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1 Department of Medicine, Vanderbilt University School of Medicine, and Department of Veterans Affairs Medical Center, Nashville, Tennessee 37232; and 2 Department of Biochemistry, University of London, Queen Mary and Westfield College, London E1 4NS, United Kingdom
A potential role for
the renin-angiotensin system (RAS) in the development and/or
maintenance of hypertension in the genetic model of rat hypertension,
spontaneously hypertensive rats (SHR), has been suggested by studies
indicating that treatment of immature animals with
angiotensin-converting enzyme (ACE) inhibitors prevents subsequent
development of hypertension. Because young SHR also demonstrate
RAS-dependent increased sodium retention, we examined proximal tubule
type 1 angiotensin II receptor
(AT1R) mRNA expression in young (4 wk) or adult (14 wk) SHR compared with age-matched Wistar-Kyoto (WKY)
rats. Proximal tubules were isolated by Percoll gradient
centrifugation, and AT1R mRNA
expression was measured by quantitative reverse
transcription-polymerase chain reaction (RT-PCR). At 14 wk, when SHR
had established hypertension [mean arterial blood pressure (MAP)
of SHR vs. WKY: 145 ± 6 vs. 85 ± 5 mmHg,
n = 14-15], there were no
differences in proximal tubule AT1R mRNA levels [SHR vs.
WKY: 79 ± 14 vs. 72 ± 14 counts/min (cpm) per cpm mutant
AT1R per cpm 
-actin × 10
6,
n = 6; not significant (NS)]. In
contrast, in 4 wk SHR, at a time of minimal elevations in blood
pressure (MAP: 70 ± 8 vs. 63 ± 3), SHR proximal tubule
AT1R mRNA levels were 263 ± 30% that of WKY (143 ± 18 vs. 60 ± 11 cpm per cpm of
mutant AT1R per cpm -actin × 106,
n = 8;
P < 0.005). We have recently shown
that chronic ACE inhibition decreases proximal tubule
AT1R expression and have also
shown that chronic
L-3,4-dihydroxyphenylalamine
(L-DOPA) administration inhibits
AT1R expression in adult
Sprague-Dawley proximal tubule and cultured proximal tubule, and this
inhibition is mediated via
Gs-coupled
DA1 receptors. When 3-wk-old
animals were given L-DOPA or
captopril for 1 wk, MAP was not altered (70 ± 8 vs. 60 ± 4 or
61 ± 5 mmHg), but proximal tubule
AT1R mRNA was no longer significantly different between SHR and WKY (68 ± 9 vs. 38 ± 7 or 20 ± 3 vs. 47 ± 15 cpm per cpm of mutant
AT1R per cpm -actin × 106), due to a
significant decrease in proximal tubule
AT1R expression in SHR
(P < 0.005, compared with untreated
SHR). Immunoreactive proximal tubule
AT1R expression also was increased
in 4 wk SHR and was reversed with captopril or
L-DOPA treatment. Therefore, these results indicate that young, but not adult, SHR have increased expression of proximal tubule AT1R
and that chronic L-DOPA or captopril treatment decreased the elevated
AT1R expression to control levels.
These results provide further support for an important role of the
RAS in the development of hypertension in SHR.
kidney; spontaneously hypertensive rats; angiotensin-converting enzyme inhibitor; L-3,4-dihydroxyphenylalaine
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