The role of MLKL in the regulation of vascular calcification in CKD

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Cardiovascular diseases such as vascular calcification are a leading cause of death in patients with chronic kidney disease (CKD). However, there is no effective therapy for vascular calcification available. In addition to uremic toxins such as indoles and phosphorus, inflammatory cytokines such as TNF play a major causative role in the regulation of CKD-dependent vascular calcification. Our long-term goal is to identify new pharmacological strategies for the prevention of vascular calcification. Our studies have demonstrated that simultaneous activation of the endoplasmic reticulum (ER) stress and IKK-NFB-inflammation pathways in vascular smooth muscles cells (VSMCs) are major events in the induction of vascular calcification in CKD. We have also revealed that ER stress-mediated integrated stress signal (ISR) in VSMCs plays a causative role in the pathogenesis of vascular calcification. Unexpectedly, however, the inhibition of IKK-mediated inflammation drastically exacerbated vascular calcification in CKD mice. In addition, both ER stress-ISR (ATF4-CHOP) activation- and IKK inhibition-mediated vascular calcification are highly associated with vascular cell death. There results led us to hypothesize that one of the regulated cell death (RCD) pathways is a major player in the initiation of vascular calcification. To find clues about the mechanism, we recently screened a library of chemicals that inhibit RCD. Based on the RCD chemical library screening, we identified an RCD pathway that selectively contributes to IKK inhibition-induced and CHOP-induced vascular calcification. We therefore propose two specific aims to elucidate. Aim 1 will examine whether the RCD pathway affects vascular calcification by altering the secretion of calcifying macrovesicles in cultured cells. Aim 2 will examine whether modulation of the RCD pathway affects CKD-dependent vascular calcification in vivo. Completion of this project will provide novel therapeutic targets for CKD-mediated vascular calcification.