Fetuin-A (AHSG) prevents extraosseous calcification induced by uraemia and phosphate challenge in mice.
BACKGROUND
Chronic kidney disease (CKD) is associated with vascular and tissue calcification. The extent of vascular calcification has been identified as an independent risk factor of cardiovascular death in patients on haemodialysis.


METHODS
We studied the role of fetuin-A in CKD-associated calcification using a mouse model of graded renal insufficiency generated by nephrectomy and high phosphate diet. We used wild-type and fetuin-A-deficient mice on the calcification resistant genetic background C57BL/6 to study the influence on calcification of CKD, dietary phosphate and fetuin deficiency. Hyperphosphataemia, elevated BUN, hyperparathyroidism and von Kossa histochemistry served as indicators of calcification disease. The expression of osteopontin, a marker of osteoblast-like cell differentiation was analyzed by realtime PCR and immunohistochemistry.


RESULTS
We detected tissue and genotype-specific susceptibility for calcification. Fetuin-A-deficient mice with CKD and high phosphate diet had only a moderately elevated serum calcium phosphate product (6.9 +/- 1.4 mmol(2)/l(2)), but suffered severe calcification of kidney, heart and lung. In contrast, wild-type mice under the same conditions developed renal calcinosis only despite an elevated serum calcium phosphate product (9.6 +/- 0.9 mmol(2)/l(2)). Calcification was preceded by the local induction of osteopontin, a marker for osteoblast-like cell differentiation.


CONCLUSIONS
Fetuin-A deficiency, CKD and high phosphate diet act synergistically in the pathogenesis of extraosseous calcification.
Westenfeld
Ralf
R
Department of Nephrology and Clinical Immunology, University Hospital Aachen, Pauwelsstrasse 30, D-52057 Aachen, Germany. ralf.westenfeld@rwth-aachen.de
Schäfer
Cora
C
Smeets
Ralf
R
Brandenburg
Vincent M
VM
Floege
Jürgen
J
Ketteler
Markus
M
Jahnen-Dechent
Willi
W
D000818:Animals; D001798:Blood Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D002114:Calcinosis / Q000139:chemically induced / Q000378:metabolism* / Q000517:prevention & control*; D002908:Chronic Disease; D004032:Diet / Q000009:adverse effects; D004195:Disease Models, Animal; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010710:Phosphates / Q000008:administration & dosage* / Q000009:adverse effects; D014511:Uremia / Q000150:complications* / Q000378:metabolism; D060749:alpha-2-HS-Glycoprotein
C556357:Ahsg protein, mouse; D001798:Blood Proteins; D010710:Phosphates; D060749:alpha-2-HS-Glycoprotein