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Radiation‐induced Afferent Arteriolar Endothelial Dysfunction Involves Decreased Epoxygenase Metabolites
Author(s) -
Sharma Amit,
Khan Md. Abdul Hye,
Fish Brian,
Cohen Eric P.,
Imig John D.
Publication year - 2016
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.30.1_supplement.739.5
Subject(s) - azotemia , medicine , acetylcholine , endocrinology , endothelial dysfunction , afferent arterioles , blood pressure , angiotensin ii , renal function
Chronic kidney disease (CKD) occurs in 15% of hematopoietic stem cell transplant (HSCT) patients, and as been clearly linked to irradiation at the time of the HSCT. CKD due to radiation also occurs after radionuclide therapy for cancer. There is a 6–8 week latent period after irradiation that leads to the development of proteinuria, azotemia, and hypertension in rats. We have previously demonstrated that impaired endothelial‐dependent responses to acetylcholine occur at 3 and 6 weeks that occur prior to the development of proteinuria, azotemia, and hypertension in rats. The current study tested the hypothesis that decreased endothelial‐derived relaxing factors contribute to the impaired afferent arteriolar responses to acetylcholine in rats exposed to total body irradiation (TBI). Male WAG/RijCmcr rats were subjected to TBI (11 Gy) and afferent arteriolar responses to acetylcholine using the juxtamedullary nephron technique were determined at three weeks. Systolic blood pressure (118 ± 5 vs. 121 ± 6 mmHg) and BUN (15.2 ± 1.3 vs. 15.7 ± 0.7 mg/dl) were not different between control and TBI groups. Afferent arteriolar diameters averaged 21.4 ± 0.9 ±m (n=25) in controls and 21.5 ± 0.8 ±m (n=25) in TBI rats. During exposure to acetylcholine (0.01. 0.1, 1, and 10 ±mol/L), afferent diameter increased by 8±2%, 18±3%, 27±2% and 31±3% in control rats (n=7), and the acetylcholine response was impaired in TBI and averaged 3±2%, 9±3%, 12±3%, and 16±3% (n=7, p<0.05). The nitric oxide synthase (NOS) inhibitor, L‐NAME, reduced the afferent arteriolar acetylcholine response by 50% in controls and 90% (p<0.05) in 3‐week TBI rats. Cyclooxygenase (COX) inhibition with indomethacin did not significantly alter the acetylcholine response in the presence or absence of L‐NAME. Epoxygenase (EPOX) inhibition with MS‐PPOH significantly decreased the acetylcholine responses (35%) in controls but did not significantly alter the acetylcholine responses (4%) in TBI rats. Combined inhibition of NOS, COX, and EPOX pathways eliminated the afferent arteriolar response to acetylcholine in control and TBI rats. Renal microvascular protein expression of CYP2C, COX2, and NOS revealed decreased EPOX expression of CYP2C23 (±45±6%) and CYP2C11 (±12±4%) at 3 weeks TBI. COX‐1, COX‐2, and eNOS renal microvascular protein expression was not altered at 3 weeks TBI. Taken together, these results indicate that the impaired afferent arteriolar endothelial‐dependent acetylcholine responses involve decreased EPOX activity that precedes the development of proteinuria, azotemia, and hypertension in irradiated rats.