Similarities and Differences of Vascular Calcification in Diabetes and Chronic Kidney Disease

Abstract

Presently, the mechanism of occurrence and development of vascular calcification (VC) is not fully understood; a range of evidence suggests a positive association between diabetes mellitus (DM) and VC. Furthermore, the increasing burden of central vascular disease in patients with chronic kidney disease (CKD) may be due, at least in part, to VC. In this review, we will review recent advances in the mechanisms of VC in the context of CKD and diabetes. The study further unveiled that VC is induced through the stimulation of pro-inflammatory factors, which in turn impairs endothelial function and triggers similar mechanisms in both disease contexts. Notably, hyperglycemia was identified as the distinctive mechanism driving calcification in DM. Conversely, in CKD, calcification is facilitated by mechanisms including mineral metabolism imbalance and the presence of uremic toxins. Additionally, we underscore the significance of investigating vascular alterations and newly identified molecular pathways as potential avenues for therapeutic intervention.

Keywords: chronic kidney disease; diabetes mellitus; vascular calcification.

Graphical abstract

Figure 1

Mechanism of oxidative stress promoting vascular calcification in diabetes. In the environment of diabetes, AGEs bind to advanced glycosylation receptor (RAGE), which activates NF-kB and promotes vascular calcification by enhancing the expression of VEGF, VCAM-1 and other genes. PKC pathway increases ROS level of endothelial cells by reducing NO production.Oxidative stress promotes VC by activating p21, JNK, p38 and NF-kB. ROS excess inhibits insulin gene transcription by opening ATP-sensitive K+channels, thus inhibiting insulin production and secretion. Oxidative stress promotes VC by activating p21, JNK, p38 and NF-kB. Upregulation of SIRT1 in VSMC leads to downregulation of endoplasmic reticulum (ER) stress signal transduction components, regulating SIRT1 and ER stress signals to inhibit arterial calcification in CKD. Graphics by Figdraw.

Figure 2

Mechanism of calcium and phosphorus imbalance in chronic kidney disease. (A) In the environment of chronic kidney disease, the decline of renal function leads to the dysfunction of P excretion and the increase of serum Pi level, and the decrease of 1.25(OH)2D3 secretion leads to the decrease of serum Ca level. At the same time, renal injury changes the intestinal microenvironment and reduces the absorption of Ca. In addition, in the environment of chronic kidney disease, hyperparathyroidism and increased PTH levels can not only promote the activity of osteoblasts and osteoclasts, thereby promoting calcification, but also increase the serum Pi level and promote changes in the intestinal microenvironment. (B) PTH, FGF-23, Klotho, and 1,25D have feedback loops to maintain calcium and phosphorus homeostasis. (C) In the environment of chronic kidney disease, the hormone levels of PTH, 1,25D and FGF-23 are dysregulated, thereby increasing the osteogenic activity of osteoclasts and promoting vascular calcification. Graphics by Figdraw.

Figure 3

Uremic toxin and intestinal flora disorder. Lipopolysaccharide and short chain fatty acid imbalance, promote intestinal flora disorder, promote intestinal microorganisms and uremic toxins to destroy intestinal barrier. Uremic toxins such as IS increase TNF-α and IL-6, leading to an increased inflammatory state by promoting oxidative stress. Graphics by Figdraw.