title: Camostat mesilate inhibits prostasin activity and reduces blood pressure and renal injury in salt-sensitive hypertension.
abstract: Prostasin, a glycosylphosphatidylinositol-anchored serine protease, regulates epithelial sodium channel (ENaC) activity. Sodium reabsorption through ENaC in distal nephron segments is a rate-limiting step in transepithelial sodium transport. Recently, proteolytic cleavage of ENaC subunits by prostasin has been shown to activate ENaC. Therefore, we hypothesized that serine protease inhibitors could inhibit ENaC activity in the kidney, leading to a decrease in blood pressure. We investigated the effects of camostat mesilate, a synthetic serine protease inhibitor, and FOY-251, an active metabolite of camostat mesilate, on sodium transport in the mouse cortical collecting duct cell line (M-1 cells) and on blood pressure in Dahl salt-sensitive rats. Treatment with camostat mesilate or FOY-251 decreased equivalent current (Ieq) in M-1 cells in a dose-dependent manner and inhibited the protease activity of prostasin in vitro. Silencing of the prostasin gene also reduced equivalent current in M-1 cells. The expression level of prostasin protein was not changed by application of camostat mesilate or FOY-251 to M-1 cells. Oral administration of camostat mesilate to Dahl salt-sensitive rats fed a high-salt diet resulted in a significant decrease in blood pressure with elevation of the urinary Na/K ratio, decrease in serum creatinine, reduction in urinary protein excretion, and improvement of renal injury markers such as collagen 1, collagen 3, transforming growth factor-beta1, and nephrin. These findings suggest that camostat mesilate can decrease ENaC activity in M-1 cells probably through the inhibition of prostasin activity, and that camostat mesilate can have beneficial effects on both hypertension and kidney injury in Dahl salt-sensitive rats. Camostat mesilate might represent a new class of antihypertensive drugs with renoprotective effects in patients with salt-sensitive hypertension.
authors.affiliation: Department of Nephrology, Kumamoto University Graduate School of Medical Sciences, Kumamoto, Japan.
authors.forename: Ai
authors.initials: A
authors.lastname: Maekawa
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Kakizoe
authors.forename: Taku
authors.initials: T
authors.lastname: Miyoshi
authors.forename: Naoki
authors.initials: N
authors.lastname: Wakida
authors.forename: Takehiro
authors.initials: T
authors.lastname: Ko
authors.forename: Naoki
authors.initials: N
authors.lastname: Shiraishi
authors.forename: Masataka
authors.initials: M
authors.lastname: Adachi
authors.forename: Kimio
authors.initials: K
authors.lastname: Tomita
authors.forename: Kenichiro
authors.initials: K
authors.lastname: Kitamura
mesh_terms: D000450:Aldosterone / Q000097:blood; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects; D002478:Cells, Cultured; D004952:Esters; D016670:Gabexate / Q000031:analogs & derivatives* / Q000494:pharmacology; D006146:Guanidines / Q000494:pharmacology; D006973:Hypertension / Q000188:drug therapy*; D007668:Kidney / Q000187:drug effects* / Q000473:pathology; D051379:Mice; D034741:RNA, Small Interfering / Q000235:genetics; D051381:Rats; D020303:Rats, Inbred Dahl; D012697:Serine Endopeptidases / Q000187:drug effects*; D015842:Serine Proteinase Inhibitors / Q000494:pharmacology*; D000099271:Prostasin
chemical_list: D000450:Aldosterone; D000959:Antihypertensive Agents; D004952:Esters; D016670:Gabexate; D006146:Guanidines; D034741:RNA, Small Interfering; D012697:Serine Endopeptidases; D015842:Serine Proteinase Inhibitors; D000099271:Prostasin; C034532:camostat; C045130:4-(4-guanidinobenzoyloxy)phenylacetic acid