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      Proteolytic activation of the epithelial sodium channel and therapeutic application of a serine protease inhibitor for the treatment of salt-sensitive hypertension.

      1 ,
      Clinical and experimental nephrology
      Springer Nature America, Inc

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          Abstract

          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.

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          Author and article information

          Journal
          Clin. Exp. Nephrol.
          Clinical and experimental nephrology
          Springer Nature America, Inc
          1437-7799
          1342-1751
          Feb 2012
          : 16
          : 1
          Affiliations
          [1 ] Department of Nephrology, Kumamoto University, Graduate School of Medical Sciences, 1-1-1 Honjo, Kumamoto, 860-8556, Japan. ken@gpo.kumamoto-u.ac.jp
          Article
          10.1007/s10157-011-0506-1
          22038264
          64ea5b4e-efca-4fdc-931f-d5060b8286e0
          History

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