Angiotensin II type 2 receptor inhibits prorenin processing in juxtaglomerular cells.
Long-term treatment with an angiotensin II type 1 receptor blocker (ARB) has been shown to decrease the plasma renin activity (PRA) of hypertensive patients, whereas PRA remains elevated during angiotensin-converting enzyme inhibitor (ACEI) treatment. In the present study, we used rat juxtaglomerular (JG) cells to elucidate the mechanism(s) involved in the differential regulation of PRA between ARB and ACEI treatment. Addition of 100 nmol/l angiotensinogen (Aogen) to JG cells (n=6 primary cultures) significantly increased the medium angiotensin (Ang) II levels from 14 +/- 2 to 440 +/- 9 pg/ml and suppressed the renin secretion rate (RSR) from 39.6 +/- 5.4% to 6.3 +/- 1.8% without affecting active renin content (ARC) or total renin content (TRC). In the Aogen-treated cells, the ACEI, delapril hydrochloride (CV3317, 10 micromol/l), significantly decreased the medium Ang II levels to 58 +/- 14 pg/ml and increased RSR to 39.8 +/- 4.1% without affecting ARC or TRC. The ARB, an active metabolite of candesartan cilexetil (CV11974, 10 micromol/l), however, significantly increased the medium Ang II levels and RSR to 486 +/- 15 pg/ml and 40.9 +/- 9.8%, respectively, and decreased ARC from 63.2 +/- 6.8 to 21.6 +/- 3.6 ng of Ang l x h(-1) x million cells(-1) without affecting TRC. The decreases in ARC of the Aogen+CV11974-treated cells (n=6 primary cultures) were inhibited by an Ang II type 2 receptor blocker, PD123319 (10 micromol/l). JG cells (n=6 primary cultures) were also treated with an Ang II type 2 receptor agonist, CGP42212A (0.1 micromol/l). CGP42212A significantly increased RSR from 38.2 +/- 1.6% to 49.7 +/- 4.7% and decreased ARC from 60.8 +/- 3.0 to 25.3 +/- 2.8 ng of Ang l x h(-1) million cells(-1) without affecting TRC. Addition of CV11974 did not alter the RSR, ARC, or TRC of the CGP42212A-treated cells; however, PD123319 abolished the effects of CGP42212A. These results indicate that, distinct from ACEIs, ARBs inhibit prorenin processing of JG cells through Ang II type 2 receptors. Long-term treatment with an ARB may decrease PRA in part by diminishing the storage of active renin in JG cells.
Ichihara
Atsuhiro
A
Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan. atzichi@sc.itc.keio.ac.jp
Hayashi
Matsuhiko
M
Hirota
Nobuhisa
N
Okada
Hirokazu
H
Koura
Yukako
Y
Tada
Yuko
Y
Kaneshiro
Yuki
Y
Tsuganezawa
Hirohiko
H
Saruta
Takao
T
D047228:Angiotensin II Type 1 Receptor Blockers; D057912:Angiotensin II Type 2 Receptor Blockers; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology; D000808:Angiotensinogen / Q000378:metabolism; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology; D001562:Benzimidazoles / Q000494:pharmacology; D001713:Biphenyl Compounds; D003470:Culture Media; D007093:Imidazoles / Q000494:pharmacology; D007150:Immunohistochemistry; D007606:Juxtaglomerular Apparatus / Q000166:cytology / Q000378:metabolism*; D008297:Male; D009842:Oligopeptides / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012083:Renin / Q000378:metabolism*; D013777:Tetrazoles / Q000494:pharmacology
D047228:Angiotensin II Type 1 Receptor Blockers; D057912:Angiotensin II Type 2 Receptor Blockers; D000806:Angiotensin-Converting Enzyme Inhibitors; D000959:Antihypertensive Agents; D001562:Benzimidazoles; D001713:Biphenyl Compounds; D003470:Culture Media; D007093:Imidazoles; D009842:Oligopeptides; D011725:Pyridines; D013777:Tetrazoles; D000808:Angiotensinogen; C060894:CGP 42112A; C073402:PD 123319; D012083:Renin; C081643:candesartan