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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^* and Darryl C. Zeldin^,1

^* Department of Medicine, Duke University Medical Center, Durham, North Carolina, USA;

National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina, USA;

Department of Pediatrics, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas, USA;

Department of Physiology, Medical College of Wisconsin, Milwaukee, Wisconsin, USA;

^|| Department of Physiology, Medical College of Georgia, Augusta, Georgia, USA; and

^¶ Department of Entomology,

^# Cancer Research Center, and

^** Department of Population Health and Reproduction, University of California, Davis, California, USA

¹Correspondence: NIH/NIEHS, 111 T.W. Alexander Dr., Bldg. 101, Rm. D236, Research Triangle Park, NC 27709, USA. E-mail: zeldin{at}niehs.nih.gov

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.—Athirakul, K., Bradbury, J. A., Graves, J. P., DeGraff, L. M., Ma, J., Zhao, Y., Couse, J. F., Quigley, R., Harder, D. R., Zhao, X., Imig, J. D., Pedersen, T. L., Newman, J. W., Hammock, B. D., Conley, A. J., Korach, K. S., Coffman, T. M., Zeldin, D. C. Increased blood pressure in mice lacking cytochrome P450 2J5.

Key Words: hypertension • estrogen • proximal tubule • vascular responsiveness • eicosanoid