Increased blood pressure in mice lacking cytochrome P450 2J5

Krairerk Athirakul, J. Alyce Bradbury, Joan P. Graves, Laura M. DeGraff, Jixiang Ma, Yun Zhao, John F. Couse, Raymond Quigley, David R. Harder, Xueying Zhao, John D. Imig, Theresa L. Pedersen, John W. Newman, Bruce D. Hammock, Alan J Conley, Kenneth S. Korach, Thomas M. Coffman, Darryl C. Zeldin

Research output: Contribution to journalArticle

48 Citations (Scopus)

Abstract

The cytochrome P450 (CYP) enzymes participate in a wide range of biochemical functions, including metabolism of arachidonic acid and steroid hormones. Mouse CYP2J5 is abundant in the kidney where its products, the cis-epoxyeicosatrienoic acids (EETs), modulate sodium transport and vascular tone. To define the physiological role of CYP2J5 in the kidney, knockout mice were generated using a conventional gene targeting approach. Cyp2j5 (-/-) mice develop normally and exhibit no overt renal pathology. While renal EET biosynthesis was apparently unaffected by the absence of CYP2J5, deficiency of this CYP in female mice was associated with increased blood pressure, enhanced proximal tubular transport rates, and exaggerated afferent arteriolar responses to angiotensin II and endothelin I. Interestingly, plasma 17β-estradiol levels were reduced in female Cyp2j5 (-/-) mice and estrogen replacement restored blood pressure and vascular responsiveness to normal levels. There was no evidence of enhanced estrogen metabolism, or altered expression or activities of steroidogenic enzymes in female Cyp2j5 (-/-) mice, but their plasma levels of luteinizing hormone and follicle stimulating hormone were inappropriately low. Together, our findings illustrate a sex-specific role for CYP2J5 in regulation of blood pressure, proximal tubular transport, and afferent arteriolar responsiveness via an estrogen-dependent mechanism.

Original languageEnglish (US)
Pages (from-to)4096-4108
Number of pages13
JournalFASEB Journal
Volume22
Issue number12
DOIs
StatePublished - Dec 2008

Fingerprint

Blood pressure
Cytochrome P-450 Enzyme System
Estrogens
Blood Pressure
Metabolism
Kidney
Steroid hormones
NSC 153174
Plasmas
Biosynthesis
Endothelins
Follicle Stimulating Hormone
Pathology
Blood Vessels
Luteinizing Hormone
Arachidonic Acid
Angiotensin II
Estradiol
Genes
Sodium

Keywords

  • Eicosanoid
  • Estrogen
  • Hypertension
  • Proximal tubule
  • Vascular responsiveness

ASJC Scopus subject areas

  • Biochemistry
  • Biotechnology
  • Genetics
  • Molecular Biology

Cite this

Athirakul, K., Bradbury, J. A., Graves, J. P., DeGraff, L. M., Ma, J., Zhao, Y., ... Zeldin, D. C. (2008). Increased blood pressure in mice lacking cytochrome P450 2J5. FASEB Journal, 22(12), 4096-4108. https://doi.org/10.1096/fj.08-114413

Increased blood pressure in mice lacking cytochrome P450 2J5. / Athirakul, Krairerk; Bradbury, J. Alyce; Graves, Joan P.; DeGraff, Laura M.; Ma, Jixiang; Zhao, Yun; Couse, John F.; Quigley, Raymond; Harder, David R.; Zhao, Xueying; Imig, John D.; Pedersen, Theresa L.; Newman, John W.; Hammock, Bruce D.; Conley, Alan J; Korach, Kenneth S.; Coffman, Thomas M.; Zeldin, Darryl C.

In: FASEB Journal, Vol. 22, No. 12, 12.2008, p. 4096-4108.

Research output: Contribution to journalArticle

Athirakul, K, Bradbury, JA, Graves, JP, DeGraff, LM, Ma, J, Zhao, Y, Couse, JF, Quigley, R, Harder, DR, Zhao, X, Imig, JD, Pedersen, TL, Newman, JW, Hammock, BD, Conley, AJ, Korach, KS, Coffman, TM & Zeldin, DC 2008, 'Increased blood pressure in mice lacking cytochrome P450 2J5', FASEB Journal, vol. 22, no. 12, pp. 4096-4108. https://doi.org/10.1096/fj.08-114413
Athirakul K, Bradbury JA, Graves JP, DeGraff LM, Ma J, Zhao Y et al. Increased blood pressure in mice lacking cytochrome P450 2J5. FASEB Journal. 2008 Dec;22(12):4096-4108. https://doi.org/10.1096/fj.08-114413
Athirakul, Krairerk ; Bradbury, J. Alyce ; Graves, Joan P. ; DeGraff, Laura M. ; Ma, Jixiang ; Zhao, Yun ; Couse, John F. ; Quigley, Raymond ; Harder, David R. ; Zhao, Xueying ; Imig, John D. ; Pedersen, Theresa L. ; Newman, John W. ; Hammock, Bruce D. ; Conley, Alan J ; Korach, Kenneth S. ; Coffman, Thomas M. ; Zeldin, Darryl C. / Increased blood pressure in mice lacking cytochrome P450 2J5. In: FASEB Journal. 2008 ; Vol. 22, No. 12. pp. 4096-4108.
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