Work from our laboratory demonstrates that P450 monooxygenases metabolize arachidonic acid (AA) to epoxyeicosatrienoic acids (EETs) and hydroxyeicosatetraenoic acids (HETEs). These eicosanoids possess potent biological activities including effects on vascular and airway smooth muscle tone, peptide hormone release, and fluid/electrolyte transport. Current research involves: (1) characterization of the CYP2J subfamily P450s at the biochemical and molecular levels; (2) studies on the regulation of CYP2J gene expression; (3) evaluation of the functional roles that CYP2J products play in cell and organ physiology; and (4) examination of this enzyme pathway in animal models of human disease (including ischemic heart disease, diabetes, and hypertension). We have cloned the mouse Cyp2j5 gene, expressed the corresponding cDNA in Sf9 insect cells and shown that the recombinant enzyme catalyzes the biosynthesis of EETs and mid-chain HETEs. Unlike human CYP2J2, mouse CYP2J5 has a relatively narrow tissue distribution and appears to be one of the major renal P450s. Within the kidney, CYP2J5 is highly localized to proximal tubules and collecting ducts, sites of the nephron where EETs and HETEs have been shown to modulate salt and water transport, and mediate the effects of angiotensin II and arginine vasopressin. Alterations in dietary salt intake do not alter renal CYP2J5 expression; however, CYP2J5 is developmentally regulated in the kidney. Maximal CYP2J5 levels occur during a critical period of postnatal renal development when the pressure-natuiresis relationship is established and when renal functional abnormalities are first demonstrable in animals who subsequently develop hypertension. CYP2J-specific antibodies immunoreact with a 55kDa kidney protein that is expressed at much higher levels in spontaneously hypertensive rats than in normotensive controls. These findings suggest a possible role for CYP2J gene products in the development and/or maintenance of the hypertensive phenotype in rodents. Efforts are currently underway to construct mice in which the Cyp2j5 gene has been disrupted in order to study the functional significance of this P450 in kidney development, renal physiology, and in the pathophysiology of hypertension.
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