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Increased blood pressure in mice lacking cytochrome P450 2J5.

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 17beta-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.

Pubmed ID: 18716027

Authors

  • 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

Journal

FASEB journal : official publication of the Federation of American Societies for Experimental Biology

Publication Data

December 2, 2008

Associated Grants

  • Agency: NIDDK NIH HHS, Id: DK38226
  • Agency: NIEHS NIH HHS, Id: ES004699
  • Agency: NIEHS NIH HHS, Id: ES02710
  • Agency: NHLBI NIH HHS, Id: HL6876
  • Agency: NIMH NIH HHS, Id: MH39917
  • Agency: NIDDK NIH HHS, Id: P01 DK038226
  • Agency: NIDDK NIH HHS, Id: P01 DK038226-200011
  • Agency: NHLBI NIH HHS, Id: R01 HL059699
  • Agency: Intramural NIH HHS, Id:

Mesh Terms

  • Angiotensin II
  • Animals
  • Arachidonic Acid
  • Arterioles
  • Blood Pressure
  • Cytochrome P-450 Enzyme System
  • Endothelin-1
  • Estradiol
  • Estrogen Replacement Therapy
  • Female
  • Follicle Stimulating Hormone
  • Kidney Tubules, Proximal
  • Luteinizing Hormone
  • Male
  • Mice
  • Ovary
  • Sex Factors
  • Testosterone
  • Vasoconstrictor Agents