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Kidney Week

Abstract: TH-PO031

The Role of Cyclophilin D in Acute vs. Chronic Aristolochic Acid Nephropathy

Session Information

Category: Acute Kidney Injury

  • 103 AKI: Mechanisms


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

Cyclophilin D (CypD) facilitates mitochondrial-dependant cell death during pathological conditions. CypD-/- mice are protected from acute kidney injury (AKI) following ischaemia/reperfusion injury and show reduced renal fibrosis in the unilateral ureteric obstruction model. However, the contribution of CypD in aristolochic acid (AA) induced AKI or AA-induced chronic kidney disease (CKD) is unknown. We aim to determine the role of CypD in: 1) acute AA-induced nephropathy (AAN); and 2) chronic AAN.


Groups (n=10) of CypD-/- and wild type (WT) C57BL/6J mice were used. Study 1: Mice were given an intraperitoneal (IP) injection of 5mg/kg AA and killed 3 days later. Study 2: Mice were given IP injections of 2mg/kg AA every 2nd day and killed on day 28. Controls were untreated.


Study 1: Acute high dose AA caused renal failure in WT mice (39.7±7.1mmol/L vs 13.5±2.3mmol/L serum creatinine (SCr) in controls; P<0.0001) with evidence of tubular damage and cell death on PAS sections and increased cleaved caspase-3+ cells. Acute AAN also caused inflammation with infiltrating neutrophils and T cells and up-regulation of IL-36a mRNA levels. CypD-/- mice were protected from AA-induced acute renal dysfunction (18.9±9.5 mmol/L SCr; P<0.0001 vs WT AAN). CypD-/- mice showed reduced tubular damage and cell death on PAS and reduced cleaved caspase-3+ cells (both P<0.001 vs WT AAN), as well as reduced neutrophil infiltration and IL-36α mRNA levels (both P<0.001 vs WT AAN). Study 2: Chronic AA administration caused renal impairment in WT mice (34.3±9.9mmol/L SCr), with evidence of chronic tubular damage (KIM-1 & a-Klotho mRNA levels), increase in tubular cell death (cleaved caspase-3+ cells), and significant renal fibrosis (increased collagen IV deposition). However, CypD-/- mice were not protected from chronic AA-induced renal dysfunction (37.0±14.3 mmol/L SCr; P=NS) and showed no reduction in tubular damage, cell death or renal fibrosis.


CypD contributes to tubular cell death and renal inflammation in acute AAN. However, CypD does not contribute to the transition of AKI to CKD in chronic AAN.