Role of calcification inhibitors in the pathogenesis of vascular calcification in chronic kidney disease (CKD)

Sharon M. Moe, Martina Reslerova, Markus Ketteler, Kalisha O'Neill, Danxia Duan, Jacob Koczman, Ralf Westenfeld, Willi Jahnen-Dechent, Neal X. Chen

Research output: Contribution to journalArticle

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Abstract

Background. The majority of patients with chronic kidney disease (CKD) have excessive vascular calcification; however, most studies demonstrate that a subset of CKD patients do not have, nor develop, vascular calcification despite similar exposure to the uremic environment. This suggests protective mechanisms, or naturally occurring inhibitors, of calcification may be important. Methods. In order to determine the role of three inhibitors, fetuin-A, matrix gla protein (MGP), and osteoprotegerin (OPG) in the vascular calcification observed in patients with CKD-5, we (1) measured serum levels of these inhibitors and compared the levels to calcification assessed by computed tomography (CT); (2) examined arteries from CKD-5 patients by immunostaining for these inhibitors; and (3) examined the expression and effect of these inhibitors in cultured bovine vascular smooth muscle cells (BVSMCs) incubated in serum pooled from uremic patients compared to healthy controls. Results. There was a negative correlation of coronary artery calcification scores with serum fetuin-A levels (r = -0.30, P = 0.034) and a positive association with OPG levels (r = 0.29, P = 0.045). There was increasing immunostaining for both fetuin-A and MGP in arteries with increasing calcification graded semiquantitatively (P < 0.003). In vitro, fetuin-A added to mineralizing BVSMCs inhibited mineralization (P < 0.001). Compared to normal serum, BVSMCs incubated with uremic serum had a progressive increase in MGP expression with mineralization (P < 0.001) and increased expression of OPG in BVSMCs (P < 0.04). Conclusion. These data demonstrate that fetuin-A, OPG, and MGP play an important role in the pathogenesis of uremic vascular calcification.

Original languageEnglish
Pages (from-to)2295-2304
Number of pages10
JournalKidney International
Volume67
Issue number6
DOIs
StatePublished - Jun 2005

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alpha-2-HS-Glycoprotein
Vascular Calcification
Osteoprotegerin
Chronic Renal Insufficiency
Vascular Smooth Muscle
Smooth Muscle Myocytes
Serum
Arteries
Coronary Vessels
Tomography
matrix Gla protein

Keywords

  • CKD
  • Dialysis
  • Fetuin-A
  • Matrix gla protein
  • Osteoprotegerin
  • Vascular calcification

ASJC Scopus subject areas

  • Nephrology

Cite this

Role of calcification inhibitors in the pathogenesis of vascular calcification in chronic kidney disease (CKD). / Moe, Sharon M.; Reslerova, Martina; Ketteler, Markus; O'Neill, Kalisha; Duan, Danxia; Koczman, Jacob; Westenfeld, Ralf; Jahnen-Dechent, Willi; Chen, Neal X.

In: Kidney International, Vol. 67, No. 6, 06.2005, p. 2295-2304.

Research output: Contribution to journalArticle

Moe, SM, Reslerova, M, Ketteler, M, O'Neill, K, Duan, D, Koczman, J, Westenfeld, R, Jahnen-Dechent, W & Chen, NX 2005, 'Role of calcification inhibitors in the pathogenesis of vascular calcification in chronic kidney disease (CKD)', Kidney International, vol. 67, no. 6, pp. 2295-2304. https://doi.org/10.1111/j.1523-1755.2005.00333.x
Moe, Sharon M. ; Reslerova, Martina ; Ketteler, Markus ; O'Neill, Kalisha ; Duan, Danxia ; Koczman, Jacob ; Westenfeld, Ralf ; Jahnen-Dechent, Willi ; Chen, Neal X. / Role of calcification inhibitors in the pathogenesis of vascular calcification in chronic kidney disease (CKD). In: Kidney International. 2005 ; Vol. 67, No. 6. pp. 2295-2304.
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T1 - Role of calcification inhibitors in the pathogenesis of vascular calcification in chronic kidney disease (CKD)

AU - Moe, Sharon M.

