Vascular Calcification: An Important Understanding in Nephrology

Abstract

Vascular calcification (VC) is a life-threatening state in chronic kidney disease (CKD). High cardiovascular mortality and morbidity of CKD cases may root from medial VC promoted by hyperphosphatemia. Vascular calcification is an active, highly regulated, and complex biological process that is mediated by genetics, epigenetics, dysregulated form of matrix mineral metabolism, hormones, and the activation of cellular signaling pathways. Moreover, gut microbiome as a source of uremic toxins (eg, phosphate, advanced glycation end products and indoxyl-sulfate) can be regarded as a potential contributor to VC in CKD. Here, an update on different cellular and molecular processes involved in VC in CKD is discussed to elucidate the probable therapeutic pathways in the future.

Keywords: CKD; calcification; chronic kidney disease; hyperphosphatemia; uremia; uremic toxins.

Figure 1

Schematic view of vascular calcification in CKD. (A) As renal function continues to fall, normal defense mechanisms for Pi and Ca homeostasis (PTH, FGF-23, and klotho) become overwhelmed and the endocrine system of FGF23-klotho-VitaminD and RAAS is disturbed. As a result of nephron loss and higher levels of FGF-23, 1α-hydroxylase activity is diminished in the kidney, leading to elevated levels of inhibitor of this enzyme (FGF-23) and a decrease in 1,25(OH)2-vitamin D (calcitriol) production that, in turn, upregulates the production of renin in the kidney. Subsequently, the elevated levels of angiotensin II lead to kidney klotho loss, disruption of FGF-23 signaling, and the impairment of phosphaturia. Elevated levels of FGF-23 may activate the RAAS either by suppressing ACE-2 directly or decreasing calcitriol levels indirectly. (B) Ca and Pi deposition in the VSMCs of medial layers may cause VC. (C) In the intimal calcification process, more diverse cells are involved including osteoclast-like cells, Gli1⁺-MSCs of the adventitia, and CCCs. The interaction of different factors and these cells causes atherosclerosis. Uremic toxins cause VSMCs trans-differentiation into osteoblast-like cells. In the process of calcification, macrophage differentiation into osteoclast-like cells is inhibited. In turn, macrophages increase apoptosis and accumulation of apoptotic bodies through transition into foam cells. A pro-inflammatory form of circulating monocytes (M1 macrophages) promotes the initial calcium deposition within the necrotic core of the lesions. All the above factors together cause atherosclerosis. For more details, see the full text. Abbreviations: CKD, chronic kidney disease; FGF-23, fibroblast growth factor-23; PTH, parathyroid hormone; VC, vascular calcification; MMPs, matrix metalloproteinases; DH-VitD, 1, 25-dihydroxyvitamin D. Gli1⁺-MSCs, Gli1⁺ mesenchymal stem cells; CCCs, calcifying circulating cells; ACE-2, angiotensin-converting enzyme-2; RAAS, renin-angiotensin-aldosterone system; HA, hydroxyapatite crystal; ECs, endothelial cells; MQ, macrophage; IS, indoxyl-sulfate; VSMC, vascular smooth muscle cell; OS, oxidative stress.

Figure 2

The impact of uremic toxins on CKD-induced VSMC dysfunction and VC. Due to hyperphosphatemia, hypercalcemia, elevated oxidative stress, and inflammation, VSMCs manifest dysregulated functions and phenotype. Uremic toxins including Pi, IS, AGEs, IL-1β, IL-6, and TNF-α are involved in CV. (A) IL-1β, IL-6, and TNF-α induce osteoblast-like trans-differentiation of VSMCs through different mechanisms. Interaction of AGEs with their receptor (RAGE) induces the expression of Pit-1 via ROS production and leads to osteogenic transition. It also causes apoptosis through NAD(P)H oxidase-derived oxidative stress. (B) In CKD, normal Ca homeostasis is also dysregulated. This homeostasis is mediated by klotho, PTH, active vitamin D metabolites, and calcitonin. In VSMCs, Ca signaling is mediated by Ca channels, CaR, and pumps that maintain Ca concentrations in these cells. Higher level of extracellular Ca is associated with the release of MVs and cell death promotion and release of apoptotic bodies. (C) Extracellular Pi, as a signaling molecule, can trigger numerous changes in VSMCs through regulating different molecular pathways. NPP1 is responsible for extracellular ATP degradation to AMP and PPi, CD73 degrades AMP to adenosine and Pi and TNAP breaks PPi into phosphate and adenosine. Higher Pi level simultaneously upregulates the expression of osteo/chondrogenic genes (Runx2, ALP, OPN, and osterix) and downregulates VSMCs genes (SM22α and αSMA). ALP controls vascular matrix mineralization by degradation and inactivation of the VC inhibitors (PPi and P-OPN) to allow uncontrolled tissue mineralization and simultaneously releasing free Pi. These osteo-/chondroblast-like cells actively induce apoptosis and vesicle release, a reduction in calcification inhibitors, elastin degradation, increased ECM remodeling, and a pro-inflammatory state. Moreover, under high levels of Pi, VSMCs synthesize collagen at high amount and provide a collagen-enriched ECM. Downregulation of Gas6 and Bcl2 may be the basic mechanism of VSMCs apoptosis. The released apoptotic bodies provide a further nidus for deposition of Pi and Ca. For more details, see the full text. Abbreviations: Ca, calcium; Pi, phosphate; PPi, pyrophosphate; ECM, extracellular matrix; MMP, matrix metalloproteinases; Gas6, growth arrest-specific gene 6; ALP, alkaline phosphatase; ROS, reactive oxygen species; SM, α-smooth muscle actin; CPPs, calciprotein particles; CaR, Ca sensing receptor; MVs, matrix vesicles; AGEs, advanced glycation end products; RAGE, receptor for advanced glycation end products.