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

Mony Shuvy*, Suzan Abedat, Ronen Beeri, Haim D. Danenberg, David Planer, Iddo Z. Ben-Dov, Karen Meir, Jacob Sosna, Chaim Lotan

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

33 Scopus citations

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.

Original languageAmerican English
Pages (from-to)492-499
Number of pages8
JournalCardiovascular Research
Volume79
Issue number3
DOIs
StatePublished - Aug 2008
Externally publishedYes

Bibliographical note

Funding Information:
The Chief Scientist Office of the Ministry of Health, Israel, the Berman Foundation for Cardiovascular Research of Hadassah Medical Center, the Joint Research Fund of the Hebrew University and Hadassah Medical Center.

Keywords

  • Aortic valve
  • Calcification
  • NFκB pathway
  • Renal failure
  • Reversibility

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