Activation of TFEB protects against diabetic vascular calcification by improving autophagic flux and activating Nrf2 antioxidant system.

Abstract

Autophagic flux blockade and excessive oxidative stress play important roles in the pathogenesis of diabetic vascular calcification (VC). Transcription factor EB (TFEB) is an important regulator of many autophagy-lysosomal related components, which is mainly involved in promoting autophagy process in cells. Nuclear factor erythroid-2 related factor 2 (Nrf2) antioxidant system is considered as one of the key pathways in response to intracellular oxidative stress. Periostin (POSTN), a matrix protein, is widely involved in regulating the formation and maintenance of organs such as bones, teeth, heart valves, and tendons. We have previously reported that POSTN interfered with autophagic flux in an oxidative stress-dependent manner in vascular smooth muscle cells (VSMCs) to aggravate the development of diabetic VC. However, how POSTN interfered with autophagic flux by regulating oxidative stress has not been clarified. This study aims to further explore the roles of TFEB, POSTN, autophagy, and Nrf2 antioxidant system in the development of diabetic VC. Our experimental results revealed that activation of TFEB attenuated diabetic VC by improving autophagic flux and activating Nrf2 antioxidant system, whereas POSTN reduced the autophagic degradation of Kelch-like ECH-associated protein 1 (KEAP1) by inhibiting lysosomal function, thus inhibiting the activation of the Nrf2 antioxidant system, and ultimately abolishing the protective effect of TFEB against diabetic VC. In conclusion, this study uncovers that TFEB play an important role in alleviating diabetic VC by improving autophagic flux and activating Nrf2 antioxidant system, suggesting that TFEB may be a new target for the prevention and treatment of diabetic VC.NEW & NOTEWORTHY This study is the first to suggest the protective effect of activation of transcription factor EB (TFEB) against diabetic vascular calcification (VC), emphasizing that activation of TFEB alleviated diabetic VC by improving the autophagic flux and activating the Nuclear factor erythroid-2 related factor 2 (Nrf2) antioxidant system in vascular smooth muscle cells (VSMCs), and revealing that periostin (POSTN) partially abolished the protective effect of TFEB on diabetic VC by inhibiting the autophagic degradation of Kelch-like ECH-associated protein 1 (KEAP1).