Targeted Proteasomal Degradation of IRAK4 Ameliorates Kidney Fibrosis Caused by AKI
- AKI: Mechanisms - III
November 05, 2022 | Location: Exhibit Hall, Orange County Convention Center‚ West Building
Abstract Time: 10:00 AM - 12:00 PM
Category: Acute Kidney Injury
- 103 AKI: Mechanisms
- Lemos, Dario R., Brigham and Women's Hospital, Boston, Massachusetts, United States
- Lopez Cantu, Diana Ofelia, Brigham and Women's Hospital, Boston, Massachusetts, United States
- Segoviano, Miriam, Brigham and Women's Hospital, Boston, Massachusetts, United States
Group or Team Name
- Lemos Lab HMS
Proteolysis targeting chimeras (PROTACs) are heterobifunctional molecules that can trigger the selective degradation of intracellular proteins through the ubiquitin-proteasome system (UPS). PROTACs are emerging as a promising therapeutic strategy for variety of diseases, including inflammatory disorders. Here we assessed the anti-fibrotic and anti-inflammatory efficacy of an IRAK4 degrader molecule in acute kidney injury.
We tested the IRAK4 degrader molecule KYM-001/IRW-1080 in vitro, on isolated kidney stroma PDGFRb+ pericyte/fibroblasts cells and on hPSC-derivedkidney organoids incubated with interleukin 1b,(IL1b) and in vivo in a mouse model of unilateral ischemia/reperfusion injury.
Our data in vitro results indicate that KYM-001 effectively abrogates myddosome signaling in kidney stromal cells in vitro. The results also show inhibition of fibrogenic and pro-inflammatory gene expression. KYM-001 also effectively inhibited fibrosis in kidney organoids induced after incubation of the organoids with IL1b for 96h. In this system, KYM-001 significantly inhibited myofibroblast formation and fibrogenic gene expression, and expression of NF-kB target genes. In vivo, IRW-1080 delivered orally via gavage alone was well tolerated and did not cause animal death, nor did it affect normal behavior in healthy wild type C57BL/6 mice. After unilateral IRI, IRW-1080 delivered by gavage at a dose of 50mg/Kg, every 48h starting on the day of IRI surgery and over a period of 14 days, showed superior anti-inflammatory and anti-fibrotic activity compared to the IRAK4 kinase activity inhibitor small molecule CA-4948 delivered at a 75mg/Kg dose. In addition, animals that received IRW-1080 showed reduced levels of tubule injury and expression of the tubule injury marker KIM1.
Collectively, our findings validate the role myddosome signaling and particularly of IRAK4 in the process of kidney fibrosis, and indicated that targeted degradation of IRAK4 is an efficacious therapy for acute kidney injury.
- NIDDK Support