Inhibition of prostasin secretion by serine protease inhibitors in the kidney.
A serine protease, prostasin, has been shown to stimulate the activity of amiloride-sensitive sodium channels (ENaC). Prostasin is a glycosylphosphatidylinositol-anchored protein that is found free in physiologic fluids and tissue culture medium, but the mechanism by which prostasin is secreted from the cells has not been elucidated. The current studies found that serine protease inhibitor aprotinin blocked the secretion of prostasin in a mouse cortical collecting duct (CCD) cell line (M-1 cells). A synthetic serine protease inhibitor, nafamostat mesilate (NM), which is commonly used for the treatment of pancreatitis and disseminated intravascular coagulation in Japan, also inhibited the secretion of prostasin in M-1 cells. Continuous infusion of NM into rats resulted in a substantial decrease in urinary prostasin and urinary sodium excretion. p-guanidinobenzoic acid and 6-amidino-2-naphtol, catalytically inactive metabolites of NM, had no effect on prostasin secretion both in M-1 cells and in rats. These findings suggest that a serine protease-sensitive mechanism is involved in the secretion of prostasin in vitro as well as in vivo. Potassium secretion in the CCD is tightly linked to sodium reabsorption through EnaC; therefore, NM-induced decrease in prostasin secretion and subsequent inhibition of ENaC activity could account for the side effects of hyponatremia and/or hyperkalemia that are found sometimes in patients treated with NM. The results indicate an important role for prostasin in sodium reabsorption in the kidney under pathophysiologic conditions.
Iwashita
Kozo
K
Third Department of Internal Medicine, Kumamoto University School of Medicine, Kumamoto, Japan.
Kitamura
Kenichiro
K
Narikiyo
Takefumi
T
Adachi
Masataka
M
Shiraishi
Naoki
N
Miyoshi
Taku
T
Nagano
Junko
J
Tuyen
Do Gia
DG
Nonoguchi
Hiroshi
H
Tomita
Kimio
K
D000818:Animals; D001550:Benzamidines; D001565:Benzoates / Q000008:administration & dosage / Q000494:pharmacology; D002461:Cell Line, Transformed; D006146:Guanidines / Q000008:administration & dosage / Q000494:pharmacology; D007262:Infusions, Intravenous; D007668:Kidney / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D051379:Mice; D009284:Naphthols / Q000008:administration & dosage / Q000494:pharmacology; D011480:Protease Inhibitors / Q000008:administration & dosage / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012697:Serine Endopeptidases / Q000187:drug effects*; D015842:Serine Proteinase Inhibitors / Q000494:pharmacology*; D000099271:Prostasin
D001550:Benzamidines; D001565:Benzoates; D006146:Guanidines; D009284:Naphthols; D011480:Protease Inhibitors; D012697:Serine Endopeptidases; D015842:Serine Proteinase Inhibitors; D000099271:Prostasin; C023856:4-guanidinobenzoate; C058874:6-amidino-2-naphthol; C032855:nafamostat