Systemic cardiovascular disease in uremic rats induced by 1,25(OH)2D3

Haffner, Dieter; Hocher, Berthold; Müller, Dominik; Simon, Katja; König, Kai; Richter, Claus-Michael; Eggert, Barbara; Schwarz, Johanna; Godes, Michael; Nissel, Richard; Querfeld, Uwe

doi:10.1097/01.hjh.0000166849.72721.1c

Cited by 100 publications

(84 citation statements)

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“…76 Diffuse, massive calcifications of the entire aortic wall, involving both the thoracic and abdominal part, develop in 1,25(OH) 2 vitamin D 3 -treated 5/6th nephrectomized rats with a mean calcified area of more than 50%. 74 This rat model for uremia-related arterial calcification shows a reproducible and comparable severe degree of medial calcifications in all rats.…”

Section: Remnant Kidney Ratmentioning

confidence: 71%

Vascular Calcification in Chronic Renal Failure

Neven

D’Haese

2011

Circulation Research

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Accelerated atherosclerotic plaque calcification and extensive medial calcifications are common and highly detrimental complications of chronic kidney disease. Valid murine models have been developed to investigate both pathologically distinguishable complications, which allow for better insight into the cellular mechanisms underlying these vascular pathologies and evaluation of compounds that might prevent or retard the onset or progression of vascular calcification. This review describes various experimental models that have been used for the study of arterial intimal and/or medial calcification and discusses the extent to which this experimental research has contributed to our current understanding of vascular calcification, particularly in the setting of chronic renal failure. (Circ Res. 2011;108:249-264.) Key Words: animal models Ⅲ vascular calcification Ⅲ chronic renal failure C ardiovascular disease is the main cause of morbidity and mortality in patients with chronic kidney disease (CKD), accounting for approximately 50% of all deaths in patients on dialysis and in recipients of renal transplants. 1 A large-scale prospective population-based study showed that renal function was inversely associated with cardiovascular and allcause mortality. 2 Vascular calcification is the major cause of cardiovascular disease in patients with CKD as it contributes to myocardial ischemia, impaired myocardial function, valvular insufficiency, arrhythmias and stroke and is shown to be a strong independent predictor of mortality in the general 3,4 as well as in the dialysis population. [5][6][7] In patients with endstage renal disease, the risk of death increases with the number of vascular sites affected by calcification in the aorta and the carotid and femoral arteries. 5 The high prevalence of vascular calcification is already reported in early stages of CKD 8,9 and in young dialysis patients. 10,11 Atherosclerotic plaque burden in the intimal layer is higher and these lesions are also more heavily calcified in CKD patients compared to the normal population. 12-14 Although intimal calcification is associated with cardiovascular mortality, 6 it remains controversial whether calcification of advanced atherosclerotic lesions stabilizes plaque vulnerability [15][16][17] or rather contributes to rupture of the fibrous cap, 18,19 leading to thrombotic events and myocardial infarction. Interestingly, Ehara et al 20 nicely showed that the pattern of calcification in the intimal plaque is of importance: small, frequent, spotty calcifications are more often found in patients with an acute myocardial infarction or with unstable angina pectoris, whereas the presence of extensive calcifications was highest in those with stable angina pectoris. Recent investigations add new insights to this observation and indicate that, in contrast to spacious calcified areas, sparse microcalcifications produce local stress, 21 activate macrophages to secrete inflammatory mediators 22 and induce apoptosis of vascular smooth muscle cells, 23...

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Section: Remnant Kidney Ratmentioning

confidence: 71%

Vascular Calcification in Chronic Renal Failure

Neven

D’Haese

2011

Circulation Research

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“…Computer-aided image analysis was performed as recently described (32). Briefly, for histologic evaluation, aortas were embedded in paraffin, cut in 3-m sections, and submitted to Elastica-van Gieson staining.…”

Section: Histologic Evaluationmentioning

confidence: 99%

Lack of Endothelial Nitric Oxide Synthase Promotes Endothelin-Induced Hypertension

