Radiation-induced afferent arteriolar endothelial-dependent dysfunction involves decreased epoxygenase metabolites

Area of Science:

• Nephrology
• Vascular Biology
• Radiation Oncology

Background:

• Chronic kidney disease is a complication of hematopoietic stem cell transplant (HSCT).
• Irradiation during HSCT can cause kidney damage.
• A latent period exists between irradiation and kidney dysfunction development.

Purpose of the Study:

• To test if decreased endothelial-derived factors impair afferent arteriolar function after total body irradiation (TBI).
• To investigate the role of nitric oxide synthase (NOS), cyclooxygenase (COX), and epoxygenase (EPOX) in TBI-induced endothelial dysfunction.

Main Methods:

• WAG/RijCmcr rats received 11 Gy TBI.
• Afferent arteriolar responses to acetylcholine were measured at 1, 3, and 6 weeks post-TBI.
• Inhibitors of NOS, COX, and EPOX were used to evaluate their contribution to acetylcholine responses.
• Urinary EPOX metabolites were quantified.

Main Results:

• Endothelial-dependent vasodilation to acetylcholine was impaired at 3 and 6 weeks post-TBI.
• Nitric oxide synthase (NOS) inhibition significantly reduced acetylcholine responses in TBI rats.
• Epoxygenase (EPOX) inhibition showed a significant decrease in controls but not in TBI rats.
• Decreased urinary EPOX metabolites were observed at 3 weeks post-TBI.

Conclusions:

• Afferent arteriolar endothelial dysfunction after TBI involves decreased EPOX metabolites.
• This decrease precedes the onset of proteinuria, azotemia, and hypertension.
• EPOX pathway dysfunction is an early event in radiation-induced kidney injury.