Abstract: TH-PO261

Activation of the Cholinergic Anti-Inflammatory Pathway by GTS-21 Attenuates Cisplatin-Induced AKI

Session Information

Category: Acute Kidney Injury

  • 001 AKI: Basic

Authors

  • Chatterjee, Prodyot K., Feinstein Institute for Medical Research, Manhasset, New York, United States
  • Yeboah, Michael M., Medical College of Wisconsin, Milwaukee, Wisconsin, United States
  • Solanki, Malvika H., Medical College of Wisconsin, Milwaukee, Wisconsin, United States
  • Kumar, Gopal, Northwell Health, Manhasset, New York, United States
  • Xue, Xiangying, Feinstein Institute for Medical Research, Manhasset, New York, United States
  • Pavlov, Valentin A, Feinstein Institute for Medical Research, Manhasset, New York, United States
  • Al-Abed, Yousef, Feinstein Institute for Medical Research, Manhasset, New York, United States
  • Metz, Christine N., Feinstein Institute for Medical Research, Manhasset, New York, United States
Background

Acute kidney injury (AKI) is the most common side effect of cisplatin, a widely used chemotherapeutic agent. Although AKI occurs in up to 1/3 of patients treated with cisplatin, effective protective strategies are lacking. Cisplatin targets renal proximal tubular epithelial cells leading to the production of reactive oxygen species (ROS), inflammation, tubular cell injury, and eventually cell death. The cholinergic anti-inflammatory pathway is a vagus nerve-mediated physiological mechanism that suppresses inflammation via α7nicotinic acetylcholine receptors (α7nAChRs). Our previous studies demonstrated the renoprotective effects of α7nAChR agonists (e.g. GTS-21) in murine renal ischemia reperfusion injury and sepsis-induced AKI. Therefore, we examined the effect of GTS-21 on cisplatin-AKI.

Methods

Male C57BL/6 mice were treated with either saline or GTS-21 (4mg/kg, i.p.) twice daily for 4 days before cisplatin (20mg/kg, i.p.); 72 hrs later mice were euthanized and their plasma and kidneys were analyzed for markers of renal injury, ROS, and inflammation, as well as renal ATP levels, renal cisplatin accumulation and the expression of cisplatin influx and efflux transporters.

Results

GTS-21 significantly reduced cisplatin-induced renal dysfunction and injury. GTS-21 significantly attenuated renal Ptgs2/COX-2, IL-6, IL-1β, and CXCL1 expression, as well as neutrophil infiltration and MPO activity after cisplatin. GTS-21 blunted cisplatin-induced ERK1/2 activation, oxidative stress, as well as renal ATP depletion and apoptosis (p<0.05). GTS-21 suppressed cisplatin influx transporter CTR1 expression and enhanced the expression of cisplatin efflux transporters MRP2, MRP4, and MRP6 (p<0.05). Using cancer cell lines we showed that GTS-21 did not inhibit cisplatin’s tumor killing activity.

Conclusion

GTS-21 protects against cisplatin-AKI by attenuating renal cytokine/chemokine expression, ROS, and mitochondrial dysfunction, as well as by decreasing renal cisplatin influx and increasing efflux. GTS-21 does not impair cisplatin-mediated tumor cell killing. Our results support further exploring the cholinergic anti-inflammatory pathway for preventing cisplatin-induced AKI.

Funding

  • Private Foundation Support