Original papers: KidneyCamostat mesilate inhibits prostasin activity and reduces blood pressure and renal injury in salt-sensitive hypertensionMaekawa, Ai*; Kakizoe, Yutaka*; Miyoshi, Taku; Wakida, Naoki; Ko, Takehiro; Shiraishi, Naoki; Adachi, Masataka; Tomita, Kimio; Kitamura, KenichiroAuthor Information Department of Nephrology, Kumamoto University Graduate School of Medical Sciences, Kumamoto, Japan * These authors contributed equally to this work. Received 21 March, 2008 Revised 23 August, 2008 Accepted 25 August, 2008 Correspondence to Kenichiro Kitamura, MD, PhD, Associate Professor, Department of Nephrology, Kumamoto University Graduate School of Medical Sciences, 1-1-1 Honjo, Kumamoto 860-8556, Japan Tel: +81 96 373 5164; fax: +81 96 366 8458; e-mail: email@example.com Journal of Hypertension: January 2009 - Volume 27 - Issue 1 - p 181-189 doi: 10.1097/HJH.0b013e328317a762 Buy Metrics 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-β1, 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. © 2009 Lippincott Williams & Wilkins, Inc.