KG LEONG1,2, E OZOLS1,2, J KANELLIS1,2, J LILES3,D NIKOLIC-PATERSON1,2, F MA1,2
1Department of Nephrology, Monash Medical Centre, Clayton, Australia, 2Centre for Inflammatory Disease, Monash University, Clayton, Australia, 3Gilead Sciences, Foster City, USA
Aims: Determine whether therapeutic inhibition of cyclophilin (Cyp) function can suppress renal fibrosis in unilateral ureteric obstruction (UUO) and if cyclophilin A (CypA) has a specific role in this response.
Background: Cyclophilins are enzymes that regulate protein folding. Within this enzyme family, CypA promotes leukocyte recruitment and inflammation while CypD facilitates mitochondrial-dependent cell death. However, the role of cyclophilins in renal fibrosis is poorly understood.
Methods: C57BL/6J mice underwent UUO surgery and were killed on day 7; groups (n=10) were treated with 30mg/kg/BID of a pan-cyclophilin inhibitor (CYPi, which does not block calcineurin function) or vehicle by oral gavage from 1hr before surgery and continued to day 7. In addition, groups (n=10) of CypA-/- and wild type mice were killed on day 7 post-UUO. Controls had no UUO surgery.
Results: Compared to vehicle, CYPi treatment significantly reduced renal fibrosis in the obstructed kidney based on ↓37% collagen IV and ↓22% α-SMA staining area (P<0.01 vs vehicle) and reduced mRNA levels of α-SMA, collagen I, III and IV and TGF-b1 (all P<0.01 vs vehicle). CYPi treatment also reduced TUNEL+ apoptotic tubular cells by 60%, and reduced macrophage infiltration (P<0.001 vs vehicle). By contrast, CypA-/- mice showed no difference in renal fibrosis or in the infiltration of macrophages or T cells compared to wild type UUO mice.
Conclusions: Cyclophilins contribute to the development of renal fibrosis, inflammation and tubular apoptosis in obstructed kidney, although this does not involve CypA. Therapeutic targetting of cyclophilins, independent of calcineurin function, has potential for the treatment of renal fibrosis.
Nephrologist undergoing my lab-based PhD studies at Department of Nephrology, Monash Health.