JNK1 BUT NOT JNK2 PROMOTES RENAL ISCHAEMIA/REPERFUSION INJURY

K GRYNBERG1,2, E OZOLS1,2, W MULLEY1,2, K BLEASE3, DJ NIKOLICPATERSON1,2, FYMA1,2

1Department of Nephrology, Monash Medical Centre, Clayton, Victoria; 2Centre for Inflammatory Diseases, Monash University, Clayton, Victoria; 3Celgene, San Diego, California, USA

Aim: To determine the relative contribution of JNK1 versus JNK2 in renal ischaemia/reperfusion (I/R) injury.

Background: Tubular activation of the c-Jun amino-terminal kinase (JNK) pathway is prominent in most forms of acute and progressive tubulointerstitial damage, including I/R injury. Both Jnk1 and Jnk2 genes are expressed in most cells of the kidney resulting in considerable redundancy. JNK1 has been linked to apoptosis but its specific role in I/R injury is unknown. Genetic deletion (Jnk1-/- or Jnk2-/-) and selective JNK1 inhibition (CC-90001) were used.

Methods: Bilateral warm renal ischaemia was induced with vascular clamps and animals killed 24hr after reperfusion. Controls were sham operated. Renal I/R injury studies were performed in Jnk1-/- (n=10), Jnk2-/- (n=8) and wild type (WT) mice (n=10). In addition, renal I/R injury was induced in Sprague-Dawley rats with groups (n=8-10) treated 3 times with CC-90001 (10mg/kg) or vehicle starting 1 hour prior to surgery.

Results: Renal I/R injury caused acute renal failure at day 1 in WT mice (178.3±6.5umol/L vs 11.8±3.5umol/L serum creatinine (sCr) in sham con- trol; P<0.001). Jnk2-/- mice had comparable renal failure (sCr 169.8±23.0; P=NS). In a separate study, Jnk1-/- mice showed significant protection from I/R injury compared to WT mice (sCr 40.8±4.7 vs 74.9±11.9umol/L, respectively; P=0.01). This protection was associated with reduced tubular damage and decreased macrophage infiltration. Treatment with CC-90001 provided significant protection in rat I/R injury (sCr 86.4±5.7 vs 193.4±19.2umol/L in drug versus vehicle, respectively; P<0.001). CC-90001 treatment reduced tubular damage and macrophage infiltration.

Conclusions: Using two complementary approaches, we have established that JNK1 is crucial in renal I/R injury. Prophylactic JNK1 inhibition may have clinical utility in anticipate renal I/R injury.

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