Abstract: TH-PO224

Role of DJ-1(PARK7) in Hepcidin-Mediated Protection of AKI in a Murine Model of Sepsis (LPS)

Session Information

Category: Acute Kidney Injury

  • 001 AKI: Basic

Authors

  • Leeds, Joseph T., University of Virginia, Charlottesville, Virginia, United States
  • Scindia, Yogesh M., Univerisity of Virginia, Charlottesville, Virginia, United States
  • Mohammad, Saleh, University of Virginia, Charlottesville, Virginia, United States
  • Loi, Valentina, AO Brotzu Cagliari, Cagliari, Italy
  • Mandziak, Ewa U., University of Virginia, Charlottesville, Virginia, United States
  • Swaminathan, Sundararaman, University of Virginia, Charlottesville, Virginia, United States
Background

Acute Kidney injury is a frequent complication of Sepsis and is associated with increased comorbidity and mortality. A new paradigm of sepsis-induced AKI suggest that responses to tubular injury with an uncontrolled pro-inflammatory response (TNFα, IL-6, IL-10) can further renal damage. Previously we have shown that Hepcidin (Hamp), an endogenous peptide which controls systemic and local iron homeostasis, ameliorates ischemia-reperfusion injury and LPS induced AKI, by reducing renal oxidative stress, inflammation and apoptosis. DJ-1 is an anti-oxidant protein that is expressed in the brain and kidney and known to reduce oxidative stress via multiple mechanisms. Importantly it is a positive regulator of glutathione peroxidase 4 (GPX-4) a protein implicated in Ferroptosis (Iron-mediated cell death).

Methods

C57BLK/6 (WT) and DJ-1 knockout mice on B6 background were injected with PBS or 50 ug of Hamp (i.p) and 24 hours later administered 6.5mg/kg LPS (i.p). Tissue were harvested 24 hours after LPS administration for measuring renal function, injury, and inflammation.

Results

Compared to PBS, Hamp pretreated WT mice were protected against LPS-induced AKI as indicated by significantly lower plasma creatinine (WT PBS+ LPS 1.11 ± 0.17 Vs Hamp + LPS 0.41 ± 0.03; p= <0.0001), NGAL and KIM-1 levels. Hamp + LPS treated animals also had less infiltrating neutrophils and CD11b positive cells compared to PBS + LPS treated ones. Hamp + LPS treated mice had significantly lower splenic IL-6, IL-10 and IL-22 mRNA levels compared to PBS + LPS. In contrast to WT mice, Hamp failed to protect DJ-1 KO mice against LPS induced AKI. DJ-1 KO mice treated with PBS or Hamp had comparable plasma creatinine (DJ-1 KO PBS + LPS; .95 ± 0.06 Vs Hamp + LPS 0.85 ± 0.15; p= 0.7776), NGAL, KIM-1 and infiltrating cells. The splenic inflammatory signature was also comparable between the two groups.

Conclusion

Hepcidin protects against LPS-induced AKI by reducing systemic inflammation. The protective effect of Hamp seems to be dependent DJ-1, as loss of DJ-1 in mice abrogated Hamp`s protective effect.

Funding

  • Other NIH Support