Abstract: SA-PO088
JNK Signalling Mediates Oxidant-Induced Tubular Epithelial Cell Death
Session Information
- AKI: Mechanisms - Primary Injury and Repair - II
November 09, 2019 | Location: Exhibit Hall, Walter E. Washington Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Acute Kidney Injury
- 103 AKI: Mechanisms
Authors
- Grynberg, Keren, Department of Nephrology, Monash Medical Centre, Monash, Victoria, Australia
- Tesch, Gregory H., Department of Nephrology, Monash Medical Centre, Monash, Victoria, Australia
- Ozols, Elyce, Department of Nephrology, Monash Medical Centre, Monash, Victoria, Australia
- Mulley, William R., Department of Nephrology, Monash Medical Centre, Monash, Victoria, Australia
- Nikolic-Paterson, David J., Department of Nephrology, Monash Medical Centre, Monash, Victoria, Australia
- Ma, Frank Yuanfang, Department of Nephrology, Monash Medical Centre, Monash, Victoria, Australia
Background
The reactive oxygen species-inducible JNK signaling pathway is activated in tubular cells within 20min of renal ischaemia/reperfusion (I/R) injury. Tubular cell death following I/R injury is reduced by systemic JNK inhibitor treatment, but whether this is a direct or indirect effect and the contribution of JNK1 versus JNK2 isoforms are unclear. We aimed to define the role of JNK1 versus JNK2 signaling in oxidant-induced tubular cell death and whether this mechanism also operates in diabetes.
Methods
Bilateral renal I/R injury was induced in groups (n=8 to 10) of male wild type (WT), Jnk1-/-, Jnk2-/-, and Jnk1f/f γGT-Cre mice (all C57BL/6J) which were killed 24hr later. Diabetes was induced in WT mice by 5 low dose streptozotocin (STZ) injections.
Results
Compared to renal I/R injury in WT mice, Jnk1-/- but not Jnk2-/- mice were significantly protected from tubular cell death (PAS and cleaved caspase 3 staining) and renal failure (serum creatinine) (both P<0.01). Furthermore, conditional deletion of Jnk1 in proximal tubular cells (Jnk1f/f γGT-Cre mice) also showed a significant reduction in tubular cell death and renal failure (both P<0.01 vs WT I/R). H2O2 (0.25 to 1mM) induced dose-dependent cell death in primary cultures of WT tubular epithelial cells (TEC); however, Jnk1-/- TEC showed 50%↓ cell death (P<0.001), whereas Jnk2-/- TEC showed no protection. A JNK inhibitor reduced H2O2-induced cell death in WT and Jnk2-/- TEC by 50%, but did not affect cell death in Jnk1-/- TEC. In a further study, renal I/R injury was induced in WT mice 8 weeks after STZ-induced diabetes. Compared to non-diabetic controls, I/R injury caused increased JNK signalling, greater tubular cell death and more severe renal failure (all P<0.01 vs non-diabetic I/R). Culture of WT TEC in high glucose for 48hr increased H2O2-induced cell death. However, a JNK inhibitor reduced H2O2-induced cell death under high glucose by 38 to 45% (P<0.001).
Conclusion
JNK1 but not JNK2 direct contributes to oxidant-induced tubular cell death in vivo and in vitro. JNK signalling may also promote the enhanced tubular cell death and renal failure seen in renal I/R injury in established diabetes.