FY MA1,2, E OZOLS1,2, P CHEW1,2, P VITORINO3, D SPERANDIO,3 AS RAY,3 J LILES3, DJ NIKOLIC-PATERSON1,2.
1Department of Nephrology, Monash Medical Centre, Clayton, Victoria; 2Centre for Inflammatory Diseases, Monash University, Clayton, Victoria; 3Gilead Sciences, Foster City, CA, USA.
Aim: To determine whether cannabinoids promote renal fibrosis via the CNR1.
Background: Cannabinoids act in the nervous system and the periphery through type 1 and 2 cannabinoid receptors (CNR1 and CNR2). These receptors play opposing roles in models of diabetic nephropathy with CNR1 antagonists and CNR2 agonists being protective. We sought to determine whether CNR1 directly promotes renal fibrosis using a selective, peripherally acting CNR1 antagonist (CNR1i).
Methods: Wistar rats underwent unilateral ureteric obstruction (UUO) surgery. Groups (n=10) were treated with 60mg/kg/BID CNR1i by oral gavage or vehicle from the time of surgery until being killed 7 days later.
Results: Vehicle treated UUO kidneys displayed a marked increase in the area of interstitial collagen IV and a-SMA staining which was reduced by 37% and 27%, respectively, by CNR1i (both P<0.001). PCR analysis showed that CNR1i treatment reduced mRNA levels of pro-fibrotic molecules (Col I, Col IV, a-SMA, TGF-b1; all P<0.01 vs vehicle). This was associated with a reduction in CCL2 mRNA expression and macrophage infiltration. Western blotting found that CNR1i treatment significantly inhibited ERK and JNK activation in the UUO kidney, whereas Akt activation was unaffected.
Conclusions: Peripheral blockade of CNR1 significantly attenuated renal interstitial fibrosis in the obstructed kidney.