Young SHR express increased type 1 angiotensin II receptors in renal proximal tubule

A potential role for the renin-angiotensin system IRAS) 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 I angiotensin II receptor (AT(1)R) 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 AT(1)R 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 AT(1)R mRNA levels [SHR vs. WKY: 79 +/- 14 vs. 72 +/- 14 counts/min (cpm) per cpm mutant AT(1)R per cpm beta-actin x 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 AT(1)R mRNA levels were 263 +/- 30% that of WKY (143 +/- 18 vs. 60 +/- II cpm per cpm of mutant AT(1)R per cpm beta-actin x 10(-6), n = 8; P < 0.005). We have recently shown that chronic ACE inhibition decreases proximal tubule AT(1)R expression and have also shown that chronic L-3,4-dihydroxyphenylalamine (L-DOPA) administration inhibits AT(1)R expression in adult Sprague-Dawley proximal tubule and cultured proximal tubule, and this inhibition is mediated via G(s)-coupled DA(1) 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 AT(1)R 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; AT(1)R per cpm beta-actin x 10(-6)), due to a significant decrease in proximal tubule AT(1)R expression in SHR (P < 0.005, compared with untreated SHR). Immunoreactive proximal tubule AT(1)R 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, SE-ER have increased expression of proximal tubule AT(1)R and that chronic L-DOPA or captopril treatment decreased the elevated AT(1)R expression to control levels. These results provide further support for an important role of the RAS in the development of hypertension in SHR.