Elucidation of the molecular mechanism for the development of salt sensitive hypertension by serine proteases.

• Project/Area Number: 24591231
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Kidney internal medicine
• Research Institution: Kumamoto University
• Principal Investigator: ADACHI Masataka 熊本大学, 医学部附属病院, 助教 (90398206)
• Project Period (FY): 2012-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥5,200,000 (Direct Cost: ¥4,000,000、Indirect Cost: ¥1,200,000); Fiscal Year 2014: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2013: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2012: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• Keywords: 高血圧 / 上皮型ナトリウムチャネル / セリンプロテアーゼ / セリンプロテアーゼ阻害薬 / 高血圧学

Outline of Final Research Achievements

Aldosterone induces a molecular weight shift of the epithelial sodium channel γ subunit (γENaC) from 85 to 70 kDa that is necessary for the channel activation. However, the in vivo contribution of serine proteases to this cleavage still remains unclear. To address this issue, we administrated a synthetic serine protease inhibitor camostat mesilate (CM) to aldosterone-infused rats. CM decreased the abundance of 70 kDa form of ENaC.Our findings strongly indicate that CM inhibited the cleavage of γENaC by prostasin and subsequently suppressed the ENaC activity. The results of our current studies also suggest the possibility that a synthetic serine protease inhibitor CM might represent a new strategy for the treatment of salt-sensitive hypertension in humans.

Research Products

• [Journal Article] The serine protease inhibitor camostat mesilate attenuates the progression of chronic kidney disease through its antioxidant effects. (2015)
  • Author(s): Ueda, M., Uchimura, K., Narita, Y., Miyasato, Y., Mizumoto, T., Morinaga, J., Hayata, M., Kakizoe, Y., Adachi, M., Miyoshi, T., Shiraishi, N., Kadowaki, D., Sakai, Y., Mukoyama, M., and Kitamura, K.
  • Journal Title: Nephron Volume: 129 Pages: 223-232
  • Peer Reviewed
• [Journal Article] In vivo contribution of serine proteases to the proteolytic activation of γENaC in aldosterone-infused rats (2012)
  • Author(s): Uchimura, K., Kakizoe, Y., Onoue, T., Hayata, M., Morinaga, J., Yamazoe, R., Ueda, M., Mizumoto, T., Adachi, M., Miyoshi, T., Shiraishi, N., Sakai, Y., Tomita, K., and Kitamura, K.
  • Journal Title: Am. J. Physiol. (Renal Physiol.) Volume: 303 Issue: 7 Pages: F939-F943
  • DOI: 10.1152/ajprenal.00705.2011
  • Peer Reviewed
• [Presentation] 腎尿細管機能制御 プロスタシンによるアルドステロン制御 (2012)
  • Author(s): 安達政隆、こう健博、冨田公夫、北村健一郎
  • Organizer: 第55回日本腎臓学会学術総会
  • Place of Presentation: パシフィコ横浜 会議場