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.
Athirakul
Krairerk
K
Department of Medicine, Duke University Medical Center, Durham, North Carolina, USA.
Bradbury
J Alyce
JA
Graves
Joan P
JP
DeGraff
Laura M
LM
Ma
Jixiang
J
Zhao
Yun
Y
Couse
John F
JF
Quigley
Raymond
R
Harder
David R
DR
Zhao
Xueying
X
Imig
John D
JD
Pedersen
Theresa L
TL
Newman
John W
JW
Hammock
Bruce D
BD
Conley
Alan J
AJ
Korach
Kenneth S
KS
Coffman
Thomas M
TM
Zeldin
Darryl C
DC
D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D016718:Arachidonic Acid / Q000378:metabolism; D001160:Arterioles / Q000187:drug effects; D001794:Blood Pressure / Q000235:genetics*; D000090762:Cytochrome P-450 CYP2J2; D003577:Cytochrome P-450 Enzyme System / Q000172:deficiency*; D019332:Endothelin-1 / Q000494:pharmacology; D004958:Estradiol / Q000097:blood; D015914:Estrogen Replacement Therapy; D005260:Female; D005640:Follicle Stimulating Hormone / Q000097:blood; D007687:Kidney Tubules, Proximal / Q000502:physiology; D007986:Luteinizing Hormone / Q000097:blood; D008297:Male; D051379:Mice; D010053:Ovary / Q000502:physiology; D012737:Sex Factors; D013739:Testosterone / Q000097:blood; D014662:Vasoconstrictor Agents / Q000494:pharmacology
C000717352:Cyp2j5 protein, mouse; D019332:Endothelin-1; D014662:Vasoconstrictor Agents; D000804:Angiotensin II; D016718:Arachidonic Acid; D013739:Testosterone; D004958:Estradiol; D007986:Luteinizing Hormone; D005640:Follicle Stimulating Hormone; D003577:Cytochrome P-450 Enzyme System; D000090762:Cytochrome P-450 CYP2J2