Vascular Calcification in Animal Models of CKD: A Review

Shobeiri, Navid; Adams, Michael; Holden, Rachel M.

doi:10.1159/000299794

Cited by 126 publications

(137 citation statements)

References 113 publications

Supporting

Mentioning

130

Contrasting

Unclassified

Order By: Relevance

“…Plaque composition in uremic apoE -/-mice demonstrates macrophage infiltration, increased cholesterol, collagen, and calcium content than classical atherosclerosis (96). Although we did not observe more than minimal changes in serum calcium and phosphate, this model and the apoE -/-model nonetheless exhibit significantly increased vascular calcification demonstrated in prior work by other groups (59,60,(96)(97)(98)(99).In conclusion, our study demonstrates for the first time that increased MPO levels and activity co-localizes with lesional macrophages in the artery wall in a mouse model of CKD-atherosclerosis. In addition to decreased cholinergic response in the vessel, our work suggests that MPO expression and activity may play an important role in the propagation of atherosclerotic lesions in CKD mice.…”

supporting

confidence: 63%

Section: Discussioncontrasting

confidence: 43%

See 1 more Smart Citation

Myeloperoxidase-derived oxidants damage artery wall proteins in an animal model of chronic kidney disease–accelerated atherosclerosis

Zeng

Mathew

Byun

et al. 2018

Journal of Biological Chemistry

View full text Add to dashboard Cite

Increased myeloperoxidase (MPO) levels and activity are associated with increased cardiovascular risk among individuals with chronic kidney disease (CKD). However, a lack of good animal models for examining the presence and catalytic activity of MPO in vascular lesions has impeded mechanistic studies into CKD-associated cardiovascular diseases. Here, we show for the first time that exaggerated atherosclerosis in a pathophysiologically relevant CKD mouse model is associated with increased macrophage-derived MPO activity. Male 7-week-old LDL receptordeficient mice underwent sham (control mice) or 5/6 nephrectomy and were fed either a low-fat or high-fat, high-cholesterol diet for 24 weeks, and the extents of atherosclerosis and vascular reactivity were assessed. MPO expression and oxidation products, and the protein-bound oxidized tyrosine moieties 3-chlorotyrosine, 3-nitrotyrosine, and o,o′-dityrosine were examined with immunoassays and confirmed with mass spectrometry (MS). As anticipated, the CKD mice had significantly higher plasma creatinine, urea nitrogen, and intact parathyroid hormone along with lower hematocrit and body weight. On both the diet regimens, CKD mice did not have hypertension but had lower cholesterol and triglyceride levels than the control mice. Despite the lower cholesterol levels, CKD mice had increased aortic plaque areas, fibrosis, and luminal narrowing. They also exhibited increased MPO expression and activity (i.e., increased oxidized tyrosines) that co-localized with infiltrating lesional macrophages and diminished vascular reactivity. In summary, unlike non-CKD mouse models of atherosclerosis, CKD mice exhibit increased MPO expression and catalytic activity in atherosclerotic lesions, which colocalize with lesional macrophages. These results implicate macrophage-derived MPO in CKDaccelerated atherosclerosis.Chronic kidney disease (CKD) affects 15% of Americans, and cardiovascular disease (CVD) continues to be the leading cause of mortality in Myeloperoxidase oxidizes artery proteins in kidney disease2 these patients (>10-fold mortality compared to the general population) (1-6). An increased risk for CVD is evident even in milder and non-albuminuric forms of CKD and cannot be fully explained by traditional risk factors (7-10). Furthermore, control of established risk factors such as hyperlipidemia results in substantially lower risk reduction in CKD patients compared to the general population (11). Recent evidence supports the key role of nontraditional risk factors (e.g., oxidative stress) in the pathogenesis of CVD in CKD (12-17), suggesting that CKD-specific mechanisms are responsible for CVD in kidney patients.Atherosclerosis, the major cause of CVD, is a chronic inflammatory disease characterized by the infiltration of lipids and inflammatory cells, such as monocyte-derived macrophages and Tlymphocytes, into the artery wall (18). While elevated levels of low-density lipoprotein (LDL) are known to increase the risk of atherosclerosis greatly (19), in vitro studies sugges...

show abstract

supporting

confidence: 63%

Section: Discussioncontrasting

confidence: 43%

Myeloperoxidase-derived oxidants damage artery wall proteins in an animal model of chronic kidney disease–accelerated atherosclerosis

