Kidney Week

Abstract: FR-PO1114

Inhibition of HMGB1 Release Through RIPK1-Associated Necroptosis Signaling Ameliorates Peritoneal Dysfunction

Session Information

• Home Dialysis: Modalities, Barriers, Utilization, and Clinical Outcomes
  October 23, 2026 | Location: Exhibit Hall A, Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Dialysis

• 802 Dialysis: Home Dialysis and Peritoneal Dialysis

Authors

• Fujii, Kenji, Department of Nephrology, Hiroshima University Hospital, Hiroshima, Japan

Kenji Fujii, MD

• Osaki, Yosuke, Department of Nephrology, Hiroshima University Hospital, Hiroshima, Japan

Yosuke Osaki, MD, PhD

• Muraoka, Shiro, Department of Nephrology, Hiroshima University Hospital, Hiroshima, Japan

Shiro Muraoka, MD

• Yoshida, Maria, Department of Nephrology, Hiroshima University Hospital, Hiroshima, Japan

Maria Yoshida, MD

• Ishiuchi, Naoki, Department of Nephrology, Hiroshima University Hospital, Hiroshima, Japan

Naoki Ishiuchi, DrMed

• Okubo, Aiko, Department of Nephrology, Hiroshima University Hospital, Hiroshima, Japan

Aiko Okubo, MD, PhD

• Maeoka, Yujiro, Department of Nephrology, Hiroshima University Hospital, Hiroshima, Japan

Yujiro Maeoka, MD, PhD

• Sasaki, Kensuke, Department of Nephrology, Hiroshima University Hospital, Hiroshima, Japan

Kensuke Sasaki, MD, PhD

• Gewin, Leslie S., Division of Nephrology, Washington University in St. Louis, St. Louis, Missouri, United States

Leslie S. Gewin, MD, FASN

• Masaki, Takao, Department of Nephrology, Hiroshima University Hospital, Hiroshima, Japan

Takao Masaki, MD, PhD

Background

High-mobility group box 1 protein (HMGB1), a damage-associated molecular pattern (DAMPs), has been implicated in peritoneal dialysis (PD)-associated peritonitis. However, its role in chronic peritoneal injury and the mechanism by which HMGB1 is released from peritoneal mesothelial cells (PMCs) remain unclear. Our previous studies have found that the receptor-interacting protein kinase1(RIPK1)-associated necroptosis signaling, a form of regulated cell death with release of DAMPs, is activated in PMCs. Therefore, we hypothesized that HMGB1 release through RIPK1-associated necroptosis signaling contributes to chronic peritoneal injury.

Methods

The association between HMGB1 levels in PD effluent from PD patients and peritoneal dysfunction were assessed. In vitro, omentum-derived primary human PMCs were treated with recombinant HMGB1(rHMGB1), and mesothelial-to-mesenchymal transition (MMT) was evaluated. Additionally, PMCs were exposed to high-glucose conditions after pharmacological inhibition of RIPK1 with Necrostatin-1s (Nec-1s, RIPK1 inhibitor) or genetic suppression of RIPK1 using siRNA. In vivo, methylglyoxal (MGO)-injected mice were treated with Nec-1s, and peritoneal injury and HMGB1 levels in peritoneal fluid were evaluated.

Results

HMGB1 expression in PMCs and HMGB1 levels in the non-cellular fraction of PD effluent were positively associated with the severity of peritoneal dysfunction. In primary PMCs, rHMGB1 increased the expression of MMT markers, including collagen I and fibronectin. High-glucose stimulation activated RIPK1-associated necroptosis signaling and enhanced HMGB1 release from PMCs. Pharmacological or genetic suppression of RIPK1-associated necroptosis signaling reduced HMGB1 release from PMCs under high-glucose conditions. In MGO-injected mice, Nec-1s ameliorated peritoneal inflammation and fibrosis and preserved peritoneal function. Moreover, HMGB1 levels in peritoneal fluid were increased in MGO-injected mice and were reduced by Nec-1s treatment.

Conclusion

These findings suggest that RIPK1-associated necroptosis signaling promotes HMGB1 release from PMCs and contributes to chronic peritoneal injury. Thus, targeting this pathway may represent a potential therapeutic strategy.

Funding

• Government Support – Non-U.S.