Phosphate-induced autophagy counteracts vascular calcification by reducing matrix vesicle release

• Published in: Kidney international Vol. 83; no. 6; pp. 1042 - 1051
• Main Authors: Dai, Xiao-Yan, Zhao, Ming-Ming, Cai, Yan, Guan, Qing-Cong, Zhao, Ying, Guan, Youfei, Kong, Wei, Zhu, Wei-Guo, Xu, Ming-Jiang, Wang, Xian
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.06.2013; Elsevier Limited
• Subjects: Adenine - analogs & derivatives; Adenine - pharmacology; Alkaline Phosphatase - metabolism; Amino Acid Chloromethyl Ketones - pharmacology; Animals; Antioxidants - pharmacology; apoptosis; autophagy; Autophagy - drug effects; Autophagy-Related Protein 5; Caspase Inhibitors - pharmacology; Cattle; Cells, Cultured; chronic renal failure; Disease Models, Animal; hyperphosphatemia; Kidney Failure, Chronic - complications; Kidney Failure, Chronic - metabolism; Kidney Failure, Chronic - pathology; Metalloporphyrins - pharmacology; Muscle, Smooth, Vascular - drug effects; Muscle, Smooth, Vascular - metabolism; Muscle, Smooth, Vascular - pathology; Myocytes, Smooth Muscle - drug effects; Myocytes, Smooth Muscle - metabolism; Myocytes, Smooth Muscle - pathology; oxidative stress; Phosphates - metabolism; Proteins - genetics; Proteins - metabolism; Rats; RNA Interference; Secretory Vesicles - drug effects; Secretory Vesicles - metabolism; Secretory Vesicles - pathology; Sodium-Phosphate Cotransporter Proteins, Type III - genetics; Sodium-Phosphate Cotransporter Proteins, Type III - metabolism; Superoxide Dismutase - genetics; Superoxide Dismutase - metabolism; Time Factors; Transfection; Valproic Acid - pharmacology; Vascular Calcification - etiology; Vascular Calcification - metabolism; Vascular Calcification - pathology; Vascular Calcification - prevention & control; apoptosis; autophagy; chronic renal failure; hyperphosphatemia; oxidative stress
• ISSN: 0085-2538; 1523-1755; 1523-1755
• DOI: 10.1038/ki.2012.482

Autophagy is a dynamic and highly regulated process of self-digestion responsible for cell survival and reaction to oxidative stress. As oxidative stress is increased in uremia and is associated with vascular calcification, we studied the role of autophagy in vascular calcification induced by phosphate. In an in vitro phosphate-induced calcification model of vascular smooth muscle cells (VSMCs) and in an in vivo model of chronic renal failure, autophagy was inhibited by the superoxide dismutase mimic MnTMPyP, superoxide dismutase-2 overexpression, and by knockdown of the sodium-dependent phosphate cotransporter Pit1. Although phosphate-induced VSMC apoptosis was reduced by an inhibitor of autophagy (3-methyladenine) and knockdown of autophagy protein 5, calcium deposition in VSMCs was increased during inhibition of autophagy, even with the apoptosis inhibitor Z-VAD-FMK. An inducer of autophagy, valproic acid, decreased calcification. Furthermore, 3-methyladenine significantly promoted phosphate-induced matrix vesicle release with increased alkaline phosphatase activity. Thus, autophagy may be an endogenous protective mechanism counteracting phosphate-induced vascular calcification by reducing matrix vesicle release. Therapeutic agents influencing the autophagic response may be of benefit to treat aging or disease-related vascular calcification and osteoporosis.