TY  - JOUR
A1  - Hecht, Eva
A1  - Freise, Christian
A1  - von Websky, Karoline
A1  - Nasser, Hamoud
A1  - Kretzschmar, Nadja
A1  - Stawowy, Philipp
A1  - Hocher, Berthold
A1  - Querfeld, Uwe
T1  - The matrix metalloproteinases 2 and 9 initiate uraemic vascular calcifications
JF  - Nephrology, dialysis, transplantation
N2  - The matrix metalloproteinases (MMP) MMP-2 and MMP-9 are physiological regulators of vascular remodelling. Their dysregulation could contribute to vascular calcification. We examined the role of the MMP-2 and MMP-9 in uraemic vascular calcification in vivo and in vitro. The impact of pharmacological MMP inhibition on the development of media calcifications was explored in an aggressive animal model of uraemic calcification. In addition, the selective effects of addition and inhibition, respectively, of MMP-2 and MMP-9 on calcium-/phosphate-induced calcifications were studied in a murine cell line of vascular smooth muscle cells (VSMCs). High-dose calcitriol treatment of uraemic rats given a high phosphate diet induced massive calcifications, apoptosis and increased gene expressions of MMP-2, MMP-9 and of osteogenic transcription factors and proteins in aortic VSMC. The MMP inhibitor doxycycline prevented the VSMC transdifferentiation to osteoblastic cells, suppressed transcription of mediators of matrix remodelling and almost completely blocked aortic calcifications while further increasing apoptosis. Similarly, specific inhibitors of either MMP-2 or -9, or of both gelatinases (Ro28-2653) and a selective knockdown of MMP-2/-9 mRNA expression blocked calcification of murine VSMC induced by calcification medium (CM). In contrast to MMP inhibition, recombinant MMP-2 or MMP-9 enhanced CM-induced calcifications and the secretion of gelatinases. These data indicate that both gelatinases provide essential signals for phenotypic VSMC conversion, matrix remodelling and the initiation of vascular calcification. Their inhibition seems a promising strategy in the prevention of vascular calcifications.
KW  - chronic kidney disease
KW  - matrix metalloproteinases
KW  - vascular calcification
KW  - vascular smooth muscle cells
Y1  - 2016
U6  - https://doi.org/10.1093/ndt/gfv321
SN  - 0931-0509
SN  - 1460-2385
VL  - 31
SP  - 789
EP  - 797
PB  - Oxford Univ. Press
CY  - Oxford
ER  -