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


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 kappaB 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.


CONCLUSIONS
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.
Shuvy
Mony
M
Cardiovascular Research Center, Heart Institute, Hadassah-Hebrew University Medical Center, Ein Karem, PO Box 12000, Jerusalem 91120, Israel. monysh@gmail.com
Abedat
Suzan
S
Beeri
Ronen
R
Danenberg
Haim D
HD
Planer
David
D
Ben-Dov
Iddo Z
IZ
Meir
Karen
K
Sosna
Jacob
J
Lotan
Chaim
C
D000225:Adenine; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D015214:Antigens, Differentiation, Myelomonocytic / Q000378:metabolism; D001021:Aortic Valve / Q000378:metabolism / Q000473:pathology*; D015153:Blotting, Western; D002114:Calcinosis / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D050659:Core Binding Factor Alpha 1 Subunit / Q000235:genetics / Q000378:metabolism; D003404:Creatinine / Q000097:blood; D004195:Disease Models, Animal; D018618:Echocardiography, Doppler, Color; D006349:Heart Valve Diseases / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D006962:Hyperparathyroidism, Secondary / Q000150:complications* / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D007249:Inflammation / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D007677:Kidney Function Tests; D008297:Male; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D015675:Osteocalcin / Q000235:genetics / Q000378:metabolism; D053495:Osteopontin / Q000235:genetics / Q000378:metabolism; D010281:Parathyroid Hormone / Q000097:blood; D010710:Phosphates / Q000097:blood; D016226:Phosphorus, Dietary; D053245:RANK Ligand / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D051437:Renal Insufficiency / Q000139:chemically induced / Q000150:complications* / Q000378:metabolism / Q000473:pathology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013997:Time Factors; D014057:Tomography, X-Ray Computed; D014511:Uremia / Q000150:complications* / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D000097382:CD68 Molecule
D000225:Adenine; D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D050659:Core Binding Factor Alpha 1 Subunit; D003404:Creatinine; D016328:NF-kappa B; D015675:Osteocalcin; D053495:Osteopontin; D010281:Parathyroid Hormone; D010710:Phosphates; D016226:Phosphorus, Dietary; D053245:RANK Ligand; C067980:CD68 antigen, human; D000097382:CD68 Molecule; C493717:Runx2 protein, rat; C506897:Spp1 protein, rat