Uraemic hyperparathyroidism causes a reversible inflammatory process of aortic valve calcification in rats

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Abstract

Aims

Renal failure is associated with aortic valve calcification (AVC). Our aim was to develop an animal model for exploring the pathophysiology and reversibility of AVC, utilizing rats with diet-induced kidney disease.

Methods and results

Sprague–Dawley rats ( n = 23) were fed a phosphate-enriched, uraemia-inducing diet for 7 weeks followed by a normal diet for 2 weeks (‘diet group’). These rats were compared with normal controls ( n = 10) and with uraemic controls fed with phosphate-depleted diet (‘low-phosphate group’, n = 10). Clinical investigations included serum creatinine, phosphate and parathyroid hormone (PTH) levels, echocardiography, and multislice computed tomography. Pathological examinations of the valves included histological characterization, Von Kossa staining, and antigen and gene expression analyses. Eight diet group rats were further assessed for reversibility of valve calcification following normalization of their kidney function. At 4 weeks, all diet group rats developed renal failure and hyperparathyroidism. At week 9, renal failure resolved with improvement in the hyperparathyroid state. Echocardiography demonstrated valve calcifications only in diet group rats. Tomographic calcium scores were significantly higher in the diet group compared with controls. Von Kossa stain in diet group valves revealed calcium deposits, positive staining for osteopontin, and CD68. Gene expression analyses revealed overexpression of osteoblast genes and nuclear factor κB activation. Valve calcification resolved after diet cessation in parallel with normalization of PTH levels. Resolution was associated with down-regulation of inflammation and osteoblastic features. Low-phosphate group rats developed kidney dysfunction similar to that of the diet group but with normal levels of PTH. Calcium scores and histology showed only minimal valve calcification.

Conclusion

We developed an animal model for AVC. The process is related to disturbed mineral metabolism. It is associated with inflammation and osteoblastic features. Furthermore, the process is reversible upon normalization of the mineral homeostasis. Thus, our model constitutes a convenient platform for studying AVC and potential remedies.

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Most cited references 33

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S C Manolagas, R L Jilka (1995)

Both osteoblasts and osteoclasts are derived from progenitors that reside in the bone marrow; osteoblasts belong to the mesenchymal lineage of the marrow stroma, and osteoclasts to the hematopoietic lineage. The development of osteoclasts from their progenitors is dependent on stromal-osteoblastic cells, which are a major source of cytokines that are critical in osteoclastogenesis, such as interleukin-6 and interleukin-11. The production of interleukin-6 by stromal osteoblastic cells, as well as the responsiveness of bone marrow cells to cytokines such as interleukin-6 and interleukin-11, is regulated by sex steroids. When gonadal function is lost, the formation of osteoclasts as well as osteoblasts increases in the marrow, both changes apparently mediated by an increase in the production of interleukin-6 and perhaps by an increase in the responsiveness of bone marrow progenitor cells not only to interleukin-6 but also to other cytokines with osteoclastogenic and osteoblastogenic properties. The cellular activity of the bone marrow is also altered by the process of aging. Specifically, senescence may decrease the ability of the marrow to form osteoblast precursors. The association between the dysregulation of osteoclast or osteoblast development in the marrow and the disruption of the balance between bone resorption and bone formation, resulting in the loss of bone, leads to the following notion. Like homeostasis of other regenerating tissues, homeostasis of bone depends on the orderly replenishment of its cellular constituents. Excessive osteoclastogenesis and inadequate osteoblastogenesis are responsible for the mismatch between the formation and resorption of bone in postmenopausal and age-related osteopenia. The recognition that changes in the numbers of bone cells, rather than changes in the activity of individual cells, form the pathogenetic basis of osteoporosis is a major advance in understanding the mechanism of this disease.

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Vitamin D: its role and uses in immunology.

Margherita T. Cantorna, Stephanie H. DeLuca (2001)

In recent years there has been an effort to understand possible noncalcemic roles of vitamin D, including its role in the immune system and, in particular, on T cell-medicated immunity. Vitamin D receptor is found in significant concentrations in the T lymphocyte and macrophage populations. However, its highest concentration is in the immature immune cells of the thymus and the mature CD-8 T lymphocytes. The significant role of vitamin D compounds as selective immunosuppressants is illustrated by their ability to either prevent or markedly suppress animal models of autoimmune disease. Results show that 1,25-dihydroxyvitamin D3 can either prevent or markedly suppress experimental autoimmune encephalomyelitis, rheumatoid arthritis, systemic lupus erythematosus, type I diabetes, and inflammatory bowel disease. In almost every case, the action of the vitamin D hormone requires that the animals be maintained on a normal or high calcium diet. Possible mechanisms of suppression of these autoimmune disorders by the vitamin D hormone have been presented. The vitamin D hormone stimulates transforming growth factor TGFbeta-1 and interleukin 4 (IL-4) production, which in turn may suppress inflammatory T cell activity. In support of this, the vitamin D hormone is unable to suppress a murine model of the human disease multiple sclerosis in IL-4-deficient mice. The results suggest an important role for vitamin D in autoimmune disorders and provide a fertile and interesting area of research that may yield important new therapies.

