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Abstract: SA-PO596

Cyclophilin A Promotes AKI and Inflammation Following Renal Ischaemia/Reperfusion Injury

Session Information

Category: Acute Kidney Injury

  • 103 AKI: Mechanisms

Authors

  • Leong, Khai Gene, Monash Health, Clayton, Victoria, Australia
  • Ozols, Elyce, Monash Health, Clayton, Victoria, Australia
  • Kanellis, John, Monash Health, Clayton, Victoria, Australia
  • Nikolic-Paterson, David J., Monash Health, Clayton, Victoria, Australia
  • Ma, Frank Yuanfang, Monash Health, Clayton, Victoria, Australia
Background

Cyclophilins are enzymes that regulate protein folding. During various pathological conditions, cyclophilin A (CypA) has been shown to promote leukocyte recruitment and inflammation. However, the contribution of CypA in acute kidney injury (AKI) and renal fibrosis is poorly understood. The aim of this study was to determine the role of CypA in renal tubular damage, inflammation, and fibrosis using the: (1) renal ischaemia/reperfusion injury (IRI), and (2) unilateral ureteric obstruction (UUO) models.

Methods

Groups (n=10) of wild type (WT) and CypA-/- mice on the 129 background were subjected to either: (1) bilateral renal IRI (19min at 37°C) and killed 24 hours post reperfusion, or (2) UUO surgery and killed on day 7. Controls were sham operated.

Results

Renal IRI induced AKI with a >6-fold rise in serum creatinine (sCr) in WT mice (41±13.8 vs 6.3±1.7umol/L in sham; P<0.0001) and marked tubular damage based on the tubular injury score, increased KIM-1 mRNA levels, and tubular cell death (TUNEL+ cells; all P<0.0001 vs sham). CypA-/- mice were protected from renal dysfunction with a 50% improvement of sCr (20.7±3.5umol/L; P<0.0001), less histologic tubular damage (P<0.01), lower KIM-1 mRNA levels (P<0.01), and less tubular cell death (P<0.001). Renal IRI caused upregulated mRNA levels of inflammatory molecules (TNF-α and IL-36-α; P<0.05), and neutrophil infiltration (Ly6G+ cells; P<0.0001). CypA-/- mice had a clear reduction in inflammatory molecules (P<0.05) and less infiltrating neutrophils (P<0.001). UUO in WT mice resulted in significant renal fibrosis (3-fold increase in collagen IV deposition by immunostaining; P<0.001 vs sham), with significant infiltrates of macrophages (F4/80+ cells), T cells (CD3+ cells) and neutrophils (Ly6G+ cells) (all P<0.0001 vs sham). CypA-/- mice were not protected from renal fibrosis or leukocyte infiltration in the UUO model.

Conclusion

CypA contributes to leukocyte infiltration and inflammation leading to AKI following IRI. In comparison, the leukocyte infiltration and renal fibrosis seen following the less severe tubular injury in UUO does not require CypA. This contrast may relate to differences in CypA release/secretion by tubular cells in the two models.