Cyclophilin Inhibition Protects Against Experimental Acute Kidney Injury and Renal Interstitial Fibrosis

Int J Mol Sci. 2020 Dec 29;22(1):271. doi: 10.3390/ijms22010271.

Abstract

Cyclophilins have important homeostatic roles, but following tissue injury, cyclophilin A (CypA) can promote leukocyte recruitment and inflammation, while CypD can facilitate mitochondrial-dependent cell death. This study investigated the therapeutic potential of a selective cyclophilin inhibitor (GS-642362), which does not block calcineurin function, in mouse models of tubular cell necrosis and renal fibrosis. Mice underwent bilateral renal ischemia/reperfusion injury (IRI) and were killed 24 h later: treatment with 10 or 30 mg/kg/BID GS-642362 (or vehicle) began 1 h before surgery. In the second model, mice underwent unilateral ureteric obstruction (UUO) surgery and were killed 7 days later; treatment with 10 or 30 mg/kg/BID GS-642362 (or vehicle) began 1 h before surgery. GS-642362 treatment gave a profound and dose-dependent protection from acute renal failure in the IRI model. This protection was associated with reduced tubular cell death, including a dramatic reduction in neutrophil infiltration. In the UUO model, GS-642362 treatment significantly reduced tubular cell death, macrophage infiltration, and renal fibrosis. This protective effect was independent of the upregulation of IL-2 and activation of the stress-activated protein kinases (p38 and JNK). In conclusion, GS-642362 was effective in suppressing both acute kidney injury and renal fibrosis. These findings support further investigation of cyclophilin blockade in other types of acute and chronic kidney disease.

Keywords: acute kidney injury; cell death; chronic kidney disease; cyclophilin; inflammation; macrophage; neutrophil; renal fibrosis.

MeSH terms

  • Acute Kidney Injury / etiology*
  • Acute Kidney Injury / pathology
  • Acute Kidney Injury / prevention & control*
  • Animals
  • Cell Death
  • Cyclophilins / pharmacology*
  • Disease Models, Animal
  • Fibrosis
  • Kidney Cortex Necrosis / etiology*
  • Kidney Cortex Necrosis / pathology
  • Kidney Cortex Necrosis / prevention & control*
  • Kidney Tubules / metabolism
  • Macrophages / metabolism
  • Macrophages / pathology
  • Mice
  • Neutrophil Infiltration
  • Neutrophils / metabolism
  • Neutrophils / pathology
  • Oxygen / metabolism
  • Protective Agents / pharmacology*
  • Reperfusion Injury / etiology
  • Reperfusion Injury / metabolism
  • Reperfusion Injury / pathology

Substances

  • Protective Agents
  • Cyclophilins
  • Oxygen