Abstract: SA-PO1069

A Dual COX2-sEH Inhibitor Prevents Sorafenib-Induced Renal Injury

Session Information

Category: Hypertension

  • 1102 Hypertension: Basic and Experimental - Renal Causes and Consequences

Authors

  • Imig, John D., Medical College of Wisconsin, Milwaukee, Wisconsin, United States
  • Khan, Abdul Hye, Medical College of Wisconsin, Milwaukee, Wisconsin, United States
  • Wang, Sung hee, UC Davis, Davis, California, United States
  • Hammock, Bruce, UC Davis, Davis, California, United States
Background

Anti-cancer drugs, vascular endothelial growth factor receptor tyrosine kinase inhibitors (VEGFRi) can cause hypertension and severe glomerular injury that compromises their effective and safe use. Glomerular cells generate arachidonic acid metabolites with actions that can cause glomerular injury. Therefore, we hypothesized that a novel dual cyclooxygenase-2 and soluble epoxide hydrolase (COX-2/sEH) inhibitor, PTUPB, would decrease deleterious arachidonic acid metabolites, lower blood pressure, and prevent glomerular injury caused by the VEGFRi, sorafenib.

Methods

Sprague-Dawley male rats were administered sorafenib (20 mg/kg/d p.o.) alone or in combination with PTUPB (10 mg/kg/d i.p.) for 4 weeks. Blood pressure was measured weekly and urine and renal tissues were collected from rats after the treatment period.

Results

Sorafenib administration increased blood pressure and this elevated blood pressure reached a plateau by day 14. PTUPB treatment slowed the progression of hypertension (control = 126 ± 7 mmHg; sorafenib = 162 ± 5 mmHg; sorafenib & PTUPB = 148 ± 4 mmHg, P<0.05). Sorafenib-induced renal injury was significantly reduced by PTUPB treatment. Albumin to creatinine ratio in sorafenib rats was significantly elevated compared to controls (sorafenib = 18.4 ± 3.5 µg/mg; control = 1.2 ± 0.3 µg/mg). PTUPB treatment decreased albuminuria by 70% (sorafenib & PTUPB = 6.3 ± 0.7 µg/mg, P<0.05). Kidney histological analysis determined that glomerular injury as well as medullary fibrosis and tubular cast formation were decreased in rats administered sorafenib and treated with PTUPB.

Conclusion

In conclusion, PTUPB slows the progression of hypertension and significantly decreases glomerular and renal injury in rats administered the VEGFRi, sorafenib. These findings indicate that a novel dual COX-2/sEH inhibitor, PTUPB combats the detrimental side effects of hypertension and severe glomerular injury that compromises the effective and safe use of anti-cancer VEGFRi therapies.

Funding

  • NIDDK Support