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Title:   Author  item
                                            ATHIRAKUL, KRAIRERK - DUKE UNIV. MED. CNT.item
                                            BRADBURY, ALYCE - NIEHS, NIHitem
                                            GRAVES, JOAN - NIEHS, NIHitem
                                            DEGRAFF, LAURA - NIEHS, NIHitem
                                            MA, JIXIANG - NIEHS, NIHitem
                                            ZHAO, YUN - NIEHS, NIHitem
                                            COUSE, JOHN - NIEHS, NIHitem
                                            QUIGLEY, RAYMOND - UNIV. TEXAS SW MED. CNT.item
                                            HARDER, DAVID - MED. COLLEGE WISCONSINitem
                                            ZHAO, XUEYING - MED. COLLEGE GEORGIAitem
                                            IMIG, JOHN - MED. COLLEGE GEORGIAitem
                                            Pedersen, Theresaitem
                                            Newman, Johnitem
                                            HAMMOCK, BRUCE - UCD ENTOMOLOGY,CANCER CNTitem
                                            CONLEY, ALAN - UCD POPULATION HEALTHitem
                                            KORACH, KENNETH - NIEHS, NIHitem
                                            COFFMAN, THOMAS - DUKE UNIV. MED. CNT.item
                                            ZELDIN, DARRYL - NIEHS, NIH
  Submitted to: Federation of American Societies for Experimental Biology Conference
                                    Publication Type: Peer Reviewed Journal
                                    Publication Acceptance Date: 7/24/2008
                                    Publication  Date: 12/22/2008
                                    Citation: Athirakul, K., Bradbury, A.J., 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. 2008. INCREASED BLOOD PRESSURE IN MICE LACKING CYTOCHROME P450 2J5. Federation of American Societies for Experimental Biology Conference. 12):4096-108.Interpretive Summary: 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-1. Interestingly, plasma 17ß-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 hormones 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.
                                Technical 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-1. Interestingly, plasma 17ß-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 hormones 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.


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