Quaschning

Voß

Relle

et al. 2007

Journal of the American Society of Nephrology

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Endothelin-1 (ET-1) is one of the most potent biologic vasoconstrictors. Nevertheless, transgenic mice that overexpress ET-1 exhibit normal BP. It was hypothesized that vascular effects of ET-1 may be antagonized by an increase of the endothelial counterpart of ET-1, nitric oxide (NO), which is produced by the endothelial NO synthase (eNOS). Therefore, cross-bred animals of ET transgenic mice (ET؉/؉) and eNOS knockout (eNOS؊/؊) mice and were generated, and BP and endothelial function were evaluated in these animals. Endothelium-dependent and -independent vascular function was assessed as relaxation/contraction of isolated preconstricted aortic rings. The tissue ET and NO system was determined in aortic rings by quantitative real-time PCR and Western blotting. Systolic BP was similar in ET؉/؉ and wild-type (WT) mice but was significantly elevated in eNOS؊/؊ mice (117 ؎ 4 mmHg versus 94 ؎ 6 mmHg in WT mice; P < 0.001) and even more elevated in ET؉/؉ eNOS؊/؊ cross-bred mice (130 ؎ 4 mmHg; P < 0.05 versus eNOS؊/؊). Maximum endothelium-dependent relaxation was enhanced in ET؉/؉ mice (103 ؎ 6 versus 87 ؎ 4% of preconstriction in WT littermates; P < 0.05) and was completely blunted in eNOS؊/؊ (؊3 ؎ 4%) and ET؉/؉ eNOS؊/؊ mice (؊4 ؎ 4%), respectively. Endothelium-independent relaxation was comparable among all groups. T he intact endothelium produces a variety of vasoactive substances, such as nitric oxide (NO), thromboxane, and the 21-amino acid peptide endothelin-1 (ET-1). ET-1 is a potent vasoconstrictor (1) and mitogen in vivo and in vitro and exerts its biologic effects via activation of specific receptors: Whereas on vascular smooth muscle cells the predominant ET receptor is the ET A receptor (ET A R) subtype (2,3), contributing to long-lasting vasoconstriction, endothelial cells express the ET B receptor (ET B R), mediating the formation of NO (4) and prostacyclin (5) and featuring the pulmonary clearance of circulating ET-1 (6) as well as the reuptake of ET-1 by endothelial cells (7).Correspondingly, intravenous administration of ET-1 causes a rapid and transient vasodilation followed by a sustained increase in BP (8). In addition to the negative feedback loop via ET B R, ET-1 production in the vascular wall is inhibited by NO (9) and prostacyclin (10) via cGMP-dependent mechanisms. Therefore, the NO system may be considered as the functional counterpart of the ET system (11-16), thus warranting the sub-

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“…Furthermore, CKD progression exposes patients to a particular risk of developing both 25D and 1,25D deficiencies (17,18). In animal models, exogenous administration of supraphysiological doses of VDR activators has been associated with both the incidence and progression of vascular calcification (19,20), whereas the administration of VDR activators at more physiologic doses (i.e., just enough to correct secondary hyperparathyroidism) protect against aortic calcification (21). In a CKD setting, a recent study in adult hemodialysis patients described an association between 25D deficiency and arterial stiffness (13), whereas dialyzed children showed a bimodal association between 1,25D levels and vascular calcification and stiffness (22).…”

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confidence: 99%

Vitamin D Affects Survival Independently of Vascular Calcification in Chronic Kidney Disease

Barreto¹,

Barreto²,

Liabeuf³

et al. 2009

Clinical Journal of the American Society of Nephrology

146

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Results: There was a high prevalence of vitamin D deficiency (42%) and insufficiency (34%). Patients with 25D < 16.7 ng/ml (median) had a significantly lower survival rate than patients with 25D >16.7 ng/ml (mean follow-up, 605 ؎ 217 d; range, 10 to 889; P ‫؍‬ 0.05). Multivariate adjustments (included age, gender, diabetes, arterial pressure, CKD stage, phosphate, albumin, hemoglobin, aortic calcification score and PWV) confirmed 25D level as an independent predictor of all-cause mortality.Conclusions: Vitamin D deficiency and insufficiency were highly prevalent in this CKD cohort. Low 25D levels affected mortality independently of vascular calcification and stiffness, suggesting that 25D may influence survival in CKD patients via additional pathways that need to be further explored.

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Systemic cardiovascular disease in uremic rats induced by 1,25(OH)2D3

Abstract: Hypertension, left ventricular hypertrophy, aortic calcification, and aneurysm, without hypercalcemia, occurred in 1,25(OH)2D3-treated, 5/6 nephrectomized rats. These data indicate a permissive effect of uremia for cardiovascular damage induced by non-hypercalcemic doses of 1,25(OH)2D3.

Cited by 100 publications

References 35 publications

Vascular Calcification in Chronic Renal Failure

Vascular Calcification in Chronic Renal Failure

Lack of Endothelial Nitric Oxide Synthase Promotes Endothelin-Induced Hypertension

Vitamin D Affects Survival Independently of Vascular Calcification in Chronic Kidney Disease

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