Kidney Week

Abstract: FR-PO117

Cyclophilin D Deficiency Is Not Protective in Aristolochic Acid Nephropathy

Session Information

• Molecular Mechanisms of CKD - II
  October 26, 2018 | Location: Exhibit Hall, San Diego Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: CKD (Non-Dialysis)

• 1903 CKD (Non-Dialysis): Mechanisms

Authors

• Leong, Khai Gene, Monash Health, Clayton, Victoria, Australia

Khai Gene Leong,

• Ozols, Elyce, Monash Health, Clayton, Victoria, Australia

Elyce Ozols,

• Kanellis, John, Monash Health, Clayton, Victoria, Australia

John Kanellis,

• Nikolic-Paterson, David J., Monash Health, Clayton, Victoria, Australia

David J. Nikolic-Paterson,

• Ma, Frank Yuanfang, Monash Health, Clayton, Victoria, Australia

Frank Yuanfang Ma,

Background

Cyclophilins are a family of enzymes which regulate protein folding. Of these enzymes, cyclophilin D (CypD) facilitates mitochondrial-dependant cell death during pathological conditions. CypD-/- mice are protected from acute kidney injury (AKI) following renal ischaemia/reperfusion injury, and exhibit less renal fibrosis in the unilateral ureteric obstruction model. However, the contribution of CypD in the transition of AKI to chronic kidney disease (CKD) is not known. The aim of this study was to determine the role of CypD in promoting the transition of AKI to CKD using the aristolochic acid-induced nephropathy (AAN) model.

Methods

Groups (n=10) of wild type (WT) and CypD-/- mice on the C57BL/6J background were given intraperitoneal injections of 2mg/kg aristolochic acid every 2^nd day for 28 days. Mice were killed on day 28. Controls were untreated.

Results

AAN caused >2.5-fold rise in serum creatinine (sCr) in WT mice (34.3±9.9mmol/L vs 13.5±2.3mmol/L in controls; P<0.0001), with evidence of tubular damage (KIM-1 & α-Klotho mRNA levels; P<0.0001), increase in tubular cell death (cleaved caspase-3+ cells; P<0.0001), and significant renal fibrosis (collagen IV immunostaining, and collagen I & α-SMA mRNA levels; all P<0.0001 vs controls). CypD-/- mice were not protected from AA-induced renal dysfunction (sCr 37.0±14.3 mmol/L; P=N.S.), and showed no reduction in tubular damage, cell death or renal fibrosis. Further analysis showed that AAN in WT mice caused loss of peritubular CD31+ capillaries (P<0.0001), and infiltration of macrophages (CD68 & CD206 mRNA levels; P<0.0001) and T-cells (CD3 & IL-2 mRNA levels; P<0.0001). CypD-/- mice were not protected from peritubular capillary loss or macrophage infiltration in AAN. However, CypD-/- mice showed reduced T-cell infiltration and activation (CD3 & IL-2 mRNA levels; P<0.0001), including Th1 cells (T-bet mRNA levels; P<0.05).

Conclusion

CypD does not contribute to the transition of AKI to CKD in experimental AAN.