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Multimodality molecular imaging identifies proteolytic and osteogenic activities in early aortic valve disease.

Gabriel T M Lok, Masanori Aikawa, Elena Aikawa … (2007)

Visualizing early changes in valvular cell functions in vivo may predict the future risk and identify therapeutic targets for prevention of aortic valve stenosis. To test the hypotheses that (1) aortic stenosis shares a similar pathogenesis to atherosclerosis and (2) molecular imaging can detect early changes in aortic valve disease, we used in vivo a panel of near-infrared fluorescence imaging agents to map endothelial cells, macrophages, proteolysis, and osteogenesis in aortic valves of hypercholesterolemic apolipoprotein E-deficient mice (30 weeks old, n=30). Apolipoprotein E-deficient mice with no probe injection (n=10) and wild-type mice (n=10) served as controls. Valves of apolipoprotein E-deficient mice contained macrophages, were thicker than wild-type mice (P<0.001), and showed early dysfunction detected by MRI in vivo. Fluorescence imaging detected uptake of macrophage-targeted magnetofluorescent nanoparticles (24 hours after injection) in apolipoprotein E-deficient valves, which was negligible in controls (P<0.01). Valvular macrophages showed proteolytic activity visualized by protease-activatable near-infrared fluorescence probes. Ex vivo magnetic resonance imaging enhanced with vascular cell adhesion molecule-1-targeted nanoparticles detected endothelial activation in valve commissures, the regions of highest mechanical stress. Osteogenic near-infrared fluorescence signals colocalized with alkaline phosphatase activity and expression of osteopontin, osteocalcin, Runx2/Cbfa1, Osterix, and Notch1 despite no evidence of calcium deposits, which suggests ongoing active processes of osteogenesis in inflamed valves. Notably, the aortic wall contained advanced calcification. Quantitative image analysis correlated near-infrared fluorescence signals with immunoreactive vascular cell adhesion molecule-1, macrophages, and cathepsin-B (P<0.001). Molecular imaging can detect in vivo the key cellular events in early aortic valve disease, including endothelial cell and macrophage activation, proteolytic activity, and osteogenesis.

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Author and article information

Journal

Journal ID (nlm-ta): Cardiovasc Res

Journal ID (publisher-id): cvrese

Journal ID (hwp): cardiovascres

Title: Cardiovascular Research

Publisher: Oxford University Press

ISSN (Print): 0008-6363

ISSN (Electronic): 1755-3245

Publication date (Print): 1 August 2008

Publication date (Electronic): 5 April 2008

Publication date PMC-release: 5 April 2008

Volume: 79

Issue: 3

Pages: 492-499

Affiliations

[1 ]Cardiovascular Research Center, Heart Institute, Hadassah-Hebrew University Medical Center, Ein Karem , PO Box 12000, Jerusalem 91120, Israel

[2 ]Minerva Center for Calcium and Bone Metabolism, Hadassah-Hebrew University Medical Center , Jerusalem, Israel

[3 ]Department of Pathology, Hadassah-Hebrew University Medical Center , Jerusalem, Israel

[4 ]Department of Radiology, Hadassah-Hebrew University Medical Center , Jerusalem, Israel

Author notes

[* ]Corresponding author. Tel: +972 26776451; fax: +972 26778190. E-mail address: monysh@ 123456gmail.com

Article

Publisher ID: cvn088

DOI: 10.1093/cvr/cvn088

PMC ID: 2492726

PubMed ID: 18390899

SO-VID: 733502cc-258a-4d3b-8579-b87bd0e0c8a1

License:

The online version of this article has been published under an open access model. Users are entitled to use, reproduce, disseminate, or display the open access version of this article for non-commercial purposes provided that the original authorship is properly and fully attributed; the Journal, Learned Society and Oxford University Press are attributed as the original place of publication with correct citation details given; if an article is subsequently reproduced or disseminated not in its entirety but only in part or as a derivative work this must be clearly indicated. For commercial re-use, please contact journals.permissions@oxfordjournals.org.

History

Date received : 6 December 2007

Date revision received : 9 March 2008

Date accepted : 26 March 2008

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primary-review-time Time for primary review: 35 days

ScienceOpen disciplines: Cardiovascular Medicine

Keywords: nfκb pathway,renal failure,calcification,aortic valve,reversibility

Data availability:

ScienceOpen disciplines: Cardiovascular Medicine

Keywords: nfκb pathway, renal failure, calcification, aortic valve, reversibility

Uraemic hyperparathyroidism causes a reversible inflammatory process of aortic valve calcification in rats

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Abstract

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Methods and results

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Karger: Nephrology

Most cited references 33

Bone marrow, cytokines, and bone remodeling. Emerging insights into the pathophysiology of osteoporosis.

Vitamin D: its role and uses in immunology.

Multimodality molecular imaging identifies proteolytic and osteogenic activities in early aortic valve disease.

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