Zeng

Mathew

Byun

et al. 2018

Journal of Biological Chemistry

View full text Add to dashboard Cite

show abstract

“…Hence, the fragmentation of elastic lamellae that was observed in aortas of A-CRF animals may be a factor causing increased vascular stiffness. In our model of A-CRF the vast majority of rats do not develop aortic media calcifications in contrast to rats in other studies (27), in which adenine often has been used specifically to cause severe alterations in mineral and bone metabolism accompanied by vascular calcifications. The discrepant findings are likely explained by the higher concentration of adenine in the chow (0.75%), which routinely has been used by others, leading to more severe renal failure and more pronounced hyperphosphatemia and hyperparathyroidism (27).…”

Section: Discussionmentioning

confidence: 63%

Rats with adenine-induced chronic renal failure develop low-renin, salt-sensitive hypertension and increased aortic stiffness

Nguy

Johansson

Grimberg

et al. 2013

American Journal of Physiology-Regulatory, Integrative and Comp

View full text Add to dashboard Cite

Guron G. Rats with adenine-induced chronic renal failure develop low-renin, salt-sensitive hypertension and increased aortic stiffness. Am J Physiol Regul Integr Comp Physiol 304: R744 -R752, 2013. First published March 20, 2013 doi:10.1152/ajpregu.00562.2012.-Rats with adenine-induced chronic renal failure (A-CRF) develop metabolic and cardiovascular abnormalities resembling those in patients with chronic kidney disease. The aim of this study was to investigate the mechanisms of hypertension in this model and to assess aortic stiffness in vivo. Male Sprague-Dawley rats were equipped with radiotelemetry probes for arterial pressure recordings and received either chow containing adenine or normal control diet. At 7 to 11 wk after study start, blood pressure responses to high NaCl (4%) diet and different pharmacological interventions were analyzed. Aortic pulse wave velocity was measured under isoflurane anesthesia. Baseline 24-h mean arterial pressure (MAP) was 101 Ϯ 10 and 119 Ϯ 9 mmHg in controls and A-CRF animals, respectively (P Ͻ 0.01). After 5 days of a high-NaCl diet, MAP had increased by 24 Ϯ 6 mmHg in A-CRF animals vs. 2 Ϯ 1 mmHg in controls (P Ͻ 0.001). Candesartan (10 mg/kg by gavage) produced a more pronounced reduction of MAP in controls vs. A-CRF animals (Ϫ12 Ϯ 3 vs. Ϫ5 Ϯ 5 mmHg, P Ͻ 0.05). Aortic pulse wave velocity was elevated in A-CRF rats (5.10 Ϯ 0.51 vs. 4.58 Ϯ 0.17 m/s, P Ͻ 0.05). Plasma levels of creatinine were markedly elevated in A-CRF animals (259 Ϯ 46 vs. 31 Ϯ 2 M, P Ͻ 0.001), whereas plasma renin activity was suppressed (0.6 Ϯ 0.5 vs. 12.3 Ϯ 7.3 g·l Ϫ1 ·h Ϫ1 , P Ͻ 0.001). In conclusion, hypertension in A-CRF animals is characterized by low plasma renin activity and is aggravated by high-NaCl diet, suggesting a pathogenic role for sodium retention and hypervolemia probably secondary to renal insufficiency. Additionally, aortic stiffness was elevated in A-CRF animals as indicated by increased aortic pulse wave velocity. chronic kidney disease; adenine; hypertension; pulse wave velocity; aortic stiffness CARDIOVASCULAR (CV) DISEASE is the major cause of morbidity and mortality in patients with chronic kidney disease (CKD) (26). There is a graded and inverse relationship between estimated glomerular filtration rate (GFR) and CV risk that is apparent already when GFR falls below 60 ml·min Ϫ1 ·1.73 m 2 (8), and the majority of CKD patients die from CV events before developing end-stage renal disease (25). Although the pathophysiological mechanisms causing increased CV risk in CKD are complex, elevated aortic pulse wave velocity (PWV), a measure of aortic stiffness, is per se an independent powerful predictor of CV death in patients with end-stage renal disease (1). In CKD patients, aortic PWV has been shown to be correlated to vascular calcification indices (14,23,29), which, in turn, are associated with disorders in bone and mineral metabolism that develop with declining GFR (15). However, increased aortic PWV is associated with mortality also in patient groups with normal kidney function...

