Kidney Week

Abstract: SA-PO586

Lack of DJ-1 Amplifies Sepsis-Associated AKI and Increases Daxx-Mediated Parenchymal Apoptosis

Session Information

• AKI: Other Mechanisms and Cell Cultures
  October 27, 2018 | Location: Exhibit Hall, San Diego Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Acute Kidney Injury

• 103 AKI: Mechanisms

Authors

• Leeds, Joseph T., University of Virginia, Charlottesville, Virginia, United States

Joseph T. Leeds,

• Scindia, Yogesh M., Univerisity of Virginia, Charlottesville, Virginia, United States

Yogesh M. Scindia,

• Loi, Valentina, AO Brotzu Cagliari, Cagliari, Italy

Valentina Loi,

• Mandziak, Ewa U., University of Virginia, Charlottesville, Virginia, United States

Ewa U. Mandziak,

• Mohammad, Saleh, University of Virginia, Charlottesville, Virginia, United States

Saleh Mohammad,

• Swaminathan, Sundararaman, University of Virginia, Charlottesville, Virginia, United States

Sundararaman Swaminathan,

Background

Sepsis is frequently complicated by acute kidney injury (AKI). AKI in sepsis is associated with increased morbidity and mortality. Studies of sepsis-induced AKI suggest that uncontrolled inflammatory responses to tubular injury can further worsen renal damage. DJ-1 is a known anti-oxidant protein that is expressed in the brain, kidney, and immune cells. The role of DJ-1 in sepsis is not clear. AKI is one of the common sepsis-associated pathologies, and there is no data on the role of DJ-1 in sepsis-associated AKI.

Methods

Wildtype and DJ-1 knockout mice both on B6 background were administered 6.5 mg/kg LPS (i.p.) and tissues were harvested 24 hours later. Renal function and injury, as well as markers for inflammation were studied. Inner Medullary Collecting Duct cells (iMCD3) were used to study activation as well as cytotoxic serum responses.

Results

Compared to WT mice, DJ-1^(-/-) mice were more susceptible to LPS-induced AKI as indicated by higher plasma creatinine (WT LPS 0.61 ± 0.11 Vs DJ-1^(-/-) LPS 0.87 ± 0.23; p= 0.0006) and Kidney Injury Marker-1 (KIM-1). Markers of renal inflammation (s100A8 and s100A9) and Reactive Oxidant/Nitrogen Stress (ROS/RNS) were increased in renal tissue of DJ-1 deficient mice. The increased oxidative stress was associated with induction of Daxx-mediated apoptosis in the kidney. We demonstrate a protective effect of DJ-1 against LPS serum toxicity with in vitro studies on IMCD3 cells.

Conclusion

Our data suggests DJ-1 plays an important protective role in against sepsis-associated renal inflammation and injury, through ROS/RNS control, and by preventing Daxx-dependent apoptosis.

Funding

• Other NIH Support