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Vol. 57, Issue 5, 1011-1020, May 2000
Department of Biopharmaceutical Sciences, School of Pharmacy,
University of California, San Francisco, California (Z.Y., L.M.H.,
D.L.K.); and Division of Intramural Research, National Institute of
Environmental Health Scienes, Research Triangle Park, North
Carolina (P.A., L.G., J.M., D.C.Z.)
Epoxyeicosatrienoic acids (EETs) are major products of cytochrome P450
(CYP)-catalyzed metabolism of arachidonic acid in the kidney. The
potent effect of EETs on renal vascular tone and tubular ion and water
transport implicates their role in the regulation of renal function and
blood pressure. The present study was designed to test the hypothesis
that CYP-catalyzed EET formation was altered in the spontaneously
hypertensive rat (SHR) kidney. The formation of 14,15- and 11,12-EET
was ~2-fold higher in incubations of arachidonic acid with SHR renal
cortical microsomes relative to microsomes from normotensive
Wistar-Kyoto (WKY) rats. This was consistent with increased expression
of a CYP2J2 immunoreactive protein in the SHR cortex and outer medulla.
In contrast, there was no significant difference in the levels of the
CYP2E and CYP2C epoxygenases in SHR and WKY kidneys. Protein and RNA
analysis suggests that the CYP2J2 immunoreactive protein that is
overexpressed in the SHR kidney is distinct from the known rat CYP2J
isoforms. EET formation also was documented in vivo from measurements
of urinary EET excretion. Importantly, the excretion rates of 14,15-, and 11,12-EETs were 2.5- and 1.8-fold higher, respectively, in SHR than
WKY kidney. These studies provide both in vitro and in vivo evidence
for increased EET formation in the SHR kidney and identify a novel
CYP2J2 immunoreactive protein that is differentially expressed in the
hypertensive kidney. In light of the known biological properties of the
EETs, these findings may be important in elucidating the mechanisms
that control renal vascular tone and tubular ion transport in the SHR.
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