show abstract

“…2,4,23 Rats in the CRF model underwent 5/6 nephrecto- mization and received a high-phosphate diet to accelerate the process of vascular calcification. 24 Based on Online Table II, CRF rats showed a significant increase in plasma level of blood urea nitrogen, creatinine, and phosphorus. Vascular calcification was successfully induced in the CRF rats, as evidenced by calcium deposition and von Kossa staining, with no calcification in sham-operated rats (Online Figure III).…”

Section: Comp Protein Level Is Decreased In Calcifying Vsmcs and Artementioning

confidence: 99%

Cartilage Oligomeric Matrix Protein Inhibits Vascular Smooth Muscle Calcification by Interacting With Bone Morphogenetic Protein-2

Wang

et al. 2011

Circulation Research

103

105

View full text Add to dashboard Cite

Rationale: Vascular calcification is a significant contributor to cardiovascular morbidity and mortality. We recently reported that cartilage oligomeric matrix protein (COMP) is pivotal for maintaining the homeostasis of vascular smooth muscle cells (VSMCs). Whether COMP affects the process of vascular calcification is unknown.Objective: We aimed to test whether COMP modulates vascular calcification. Methods and Results: VSMC calcification in vitro was induced by calcifying media containing high inorganic phosphate or calcium. In vivo medial vessel calcification was induced in rats by 5/6 nephrectomy with a high-phosphate diet or by periadventitial application of CaCl 2 to the abdominal aorta. COMP protein level was markedly reduced in both calcified VSMCs and arteries. COMP deficiency remarkably exacerbated VSMC calcification, whereas ectopic expression of COMP greatly reduced calcification. Furthermore, COMP knockdown facilitated osteogenic markers expression by VSMCs even in the absence of calcifying media. By contrast, COMP overexpression significantly inhibited high phosphate-or high calcium-induced VSMC osteochondrogenic transition. Induction of osteogenic marker expression by COMP silencing was reversed by a soluble form of bone morphogenetic protein (BMP)-2 receptor IA, which suggests a BMP-2-dependent mechanism. Our data revealed that COMP bound directly to BMP-2 through the C terminus, inhibited BMP-2 receptor binding, and blocked BMP-2 osteogenic signaling, indicating COMP inhibits osteochondrogenic transition of VSMCs at least partially through inhibiting BMP-2. V ascular calcification is a common complication of chronic kidney disease, atherosclerosis, and diabetes mellitus. 1,2 It is directly related to cardiovascular morbidity and mortality. 3,4 Previously viewed as an inevitable, passive, and degenerative process, vascular calcification is increasingly being considered a complex and regulated process, with great similarities to skeletal mineralization. 1,5,6 These findings have led to the important question of which cell types give rise to the skeletal elements of calcified arteries and what mechanisms regulate vascular calcification. To date, substantive studies have demonstrated that vascular smooth muscle cells (VSMCs) retain multipotential capability and can transform into osteo-/chondrocytic-like cells and express genes that are typically expressed by osteoblasts and chondrocytes during osteogenesis. [7][8][9][10] Several factors facilitate osteochondrogenic transition of VSMCs and vascular calcification, including high calcium-phosphate products, oxidative stress, bone morphogenetic proteins (BMPs) (BMP-2, -4, -6), and vitamin D. Alternatively, loss of inhibitors of mineralization, such as matrix Gla protein (MGP) and osteopontin, also predispose vascular calcification. 5,11,12 A finely tuned balance between inducers and inhibitors likely controls whether calcification occurs under pathological conditions. Other important mechanisms including apoptosis, mineral imbalOriginal received Oc...

show abstract

Vascular Calcification in Animal Models of CKD: A Review

Cited by 126 publications

References 113 publications

Myeloperoxidase-derived oxidants damage artery wall proteins in an animal model of chronic kidney disease–accelerated atherosclerosis

Myeloperoxidase-derived oxidants damage artery wall proteins in an animal model of chronic kidney disease–accelerated atherosclerosis

Rats with adenine-induced chronic renal failure develop low-renin, salt-sensitive hypertension and increased aortic stiffness

Cartilage Oligomeric Matrix Protein Inhibits Vascular Smooth Muscle Calcification by Interacting With Bone Morphogenetic Protein-2

Contact Info

Product

Resources

About