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Abstract: SA-PO067

KUS121, an ATP-Retaining VCP Modulator, Exerts Renoprotective Effects in Ischemia-Reperfusion Injury With Enhancing Endoplasmic Reticulum-Associated Degradation

Session Information

  • 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

Authors

  • Date, Ryosuke, Department of Nephrology, Kumamoto University Graduate School of Medical Sciences, Kumamoto, Kumamoto, Japan
  • Kuwabara, Takashige, Department of Nephrology, Kumamoto University Graduate School of Medical Sciences, Kumamoto, Kumamoto, Japan
  • Hata, Yusuke, Department of Nephrology, Kumamoto University Graduate School of Medical Sciences, Kumamoto, Kumamoto, Japan
  • Fujimoto, Daisuke, Department of Nephrology, Kumamoto University Graduate School of Medical Sciences, Kumamoto, Kumamoto, Japan
  • Mizumoto, Teruhiko, Department of Nephrology, Kumamoto University Graduate School of Medical Sciences, Kumamoto, Kumamoto, Japan
  • Izumi, Yuichiro, Department of Nephrology, Kumamoto University Graduate School of Medical Sciences, Kumamoto, Kumamoto, Japan
  • Mukoyama, Masashi, Department of Nephrology, Kumamoto University Graduate School of Medical Sciences, Kumamoto, Kumamoto, Japan
Background

Acute kidney injury (AKI) is a life-threatening condition and often progresses to chronic kidney disease or may develop other organ dysfunction even after recovery, but there has been no established treatment for AKI so far. Valosin-containing protein (VCP) is a major ATPase in the cells and is expressed ubiquitously in various organs including the kidney. VCP is also involved in many cellular functions including endoplasmic reticulum (ER)-associated degradation (ERAD). The aim of this study was to investigate the renoprotective effect of Kyoto University substance 121 (KUS121), a novel VCP modulator, on AKI.

Methods

In in vitro experiments, we evaluated cell viability and ATP levels of cultured proximal tubular cells with or without KUS121 under ER stress conditions. In in vivo experiments, the effects of KUS121 were examined in mice with AKI caused by ischemia-reperfusion injury. ERAD-processing capacity was evaluated by quantification of the ERAD substrate CD3delta-YFP.

Results

KUS121 protected proximal tubular cells from cell death under ER stress. The apoptotic response was mitigated as indicated by the suppression of C/EBP homologous protein expression and caspase-3 cleavage, with maintained intracellular ATP levels by KUS121 administration. KUS121 treatment suppressed the elevation of serum creatinine and neutrophil gelatinase-associated lipocalin levels and attenuated renal tubular damage after ischemia-reperfusion. The expression of inflammatory cytokines in the kidney was also suppressed in the KUS121-treated group. VCP expression levels were not altered by KUS121 both in vitro and in vivo. KUS121 treatment restored ERAD-processing capacity associated with potentiation of its upstream pathway, phosphorylated inositol-requiring enzyme-1α, and spliced X box-binding protein-1. Furthermore, KUS121 recovered from stagnation of CD3delta caused by Eeyarestatin I known as an ERAD inhibitor.

Conclusion

These findings indicate that KUS121 may contribute to protect renal tubular cells from ER stress-induced injury, suggesting that KUS121 could be a novel and promising therapeutic compound against ischemia-associated AKI.