title: In vivo contribution of serine proteases to the proteolytic activation of γENaC in aldosterone-infused rats.
abstract: Aldosterone plays an important role in the regulation of blood pressure by modulating the activity of the epithelial sodium channel (ENaC) that consists of α-, β-, and γ-subunits. Aldosterone induces a molecular weight shift of γENaC from 85 to 70 kDa that is necessary for the channel activation. In vitro experiments demonstrated that a dual cleavage mechanism is responsible for this shift. It has been postulated that furin executes the primary cleavage in the Golgi and that the second cleavage is provided by other serine proteases such as prostasin or plasmin at the plasma membrane. However, the in vivo contribution of serine proteases to this cleavage remains unclear. To address this issue, we administered the synthetic serine protease inhibitor camostat mesilate (CM) to aldosterone-infused rats. CM decreased the abundance of the 70-kDa form of ENaC and led to a new 75-kDa form with a concomitant increase in the urinary Na-to-K ratio. Because CM inhibits the protease activity of serine proteases such as prostasin and plasmin, but not furin, our findings strongly indicate that CM inhibited the second cleavage of γENaC and subsequently suppressed ENaC activity. The results of our current studies also suggest the possibility that the synthetic serine protease inhibitor CM might represent a new strategy for the treatment of salt-sensitive hypertension in humans.
authors: Dept. of Nephrology, Kumamoto Univ. Graduate School of Medical Sciences, 1-1-1 Honjo, Kumamoto 860-8556, Japan.
authors: Kohei
authors: K
authors: Uchimura
authors: Yutaka
authors: Y
authors: Kakizoe
authors: Tomoaki
authors: T
authors: Onoue
authors: Manabu
authors: M
authors: Hayata
authors: Jun
authors: J
authors: Morinaga
authors: Rika
authors: R
authors: Yamazoe
authors: Miki
authors: M
authors: Ueda
authors: Teruhiko
authors: T
authors: Mizumoto
authors: Masataka
authors: M
authors: Adachi
authors: Taku
authors: T
authors: Miyoshi
authors: Naoki
authors: N
authors: Shiraishi
authors: Yoshiki
authors: Y
authors: Sakai
authors: Kimio
authors: K
authors: Tomita
authors: Kenichiro
authors: K
authors: Kitamura
mesh_terms: D000450:Aldosterone / Q000494:pharmacology*; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology*; D002712:Chlorides / Q000378:metabolism; D053503:Epithelial Sodium Channels / Q000378:metabolism*; D004952:Esters; D016670:Gabexate / Q000031:analogs & derivatives / Q000494:pharmacology; D006146:Guanidines; D008297:Male; D011188:Potassium / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D057057:Serine Proteases / Q000378:metabolism*; D015842:Serine Proteinase Inhibitors / Q000494:pharmacology; D012964:Sodium / Q000378:metabolism
chemical_list: D002712:Chlorides; D053503:Epithelial Sodium Channels; D004952:Esters; D006146:Guanidines; D015842:Serine Proteinase Inhibitors; C034532:camostat; D000450:Aldosterone; D016670:Gabexate; D012964:Sodium; D057057:Serine Proteases; D011188:Potassium