TY  - JOUR
A1  - Frauscher, Bianca
A1  - Kirsch, Alexander H.
A1  - Schabhüttl, Corinna
A1  - Schweighofer, Kerstin
A1  - Kétszeri, Máté
A1  - Pollheimer, Marion
A1  - Dragun, Duska
A1  - Schröder, Katrin
A1  - Rosenkranz, Alexander
A1  - Eller, Kathrin
A1  - Eller, Philipp
T1  - Autophagy protects from uremic vascular media calcification
T2  - Frontiers in immunology
N2  - Chronic kidney disease and diabetes mellitus are associated with extensive media calcification, which leads to increased cardiovascular morbidity and mortality. Here, we investigated the role of autophagy in the pathogenesis of uremic vascular media calcification. DBA/2 mice were fed with high-phosphate diet (HPD) in order to cause vascular calcification. DBA/2 mice on standard chow diet were used as control. In parallel, autophagy and its response to rapamycin, 3-methyladenine (3-MA), and bafilomycin were studied in an in vitro model using mouse vascular smooth muscle cells (MOVAS). DBA/2 mice on HPD developed severe vascular media calcification, which is mirrored in vitro by culturing MOVAS under calcifying conditions. Both, in vitro and in vivo, autophagy significantly increased in MOVAS under calcifying conditions and in aortas of HPD mice, respectively. Histologically, autophagy was located to the aortic Tunica media, but also vascular endothelial cells, and was found to continuously increase during HPD treatment. 3-MA as well as bafilomycin blocked autophagy in MOVAS and increased calcification. Vice versa, rapamycin treatment further increased autophagy and resulted in a significant decrease of vascular calcification in vitro and in vivo. Rapamycin reduced Runx2 transcription levels in aortas and MOVAS to control levels, whereas it increased α-smooth muscle actin and Sm22α transcription in MOVAS to control levels. Furthermore, rapamycin-treated HPD mice survived significantly longer compared to HPD controls. These findings indicate that autophagy is an endogenous response of vascular smooth muscle cells (VSMC) to protect from calcification in uremia. Induction of autophagy by rapamycin protects cells and mice from uremic media calcification possibly by inhibiting osteogenic transdifferentiation of VSMC.
KW  - vascular smooth muscle cells
KW  - rapamycin
KW  - hydroxyapatite crystals
KW  - inflammation
KW  - phosphate
KW  - chronic kidney disease
Y1  - 2018
UR  - http://publikationen.ub.uni-frankfurt.de/frontdoor/index/index/docId/47737
UR  - https://nbn-resolving.org/urn:nbn:de:hebis:30:3-477372
SN  - 1664-3224
N1  - Copyright: © 2018 Frauscher, Kirsch, Schabhüttl, Schweighofer, Kétszeri, Pollheimer, Dragun, Schröder, Rosenkranz, Eller and Eller. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
VL  - 9
IS  - Art. 1866
SP  - 1
EP  - 14
PB  - Frontiers Media
CY  - Lausanne
ER  -