In vivo contribution of serine proteases to the proteolytic activation of gamma ENaC in aldosterone-infused rats

作者：Uchimura Kohei; Kakizoe Yutaka; Onoue Tomoaki; Hayata Manabu; Morinaga Jun; Yamazoe Rika; Ueda Miki; Mizumoto Teruhiko; Adachi Masataka; Miyoshi Taku; Shiraishi Naoki; Sakai Yoshiki; Tomita Kimio; Kitamura Kenichiro^*

来源：American Journal of Physiology - Renal Fluid and Electrolyte Physiology, 2012, 303(7): F939-F943.

DOI：10.1152/ajprenal.00705.2011

• prostasin
• furin
• sodium
• serine protease inhibitor

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, Kitamura K. In vivo contribution of serine proteases to the proteolytic activation of gamma ENaC in aldosterone-infused rats. Am J Physiol Renal Physiol 303: F939-F943, 2012. First published July 25, 2012; doi:10.1152/ajprenal.00705.2011.-Aldosterone plays an important role in the regulation of blood pressure by modulating the activity of the epithelial sodium channel (ENaC) that consists of alpha-, beta-, and gamma-subunits. Aldosterone induces a molecular weight shift of gamma ENaC from 85 to 70 kDa that is necessary for the channel activation. In vitro experiments demonstrated that a dual cleavage mechanism is responsible for this shift. It has been postulated that furin executes the primary cleavage in the Golgi and that the second cleavage is provided by other serine proteases such as prostasin or plasmin at the plasma membrane. However, the in vivo contribution of serine proteases to this cleavage remains unclear. To address this issue, we administered the synthetic serine protease inhibitor camostat mesilate (CM) to aldosterone-infused rats. CM decreased the abundance of the 70-kDa form of ENaC and led to a new 75-kDa form with a concomitant increase in the urinary Na-to-K ratio. Because CM inhibits the protease activity of serine proteases such as prostasin and plasmin, but not furin, our findings strongly indicate that CM inhibited the second cleavage of gamma ENaC and subsequently suppressed ENaC activity. The results of our current studies also suggest the possibility that the synthetic serine protease inhibitor CM might represent a new strategy for the treatment of salt-sensitive hypertension in humans.

• 出版日期2012-10