronic circulating stress factors such as pro-inflammatory, uremic, and disordered metabolic conditions, which can accelerate the development of human artery calcification and mediate resistance to FGF-23. Others argue that soluble klotho improves VC via increasing phosphaturia, maintaining glomerular filtration, and directly blocking phosphate absorption by vascular smooth muscle. Nevertheless, Cha et al. found that released klotho protein activates transient receptor potential vanilloid-5, which is involved for calcium reabsorption in the kidney and can cause vascular calcification. As a result, the link between klotho and vascular calcification remains unknown. The Wnt pathways are a collection of signal transduction pathways that include the canonical Wnt pathway as well as the non-canonical Wnt/calcium pathway. When Wnt ligands (e.g., Wnt1, Wnt3a) bind to their receptors, cell-surface Frizzled (FZD) and low density-lipoprotein-receptor-related protein 5/6 (LRP 5/6), the canonical Wnt signalling pathway is activated. When the FZD/LRP 5/6 receptor complex is activated, GSK-3b is inactivated, and catenin accumulates in the cytoplasm and translocates to the nucleus, where it can heterodimerize with members of the lymphoid enhancer factor/Tcell factor transcription factor family to induce the expression of specific genes. Wnt signalling pathways have been implicated in vascular diseases, including endothelial dysfunction and migration, VSMC trans differentiation, and VC. Wnt signalling is important in VSMC calcification produced by high-phosphate and bone morphogenetic protein 2 (BMP-2). We found higher expressions of -catenin, GSK-3, and Wnt-5a in the calcific region of VC in patients with end-stage renal disease (ESRD), and logistic regression analysis revealed that Wnt-5a was an independent risk factor for vascular calcification in ESRD patients. Moreover, PI3K/Akt can activate the -catenin signalling pathway by cross-linking the MAPK signalling pathway to cause VC and CKD. The MAPK signalling pathway is an important mechanism that facilitates eukaryotic signal transmission and is important in osteoblast development and mineralization of VSMCs. A recent research found that P38MAPK can modulate the canonical Wnt-catenin signalling pathway in the brain, thymus gland, and spleen by inactivating GSK-3. Nevertheless, whether this route is implicated in calcification has to be investigated further. MicroRNAs (miRs) are short noncoding RNAs that control cellular processes such as proliferation, differentiation, and death by regulating target gene expression via mRNA degradation, translational repression, or mRNA modification. Many investigations have found that miRs are linked to VSMC calcification. MiR-125b was shown to be down regulated in calcified aortas of apoE mutant rats, and its analogues have been shown to suppress calcification of rat aortic SMCs cultivated in high-phosphate media. BMP-2 inhibited the expression of miR-30b and miR-30c in vitro, and miR-30b expression was likewise inhibited in calcified human coronary arteries. MiR-29 a/b expression was shown to be low in calcific aortas from mice as well as CKD patients. The Wnt pathways are a collection of signal transduction pathways that include the canonical Wnt pathway as well as the non-canonical Wnt/calcium pathway. When Wnt ligands (e.g., Wnt1, Wnt3a) bind to their receptors, cell-surface Frizzled (FZD) and low density-lipoproteinreceptor- related protein 5/6 (LRP 5/6), the canonical Wnt signalling pathway is activated. When the FZD/LRP 5/6 receptor complex is activated, GSK-3b is inactivated, and -catenin accumulates in the cytoplasm and translocates to the nucleus, where it can heterodimerize with members of the lymphoid enhancer factor/T-cell factor transcription factor family to induce the expression of specific genes. Clinical investigations have revealed that diabetics have a high risk of vascular calcification, and valve failure is a more severe disease. High blood glucose and carbohydrate metabolic products such as AGEs can harm human cells, including endothelial cells, by activating numerous signalling pathways (e.g., PI3K and JAK/STAT) and downstream factors (e.g., RANK). Hypertension was seen in almost 70% of the CKD patients studied in China, and blood pressure regulation was inadequate. Hypertension-induced vasospasm contraction and endothelial dysfunction might impair the synthesis and release of vascular dilators, worsening the endothelium-dependent vasodilator response system. Pathological investigations of aortic valve disorders revealed that the most prominent pathological features are lipidosis and inflammatory infiltration. As a result, hyperlipemia, hypertension, and diabetes can all cause endothelial dysfunction, which can then lead to valvular and vascular calcification. Inflammation and reactive oxygen species (ROS) are two prevalent diseases related with CVC in CKD patients. Inflammatory cytokines such as the interleukin-6 (IL-6) and TNF superfamilies, as well as the inflammation-related transcription factor NF-B, have been shown to increase calcification in cultured VICs, VSMCs, and experimental animal models. Leskinen et colleagues. discovered that IL-6 levels in CKD patients are risk factors for valvular calcification. Moreover, TNF production may stimulate the Wnt signalling pathway, leading CVC. Miller et al. found that individuals with aortic valve calcification had a higher hydrogen peroxide level than the control group, indicating that hydrogen peroxide-mediated oxidative stress may play a major role in CVC.

Discussion

Many CKD patients have arterial or valvular calcification, which has a significant impact on their survival chances. There are currently relatively few alternatives for either preventing or treating arterial or valvular calcification in CKD.

