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Departments of
Biopharmaceutical Sciences (D.L.K., L.M.H., A.T.,
M.P.G.) and
Pharmaceutical Chemistry (D.L.K.), The CYP4A enzymes catalyze the formation of 20-hydroxyeicosatetraenoic
acid (20-HETE), which has potent effects on the renal vasculature and
tubular ion transport. Based on an increased 20-HETE formation in renal
microsomes from spontaneously hypertensive rats, it has been proposed
that increased expression of the CYP4A genes is an early
event in the development of hypertension in these animals. To test this
hypothesis, we developed RNase protection assays for specific detection
of the individual CYP4A genes in the kidneys of
spontaneously hypertensive and Wistar-Kyoto rats. Distinct
age-dependent patterns of expression were observed for the individual
CYP4A genes, with only CYP4A3 mRNA measurable in the kidneys
of 1-week-old rats. CYP4A1 and CYP4A8 mRNA were detectable by 3 weeks
of age and CYP4A2 mRNA at 5 weeks of age. The expression of CYP4A1 and
CYP4A3 varied 4-5-fold throughout development and was highest between
3 and 5 weeks of age, declining steadily thereafter to 20% of their
maximal level by 9 weeks of age. CYP4A2 mRNA levels increased steadily
between 5 and 9 weeks of age, whereas CYP4A8 mRNA levels were
relatively constant throughout development. The CYP4A3 mRNA level was
significantly increased 1.6-2-fold in the cortex and outer medulla of
1-4-week-old spontaneously hypertensive rat kidneys relative to the
corresponding level in the Wistar-Kyoto. A similar 1.4-1.7-fold
increase in CYP4A8 mRNA was also found in 3- and 4-week-old
spontaneously hypertensive kidneys. Accompanying the increased
expression of CYP4A3 and CYP4A8 mRNA in the prehypertensive rats were
corresponding changes in functional CYP4A measured as either
arachidonic acid or lauric acid 
-hydroxylase activity (1.4-2.0-fold
increases) and CYP4A protein levels. After 4 weeks of age, the level of
CYP4A mRNA, enzyme activity, and protein were similar in the kidneys of
Wistar-Kyoto and spontaneously hypertensive rats. The findings suggest
that the expression of CYP4A3 and CYP4A8 may be critical to the early
changes in eicosanoid formation and renal function in the young
spontaneously hypertensive rat.
Copyright © by The American Society for Pharmacology and Experimental Therapeutics
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