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Kidney Week

Abstract: FR-PO166

Targeted IRAK4 Degradation Impairs Kidney Stromal Cell Myddosome Signaling and Reduces Tubulointerstitial Fibrosis in AKI

Session Information

  • AKI: Mechanisms - II
    November 03, 2023 | Location: Exhibit Hall, Pennsylvania Convention Center
    Abstract Time: 10:00 AM - 12:00 PM

Category: Acute Kidney Injury

  • 103 AKI: Mechanisms

Authors

  • López-Marfil, Marta, Renal Division, Brigham and Women’s Hospital, Boston, Massachusetts, United States
  • Wang, Xichi, Renal Division, Brigham and Women’s Hospital, Boston, Massachusetts, United States
  • Lopez Cantu, Diana Ofelia, Renal Division, Brigham and Women’s Hospital, Boston, Massachusetts, United States
  • Colunga Minutti, Jocelynn Gianna, Renal Division, Brigham and Women’s Hospital, Boston, Massachusetts, United States
  • Esquivel-Herrera, Antonio, Renal Division, Brigham and Women’s Hospital, Boston, Massachusetts, United States
  • Abdi, Reza, Transplantation Research Center, Renal Division, Boston, Massachusetts, United States
  • Lemos, Dario R., Renal Division, Brigham and Women’s Hospital, Boston, Massachusetts, United States
Background

Renal fibrosis is a process of pervasive interstitial scarring driven by kidney stromal fibrogenic cells. Previous data have indicated that inflammatory signaling via the fibrogenic cell myddosome complex is critical for kidney fibrosis development. Within the myddosome, modulation of interleukin-1 receptor associated kinase 4 (IRAK4) by small molecule kinase inhibitors reduces fibrosis, but has limited anti-inflammatory effect, indicating that the IRAK4 scaffold function is sufficient for canonical activation of NF- kB.

Methods

Here we used a novel strategy to abrogate IRAK4 by means of targeted ubiquitination followed by proteasomal degradation. We tested the antifibrotic and anti-inflammatory activity of an IRAK4 degrader molecule in vitro and in vivo in a model of acute kidney injury in mice.

Results

Incubation with degrader resulted in abrogation of IRAK4 protein levels, and reduced formation of myddosome complex in primary kidney fibrogenic cells. In human kidney organoids, IRAK4 degradation reduced both extracellular matrix deposition, as well as fibrosis gene expression caused by nephron tubule damage. Further, the treatment resulted in inhibition of NF-kB activation and downstream inflammatory cytokine expression. In vivo, the IRAK4 degrader showed increased efficacy compared to the small molecule kinase inhibitor CA-4948 in ameliorating fibrosis and inflammation following ischemia/reperfusion injury.

Conclusion

Collectively, our results indicate that targeted degradation of IRAK4 is a superior therapeutic approach to kinase inhibitors for the treatment of renal fibrosing disorders.

Funding

  • Other NIH Support – Kymera Therapeutics