title: Angiotensin II type 2 receptor inhibits prorenin processing in juxtaglomerular cells.
abstract: 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.
authors.affiliation: Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan. atzichi@sc.itc.keio.ac.jp
authors.forename: Atsuhiro
authors.initials: A
authors.lastname: Ichihara
authors.forename: Matsuhiko
authors.initials: M
authors.lastname: Hayashi
authors.forename: Nobuhisa
authors.initials: N
authors.lastname: Hirota
authors.forename: Hirokazu
authors.initials: H
authors.lastname: Okada
authors.forename: Yukako
authors.initials: Y
authors.lastname: Koura
authors.forename: Yuko
authors.initials: Y
authors.lastname: Tada
authors.forename: Yuki
authors.initials: Y
authors.lastname: Kaneshiro
authors.forename: Hirohiko
authors.initials: H
authors.lastname: Tsuganezawa
authors.forename: Takao
authors.initials: T
authors.lastname: Saruta
mesh_terms: 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
chemical_list: 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