Abstract
Cyclophilin A (CypA) is a highly abundant protein in the cytoplasm of most mammalian cells. Beyond its homeostatic role in protein folding, CypA is a Damage-Associated Molecular Pattern which can promote inflammation during tissue injury. However, the role of CypA in kidney disease is largely unknown. This study investigates the contribution of CypA in two different types of kidney injury: acute tubular necrosis and progressive interstitial fibrosis. CypA (Ppia) gene deficient and wild type (WT) littermate controls underwent bilateral renal ischaemia/reperfusion injury (IRI) and were killed 24 h later or underwent left unilateral ureteric obstruction (UUO) and were killed 7 days later. In the IRI model, CypA−/− mice showed substantial protection against the loss of renal function and from tubular cell damage and death. This was attributed to a significant reduction in neutrophil and macrophage infiltration since CypA−/− tubular cells were not protected from oxidant-induced cell death in vitro. In the UUO model, CypA−/− mice were not protected from leukocyte infiltration or renal interstitial fibrosis. In conclusion, CypA promotes inflammation and acute kidney injury in renal IRI, but does not contribute to inflammation or interstitial fibrosis in a model of progressive kidney fibrosis.
Highlights
Cyclophilins are ubiquitously expressed proteins which belong to the immunophilin family [1,2]
This study found Cyclophilin A (CypA) to be important in leukocyte accumulation and acute renal injury in the ischaemia/reperfusion injury (IRI) model, but to be redundant in leukocyte accumulation and renal fibrosis in the ureteric obstruction (UUO) model
Necrosis is the main form of tubular cell death occurring after renal IRI, which is most prominent in the S3 segment of the proximal tubule due to its high energy requirements and disproportionate reduction in blood flow [31]
Summary
Cyclophilins are ubiquitously expressed proteins which belong to the immunophilin family [1,2]. Cyclophilin A (CypA) is a highly abundant cytoplasmic protein that is expressed by virtually all mammalian cells [1,2]. CypA can be released from cells via active secretion, or passively during necrotic cell death, and bind to CD147 on the surface of leukocytes, including neutrophils, monocyte/macrophages and T cells. CD147, the only known CypA receptor, is expressed by many non-leukocyte populations, including tubular epithelial cells of the kidney [1,9,10]. CD147 is a scavenger receptor which can bind many other ligands, including leukocyte integrins, Selectin E, CD44 and S100A9 [11]. Cd147 gene-deficient mice are sterile with a variety of abnormalities, consistent with CD147 being a receptor for multiple ligands [12,13]
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