Cyclophilin A Promotes Inflammation in Acute Kidney Injury but Not in Renal Fibrosis

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.

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

“…CypA−/− mice were protected against loss of renal function and tubular cell death in a 24 h model of renal IRI model. This protection was attributed to the profound reduction in neutrophil infiltration in CypA−/− mice, given that CypA−/− tubular cells are not protected from reactive oxygen species-induced cell death [ 36 ]. Thus, the dramatic protection seen against the loss of renal function with GS-642362 treatment in severe renal IRI may be due to the additive benefits of blockade of both CypD-mediated tubular necrosis and inhibition of CypA-dependent neutrophil-mediated tubular cell death and damage.…”

“…While CypA−/− mice are protected from renal IRI, they do not show protection in the day 7 UUO model in terms of tubular damage, macrophage infiltration, interstitial collagen IV deposition, or upregulation of kidney collagen I or α-SMA mRNA levels [ 36 ]. However, we cannot rule out a potential added benefit of blockade of both CypA and CypD using GS-642362 in the UUO model.…”

JUN Amino-Terminal Kinase 1 Signaling in the Proximal Tubule Causes Cell Death and Acute Renal Failure in Rat and Mouse Models of Renal Ischemia/Reperfusion Injury

“…Rats underwent bilateral IRI, as previously described. 14,15 Male rats were anesthetized with ketamine and xylazine. A heating blanket connected to a rectal thermometer was used to maintain body temperature at 37 C. Following a midline abdominal incision, both renal pedicles were clamped using non-traumatic vascular clamps for 25 minutes, during which the abdomen was temporarily sutured.…”

Kidney Inflammation, Injury and Regeneration 2020

“…In this current Special Edition, thirteen original research articles are presented: twelve in vivo studies in a murine or rat model and one in vitro study [ 3 ]. Seven studies show results from AKI models [ 4 , 5 , 6 , 7 , 8 , 9 , 10 ], five from fibrosis models (or CKD models) [ 9 , 11 , 12 , 13 , 14 ] and two from a transplant rejection model [ 4 , 15 ] (two studies used two different in vivo models).…”

“…Leong and coworkers showed that cyclophilin A, a damage-associated molecular pattern, promoted inflammation and acute kidney injury in a renal IR model but did not contribute to inflammation or interstitial fibrosis in a model of progressive kidney fibrosis (unilateral ureteric obstruction (UUO)) [ 9 ]. Other studies showed the effects of different proteins/peptides against UUO-induced renal injury, inflammation and fibrosis.…”