Conclusion

Despite recent advances in understanding of the processes of ectopic calcification, further research and understanding of this complex process is required, particularly the interplay between VECs and VICs and their regulatory mechanisms in the development of valve calcification. Only by better understanding the mechanism of vascular and valvular calcification will we be able to develop more effective treatments for CKD patients.

Acknowledgement

Not applicable.

Conflict of Interest

Author declares no conflict of interest.

1. London GM (2013) Mechanisms of arterial calcifications and consequences for cardiovascular function. Kidney Int Suppl 3:442-445.

Indexed at, Google Scholar, Crossref

2. London GM, Guérin AP, MarchaisSJ, Métivier F, Pannier B, et al. (2003) Arterial media calcification in end-stage renal disease: impact on all-cause and cardiovascular mortality. Nephrol Dial Transplant 18:1731-1740.

Indexed at, Google Scholar, Crossref

3. Wang AY, Ho SS, Wang M, Liu EK, Ho S, et al. (2005) Cardiac valvular calcification as a marker of atherosclerosis and arterial calcification in end-stage renal disease. Arch Intern Med 165:327-332.

Indexed at, Google Scholar, Crossref

4. Hruska KA, Mathew S, Lund RJ, Menom I, Saab G, et al. (2009) The pathogenesis of vascular calcification in the chronic kidney disease mineral bone disorder: the links between bone and the vasculature. Semin Nephrol 29:156-165.

Indexed at, Google Scholar, Crossref

5. Drüeke TB, Massy ZA (2010) Atherosclerosis in CKD: differences from the general population. Nat Rev Nephrol 6:723-735.

Indexed at, Google Scholar, Crossref

6. Masho Y, Shigematsu T (2007) Arteriosclerosis and vascular calcification in chronic kidney disease (CKD) patients. Clin Calcium 17:354-359.

Indexed at, Google Scholar                

7. Leopold JA (2012) Cellular mechanisms of aortic valve calcification. Circ Cardiovasc Interv 5:605-614.

Indexed at, Google Scholar, Crossref

8. Olauson H, Vervloet MG, Cozzolino M, Massy ZA, Urena Torres P, et al. (2014) New insights into the FGF23-Klotho axis. Semin Nephrol 34:586-597.

Indexed at, Google Scholar, Crossref

9. Messa P (2014) FGF23 and vascular calcifications: another piece of the puzzle?. Nephrol Dial Transplant 29:1447-1449.

Indexed at, Google Scholar, Crossref

10. Moe SM (2012) Klotho: a master regulator of cardiovascular disease?. Circulation 125:2181-2183.

Indexed at, Google Scholar, Crossref

11. Kuro-o M (2012) Klotho in health and disease. Curr Opin Nephrol Hypertens 21:362-368.

Indexed at, Google Scholar, Crossref

12. Urakawa I, Yamazaki Y, Shimada T, Iijima K, Hasegawa H, et al. (2006) Klotho converts canonical FGF receptor into a specific receptor for FGF23. Nature 444:770-774.

Indexed at, Google Scholar, Crossref

13. Kitagawa M, Sugiyama H, Morinaga H, Inoue T, Takiue K, et al. (2013) A decreased level of serum soluble Klotho is an independent biomarker associated with arterial stiffness in patients with chronic kidney disease. PLoS One 8:6695.

Indexed at, Google Scholar, Crossref

14. Van Ark J, Hammes HP, Van Dijk MC, Lexis CP, Van Der Horst IC, et al. (2013) Circulating alpha-klotho levels are not disturbed in patients with type 2 diabetes with and without macrovascular disease in the absence of nephropathy. Cardiovasc Diabetol 12:116.

Indexed at, Google Scholar, Crossref

15. Zhu D, Mackenzie NC, Millan JL, Farquharson C, MacRae VE, et al. (2013) A protective role for FGF-23 in local defence against disrupted arterial wall integrity?. Mol Cell Endocrinol 372:1-11.

Indexed at, Google Scholar, Crossref

16. Ozkok A, Kekik C, Karahan GE, Sakaci T, Ozel A, et al. (2013) FGF-23 associated with the progression of coronary artery calcification in hemodialysis patients. BMC Nephrol 14: 241.

Indexed at, Google Scholar, Crossref

17. Yilmaz G, Ustundag S, Temizoz O, Sut N, Demir M, et al. (2015) Fibroblast Growth Factor-23 and Carotid Artery Intima Media Thickness in Chronic Kidney Disease. Clin Lab 61:1061-1070.

Indexed at, Google Scholar, Crossref

18. Rastogi A (2013) Sevelamer revisited: pleiotropic effects on endothelial and cardiovascular risk factors in chronic kidney disease and end-stage renal disease. Ther Adv Cardiovasc Dis 7:322-342.

Indexed at, Google Scholar, Crossref

19. Lau WL, Leaf EM, Hu MC, Takeno MM, Kuro-o M, et al. (2012) 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 82:1261-1270.

Indexed at, Google Scholar, Crossref

20. Watson KE, Abrolat ML, Malone LL, Hoeg JM, Doherty T, et al. (1997) Active serum vitamin D levels are inversely correlated with coronary calcification. Circulation 96:1755-1760.

Indexed at, Google Scholar, Crossref

21. Vervloet MG, Adema AY, Larsson TE, Massy ZA (2014) The role of klotho on vascular calcification and endothelial function in chronic kidney disease. Semin Nephrol 34:578-585.

Indexed at, Google Scholar, Crossref