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Kidney Week

Abstract: FR-PO1120

JAK Inhibitor Exaggerates Kidney Injury in the Early Phase of SARS-CoV-2 Infection in a Murine COVID-19 Model

Session Information

  • COVID-19 - II
    November 03, 2023 | Location: Exhibit Hall, Pennsylvania Convention Center
    Abstract Time: 10:00 AM - 12:00 PM

Category: Coronavirus (COVID-19)

  • 000 Coronavirus (COVID-19)

Authors

  • Sakai, Hibiki, Osaka Daigaku, Suita, Osaka, Japan
  • Obana, Masanori, Osaka Daigaku, Suita, Osaka, Japan
  • Kamuro, Hiroyasu, Osaka Daigaku, Suita, Osaka, Japan
  • Tokunoh, Nagisa, Osaka Daigaku Biseibutsubyo Kenkyujo, Suita, Osaka, Japan
  • Yamamoto, Ayaha, Osaka Daigaku, Suita, Osaka, Japan
  • Okada, Yoshiaki, Osaka Daigaku, Suita, Osaka, Japan
  • Yoshioka, Yasuo, Osaka Daigaku Biseibutsubyo Kenkyujo, Suita, Osaka, Japan
  • Fujio, Yasushi, Osaka Daigaku, Suita, Osaka, Japan
Background

COVID-19 is a respiratory illness caused by SARS-CoV-2 infection, and its clinical manifestations range from mild respiratory illness to severe progressive pneumonia and multiple organ failure. The serious cases of COVID-19 are treated with blockade of IL-6/JAK signaling, such as anti-IL-6 receptor antibody (anti-IL-6R mAb) and JAK inhibitor Baricitinib. Kidney injury is one of the complications of COVID-19; however, the mechanisms by which SARS-CoV-2 infection results in kidney injury and the effects of current therapies against COVID-19 on kidneys are not fully understood.

Methods

Male Balb/c mice (6-10-week old) were nasally infected with mouse-adapted SARS-CoV-2 (MA10). PCR was performed with specific primers for the detection of MA10 to examine for viral entry into the lungs and kidneys. MA10 infection-induced lung injury was evaluated with H&E staining and the expression of inflammatory cytokines. Measurements of serum creatinine (sCr) level, urinary albumin/creatinine ratio (ACR), and urinary Ngal/Cr ratio, and histological analyses were performed to evaluate kidney injury day 4 after MA10 infection. MA10-infected mice were treated with anti-IL-6R mAb (1.4 mg/head, i.p.) or Baricitinib (10 mg/kg, p.o.) at day 1 or day1-3, respectively.

Results

MA10 infection caused about 20% body weight loss in mice day 4 after infection. H&E staining and quantitative PCR revealed that inflammation was induced in the lungs of MA10-infected mice. sCr level, ACR, and Ngal/Cr ratio was increased, and tubular damage was observed in the kidneys day 4 after MA10 infection, suggesting that kidney injury was evoked in the murine COVID-19 model. However, PCR analysis revealed that MA10 was not detected in the kidneys, whereas in the lungs. As we hypothesized that cytokine storm induced kidney injury in COVID-19, MA10-infected mice were treated with anti-IL-6R mAb or Baricitinib. Unexpectedly, ACR and Ngal/Cr ratio tended to be increased in anti-IL-6R mAb group. Upon Baricitinib treatment, ACR and Ngal/Cr ratio was significantly increased.

Conclusion

Blockade of IL-6/JAK signaling in the early phase of SARS-CoV-2 infection exaggerates kidney injury, providing a novel insight into the pathogenesis of COVID-19-related kidney injury.