AU - Reslerova, Martina

AU - Ketteler, Markus

AU - O'Neill, Kalisha

AU - Duan, Danxia

AU - Koczman, Jacob

AU - Westenfeld, Ralf

AU - Jahnen-Dechent, Willi

AU - Chen, Neal X.

PY - 2005/6

Y1 - 2005/6

N2 - Background. The majority of patients with chronic kidney disease (CKD) have excessive vascular calcification; however, most studies demonstrate that a subset of CKD patients do not have, nor develop, vascular calcification despite similar exposure to the uremic environment. This suggests protective mechanisms, or naturally occurring inhibitors, of calcification may be important. Methods. In order to determine the role of three inhibitors, fetuin-A, matrix gla protein (MGP), and osteoprotegerin (OPG) in the vascular calcification observed in patients with CKD-5, we (1) measured serum levels of these inhibitors and compared the levels to calcification assessed by computed tomography (CT); (2) examined arteries from CKD-5 patients by immunostaining for these inhibitors; and (3) examined the expression and effect of these inhibitors in cultured bovine vascular smooth muscle cells (BVSMCs) incubated in serum pooled from uremic patients compared to healthy controls. Results. There was a negative correlation of coronary artery calcification scores with serum fetuin-A levels (r = -0.30, P = 0.034) and a positive association with OPG levels (r = 0.29, P = 0.045). There was increasing immunostaining for both fetuin-A and MGP in arteries with increasing calcification graded semiquantitatively (P < 0.003). In vitro, fetuin-A added to mineralizing BVSMCs inhibited mineralization (P < 0.001). Compared to normal serum, BVSMCs incubated with uremic serum had a progressive increase in MGP expression with mineralization (P < 0.001) and increased expression of OPG in BVSMCs (P < 0.04). Conclusion. These data demonstrate that fetuin-A, OPG, and MGP play an important role in the pathogenesis of uremic vascular calcification.

AB - Background. The majority of patients with chronic kidney disease (CKD) have excessive vascular calcification; however, most studies demonstrate that a subset of CKD patients do not have, nor develop, vascular calcification despite similar exposure to the uremic environment. This suggests protective mechanisms, or naturally occurring inhibitors, of calcification may be important. Methods. In order to determine the role of three inhibitors, fetuin-A, matrix gla protein (MGP), and osteoprotegerin (OPG) in the vascular calcification observed in patients with CKD-5, we (1) measured serum levels of these inhibitors and compared the levels to calcification assessed by computed tomography (CT); (2) examined arteries from CKD-5 patients by immunostaining for these inhibitors; and (3) examined the expression and effect of these inhibitors in cultured bovine vascular smooth muscle cells (BVSMCs) incubated in serum pooled from uremic patients compared to healthy controls. Results. There was a negative correlation of coronary artery calcification scores with serum fetuin-A levels (r = -0.30, P = 0.034) and a positive association with OPG levels (r = 0.29, P = 0.045). There was increasing immunostaining for both fetuin-A and MGP in arteries with increasing calcification graded semiquantitatively (P < 0.003). In vitro, fetuin-A added to mineralizing BVSMCs inhibited mineralization (P < 0.001). Compared to normal serum, BVSMCs incubated with uremic serum had a progressive increase in MGP expression with mineralization (P < 0.001) and increased expression of OPG in BVSMCs (P < 0.04). Conclusion. These data demonstrate that fetuin-A, OPG, and MGP play an important role in the pathogenesis of uremic vascular calcification.

KW - CKD

KW - Dialysis

KW - Fetuin-A

KW - Matrix gla protein

KW - Osteoprotegerin

KW - Vascular calcification

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