Epoxyeicosatrienoic acid analogue mitigates kidney injury in a rat model of radiation nephropathy

Md Abdul Hye Khan, Brian Fish, Geneva Wahl, Amit Sharma, J R Falck, Mahesh P. Paudyal, John E. Moulder, John D. Imig, Eric P. Cohen

Research output: Contribution to journalArticle

10 Citations (Scopus)

Abstract

Arachidonic acid is metabolized to epoxyeicosatrienoic acids (EETs) by CYP epoxygenases, and EETs are kidney protective in multiple pathologies. We determined the ability of an EET analogue, EET-A, to mitigate experimental radiation nephropathy. The kidney expression of the EET producing enzyme CYP2C11 was lower in rats that received total body irradiation (TBI rat) compared with non-irradiated control. At 12 weeks after TBI, the rats had higher systolic blood pressure and impaired renal afferent arteriolar function compared with control, and EET-A or captopril mitigated these abnormalities. The TBI rats had 3-fold higher blood urea nitrogen (BUN) compared with control, and EET-A or captopril decreased BUN by 40-60 %. The urine albumin/creatinine ratio was increased 94-fold in TBI rats, and EET-A or captopril attenuated that increase by 60-90 %. In TBI rats, nephrinuria was elevated 30-fold and EET-A or captopril decreased it by 50-90 %. Renal interstitial fibrosis, tubular and glomerular injury were present in the TBI rats, and each was decreased by EET-A or captopril. We further demonstrated elevated renal parenchymal apoptosis in TBI rats, which was mitigated by EET-A or captopril. Additional studies revealed that captopril or EET-A mitigated renal apoptosis by acting on the p53/Fas/FasL (Fas ligand) apoptotic pathway. The present study demonstrates a novel EET analogue-based strategy for mitigation of experimental radiation nephropathy by improving renal afferent arteriolar function and by decreasing renal apoptosis.

Original languageEnglish (US)
Pages (from-to)587-599
Number of pages13
JournalClinical Science
Volume130
Issue number8
DOIs
StatePublished - Apr 1 2016

Fingerprint

Captopril
Radiation
Kidney
Acids
Wounds and Injuries
Blood Urea Nitrogen
Apoptosis
Fas Ligand Protein
Whole-Body Irradiation
Arachidonic Acid
Albumins
Creatinine
Fibrosis
Urine
Pathology
Blood Pressure
Hypertension
Enzymes

Keywords

  • Afferent arteriole
  • Apoptosis
  • Fas
  • Novel small lipid molecule
  • Radiotherapy

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Khan, M. A. H., Fish, B., Wahl, G., Sharma, A., Falck, J. R., Paudyal, M. P., ... Cohen, E. P. (2016). Epoxyeicosatrienoic acid analogue mitigates kidney injury in a rat model of radiation nephropathy. Clinical Science, 130(8), 587-599. https://doi.org/10.1042/CS20150778

Epoxyeicosatrienoic acid analogue mitigates kidney injury in a rat model of radiation nephropathy. / Khan, Md Abdul Hye; Fish, Brian; Wahl, Geneva; Sharma, Amit; Falck, J R; Paudyal, Mahesh P.; Moulder, John E.; Imig, John D.; Cohen, Eric P.

In: Clinical Science, Vol. 130, No. 8, 01.04.2016, p. 587-599.

Research output: Contribution to journalArticle

Khan, MAH, Fish, B, Wahl, G, Sharma, A, Falck, JR, Paudyal, MP, Moulder, JE, Imig, JD & Cohen, EP 2016, 'Epoxyeicosatrienoic acid analogue mitigates kidney injury in a rat model of radiation nephropathy', Clinical Science, vol. 130, no. 8, pp. 587-599. https://doi.org/10.1042/CS20150778
Khan, Md Abdul Hye ; Fish, Brian ; Wahl, Geneva ; Sharma, Amit ; Falck, J R ; Paudyal, Mahesh P. ; Moulder, John E. ; Imig, John D. ; Cohen, Eric P. / Epoxyeicosatrienoic acid analogue mitigates kidney injury in a rat model of radiation nephropathy. In: Clinical Science. 2016 ; Vol. 130, No. 8. pp. 587-599.
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AU - Paudyal, Mahesh P.

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AB - Arachidonic acid is metabolized to epoxyeicosatrienoic acids (EETs) by CYP epoxygenases, and EETs are kidney protective in multiple pathologies. We determined the ability of an EET analogue, EET-A, to mitigate experimental radiation nephropathy. The kidney expression of the EET producing enzyme CYP2C11 was lower in rats that received total body irradiation (TBI rat) compared with non-irradiated control. At 12 weeks after TBI, the rats had higher systolic blood pressure and impaired renal afferent arteriolar function compared with control, and EET-A or captopril mitigated these abnormalities. The TBI rats had 3-fold higher blood urea nitrogen (BUN) compared with control, and EET-A or captopril decreased BUN by 40-60 %. The urine albumin/creatinine ratio was increased 94-fold in TBI rats, and EET-A or captopril attenuated that increase by 60-90 %. In TBI rats, nephrinuria was elevated 30-fold and EET-A or captopril decreased it by 50-90 %. Renal interstitial fibrosis, tubular and glomerular injury were present in the TBI rats, and each was decreased by EET-A or captopril. We further demonstrated elevated renal parenchymal apoptosis in TBI rats, which was mitigated by EET-A or captopril. Additional studies revealed that captopril or EET-A mitigated renal apoptosis by acting on the p53/Fas/FasL (Fas ligand) apoptotic pathway. The present study demonstrates a novel EET analogue-based strategy for mitigation of experimental radiation nephropathy by improving renal afferent arteriolar function and by decreasing renal apoptosis.

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