D NGUYEN-NGO1,2, B SANGANERIA1,2, M EL-RASHID1,2, S GREY4, NM ROGERS1,2,3
1The Westmead Institute of Medical Research , Westmead, Australia, 2The University of Sydney, Camperdown, Australia, 3Westmead Hospital, Westmead , Australia, 4The Garvan Institute of Medical Research, Darlinghurst, Australia
Aim: To determine the role of A20 in acute kidney injury.Background: Acute kidney injury (AKI) is a major contributor to mortality and morbidity in hospitalized patients. A20 is a zinc finger protein that is upregulated in cells during inflammation, specifically in response to the production of tumor necrosis factor-alpha (TNF-α). The role of A20 is to mitigate apoptosis and inhibit NF-kB activation. Therefore, it is vital in regulation of the inflammatory response. Overexpression of A20 has been previously shown to be protective during inflammation. However, investigation on the role of A20 in acute kidney injury is unknown.
Methods: C57BL/6 mice underwent ENU mutagenesis to produce mutant A20 (∆) mice, which possess a single nucleotide polymorphism (SNP) within the A20 locus. Age- and gender-matched littermate control mice (wild-type, WT), heterozygous mice (A20¬∆/+) and homozygous (A20¬∆/∆) were challenged with renal ischemia reperfusion injury (IRI). All animals underwent analysis of renal function and biomolecular phenotyping.
Results: WT mice subjected to IRI demonstrated upregulation of the pro-inflammatory cytokine TNF-α but no significant change in A20 expression compared to sham-operated animals. A20¬∆/∆ and A20¬∆/+ mice both demonstrated lower serum creatinine (mean 56.3 ± 33.74, 91.69 ± 51.24 µmol/L respectively) compared to their littermate controls at 24 h reperfusion (mean 119.3 ± 57.62 µmol/L). There was a significant difference between A20¬∆/∆ and WT serum creatinine (p-value 0.01). There was no difference in weight loss. This result was reflected in decreased histological damage by light microscopy.
Conclusion: This SNP variant of A20 seems to be paradoxically protective in ischemic AKI. Identifying human A20 homologs to this SNP variant may provide an additional screening marker in the clinic.
Danny has previously completed a Bachelor of Medical Science at the University of Sydney studying Cell Pathology and Immunobiology. He also has previously completed a Winter Research Scholarship at the Heart Research Institute in cell therapeutics. He is currently undertaking an Honours year at the Centre for Transplant and Renal Research, Westmead Institute of Medical Research under the supervision of Dr Natasha Rogers.