Autophagy Protects From Uremic Vascular Media Calcification.
Bianca Frauscher, Alexander H Kirsch, Corinna Schabhüttl, Kerstin Schweighofer, Máté Kétszeri, Marion Pollheimer, Duska Dragun, Katrin Schröder, Alexander R Rosenkranz, Kathrin Eller, Philipp Eller
Author Information
Bianca Frauscher: Clinical Division of Nephrology, Department of Internal Medicine, Medical University of Graz, Graz, Austria.
Alexander H Kirsch: Clinical Division of Nephrology, Department of Internal Medicine, Medical University of Graz, Graz, Austria.
Corinna Schabhüttl: Clinical Division of Nephrology, Department of Internal Medicine, Medical University of Graz, Graz, Austria.
Kerstin Schweighofer: Clinical Division of Nephrology, Department of Internal Medicine, Medical University of Graz, Graz, Austria.
Máté Kétszeri: Clinical Division of Nephrology, Department of Internal Medicine, Medical University of Graz, Graz, Austria.
Marion Pollheimer: Institute of Pathology, Medical University of Graz, Graz, Austria.
Duska Dragun: Clinic for Nephrology and Critical Care Medicine, Charité - Universitätsmedizin Berlin, Freie Universitat Berlin, Humboldt-Universitat zu Berlin, Berlin, Germany.
Katrin Schröder: Institute for Cardiovascular Physiology, Goethe-University, Frankfurt, Germany.
Alexander R Rosenkranz: Clinical Division of Nephrology, Department of Internal Medicine, Medical University of Graz, Graz, Austria.
Kathrin Eller: Clinical Division of Nephrology, Department of Internal Medicine, Medical University of Graz, Graz, Austria.
Philipp Eller: Intensive Care Unit, Department of Internal Medicine, Medical University of Graz, Graz, Austria.
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/2mice were fed with high-phosphate diet (HPD) in order to cause vascular calcification. DBA/2mice 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 model using mouse vascular smooth muscle cells (MOVAS). DBA/2mice on HPD developed severe vascular media calcification, which is mirrored by culturing MOVAS under calcifying conditions. Both, and , autophagy significantly increased in MOVAS under calcifying conditions and in aortas of HPD mice, respectively. Histologically, autophagy was located to the aortic , 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. , rapamycin treatment further increased autophagy and resulted in a significant decrease of vascular calcification and . rapamycin reduced transcription levels in aortas and MOVAS to control levels, whereas it increased α-smooth muscle actin and 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.
