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  - 
TY  - JOUR
A1  - Prommer, Hans-Ulrich
A1  - Maurer, Johannes
A1  - von Websky, Karoline
A1  - Freise, Christian
A1  - Sommer, Kerstin
A1  - Nasser, Hamoud
A1  - Samapati, Rudi
A1  - Reglin, Bettina
A1  - Guimaraes, Pedro
A1  - Pries, Axel Radlach
A1  - Querfeld, Uwe
T1  - Chronic kidney disease induces a systemic microangiopathy, tissue hypoxia and dysfunctional angiogenesis
JF  - Scientific reports
N2  - Chronic kidney disease (CKD) is associated with excessive mortality from cardiovascular disease (CVD). Endothelial dysfunction, an early manifestation of CVD, is consistently observed in CKD patients and might be linked to structural defects of the microcirculation including microvascular rarefaction. However, patterns of microvascular rarefaction in CKD and their relation to functional deficits in perfusion and oxygen delivery are currently unknown. In this in-vivo microscopy study of the cremaster muscle microcirculation in BALB/c mice with moderate to severe uremia, we show in two experimental models (adenine feeding or subtotal nephrectomy), that serum urea levels associate incrementally with a distinct microangiopathy. Structural changes were characterized by a heterogeneous pattern of focal microvascular rarefaction with loss of coherent microvascular networks resulting in large avascular areas. Corresponding microvascular dysfunction was evident by significantly diminished blood flow velocity, vascular tone, and oxygen uptake. Microvascular rarefaction in the cremaster muscle paralleled rarefaction in the myocardium, which was accompanied by a decrease in transcription levels not only of the transcriptional regulator HIF-1 alpha, but also of its target genes Angpt-2, TIE-1 and TIE-2, Flkt-1 and MMP-9, indicating an impaired hypoxia-driven angiogenesis. Thus, experimental uremia in mice associates with systemic microvascular disease with rarefaction, tissue hypoxia and dysfunctional angiogenesis.
Y1  - 2018
U6  - https://doi.org/10.1038/s41598-018-23663-1
SN  - 2045-2322
VL  - 8
PB  - Nature Publ. Group
CY  - London
ER  -