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

> **NIH NIH R01** · UNIVERSITY OF COLORADO DENVER · 2023 · $552,376

## Abstract

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.

## Key facts

- **NIH application ID:** 10543138
- **Project number:** 5R01HL132318-06
- **Recipient organization:** UNIVERSITY OF COLORADO DENVER
- **Principal Investigator:** Makoto Miyazaki
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $552,376
- **Award type:** 5
- **Project period:** 2016-06-01 → 2026-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10543138

## Citation

> US National Institutes of Health, RePORTER application 10543138, The role of MLKL in the regulation of vascular calcification in CKD (5R01HL132318-06). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10543138. Licensed CC0.

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