Proteolytic activation of the epithelial sodium channel and therapeutic application of a serine protease inhibitor for the treatment of salt-sensitive hypertension.
Proteases are involved in numerous essential biological processes including blood clotting, controlled cell death, and tissue differentiation. Prostasin, a glycosylphosphatidylinositol-anchored serine protease, has been identified as a potential regulator of the epithelial sodium channel (ENaC) function in the kidney, lung, and airways. ENaC is composed of three homologous subunits α, β, and, γ. The dual cleavage of α subunit by furin and γ subunit by prostasin and furin releases inhibitory segments from ENaC, leading to the channel activation. Protease nexin-1, an endogenous prostasin inhibitor, inhibits ENaC activity through the suppression of prostasin activity, strongly suggesting the possibility that a coordinated regulation of serine proteases and serine protease inhibitors plays a key role in the sodium handling in the kidney. Camostat mesilate (CM), a synthetic serine protease inhibitor, reduced prostasin activity and subsequently decreased ENaC current. Oral administration of CM to Dahl salt-sensitive rats resulted in a significant decrease in blood pressure with an elevation of the urinary sodium/potassium ratio. These findings suggest that synthetic serine protease inhibitors such as CM might represent a new class of antihypertensive drugs in patients with salt-sensitive hypertension.
Department of Nephrology, Kumamoto University, Graduate School of Medical Sciences, 1-1-1 Honjo, Kumamoto, 860-8556, Japan. ken@gpo.kumamoto-u.ac.jp
Kenichiro
K
Kitamura
Kimio
K
Tomita
D000818:Animals; D053503:Epithelial Sodium Channels / Q000378:metabolism; D004952:Esters; D045683:Furin / Q000378:metabolism; D016670:Gabexate / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use; D006146:Guanidines; D006801:Humans; D006973:Hypertension / Q000188:drug therapy* / Q000378:metabolism; D051381:Rats; D020303:Rats, Inbred Dahl; D012697:Serine Endopeptidases / Q000378:metabolism*; D015842:Serine Proteinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D000099271:Prostasin
D053503:Epithelial Sodium Channels; D004952:Esters; D045683:Furin; D016670:Gabexate; D006146:Guanidines; D012697:Serine Endopeptidases; D015842:Serine Proteinase Inhibitors; D000099271:Prostasin; C034532:camostat