Abstract: TH-OR013
JNK1 Promotes Renal Ischaemia-Reperfusion Injury
Session Information
- Cellular Responses to Kidney Injury
November 02, 2017 | Location: Room 395, Morial Convention Center
Abstract Time: 04:54 PM - 05:06 PM
Category: Acute Kidney Injury
- 001 AKI: Basic
Authors
- Grynberg, Keren, Department of Nephrology, Monash Medical Centre, Monash, Victoria, Austria
- Ozols, Elyce, Department of Nephrology, Monash Medical Centre, Monash, Victoria, Austria
- Mulley, William R., Department of Nephrology, Monash Medical Centre, Monash, Victoria, Austria
- Blease, Kate, Celgene, San Diego, California, United States
- Nikolic-Paterson, David J., Department of Nephrology, Monash Medical Centre, Monash, Victoria, Austria
- Ma, Frank Yuanfang, Department of Nephrology, Monash Medical Centre, Monash, Victoria, Austria
Background
Tubular activation of the c-Jun amino-terminal kinase (JNK) pathway is prominent in most forms of acute and progressive tubulointerstitial damage, including renal ischaemia/reperfusion (I/R) injury. Both Jnk1 and Jnk2 genes are expressed in most cells of the kidney resulting in considerable redundancy. Combined blockade of JNK1/2 is known to be protective in renal I/R injury; however, the relative contribution of each isoform is unknown. The aim of this study is to determine the relative contribution of JNK1 versus JNK2 in renal I/R injury.
Methods
Preferential pharmacological inhibition of JNK1 (CC90001) was compared to mice with global deletion of Jnk1 or Jnk2 and mice with combined global Jnk2 deletion plus Jnk1 deletion in proximal tubular cells (Jnk-PT mice). Bilateral warm renal ischaemia injury was induced with vascular clamps and animals killed 24hr after reperfusion. Controls were sham operated. Sprague-Dawley rats (n=8-10/group) were treated 3 times with CC-90001 (10mg/kg) or vehicle starting 1 hour prior to surgery. Renal I/R injury studies were also performed in Jnk1-/- (n=10), Jnk2-/- (n=8), Jnk PT (n=8) and wild type (WT) mice (n=10).
Results
Treatment with CC-90001 provided significant protection in rat I/R injury
(8±0.5 vs 20±2 fold increase in serum creatinine (sCR), drug versus vehicle, respectively; P<0.001). In a separate study, Jnk1-/- mice also showed significant protection from I/R injury compared to WT mice (4±0.5 vs 8±1 fold increase in sCr respectively; p=0.01); however, this was not replicated in Jnk2-/- mice (16±0.5 vs 15±2 fold increase in sCr, Jnk2-/- versus WT, respectively; p=NS). Jnk-PT mice exposed to renal I/R injury showed significant protection from injury compared to WT mice (5.5±0.7 vs 15±2 fold increase in sCr respectively p<0.01). CC-90001 treatment reduced tubular damage and macrophage infiltration. This protection was replicated in Jnk1-/- and Jnk-PT mice.
Conclusion
Using complementary approaches, we have established that JNK1 in the proximal tubule is crucial for renal IR injury. Prophylactic JNK1 inhibition may have clinical utility in anticipated renal IR injury.
Funding
- Commercial Support –