Abstract
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.
Highlights
Chronic kidney disease (CKD) and especially end stage renal disease (ESRD) are associated with an extensive increase in cardiovascular mortality and morbidity [1]
Since pharmacologically enhancing autophagy resulted in improved uremic media calcification and survival, autophagy provides an endogenous protective response
There exist increasing data that autophagy is a protective response of the body to counteract atherosclerosis, but those models mainly used Apo E knockout mice thereby reflecting human atherosclerosis rather than uremic media calcification [21]
Summary
Chronic kidney disease (CKD) and especially end stage renal disease (ESRD) are associated with an extensive increase in cardiovascular mortality and morbidity [1]. Cardiovascular disease is the single greatest cause of mortality in CKD/ESRD, and it is to a large extent driven by abnormal mineral metabolism leading to extensive arterial calcifications, a reduced vascular compliance, Autophagy in Vascular Calcification left ventricular hypertrophy, and sudden cardiac death [2]. It is currently believed that increase in serum phosphate levels is the driving force leading to vascular media calcification [5]. High-phosphate levels in combination with other mediators, which are dysregulated in uremia, induce vascular smooth muscle cells (VSMC) to transdifferentiate from a contractile to proliferative, osteoblastic, and/or inflammatory phenotypes [6, 7]. The adverse effects of high serum phosphate and/ or phosphate overload in human health do not seem to be limited to advanced stages of CKD, as it has been found in earlier stages of CKD and in the general population [8,9,10]
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