Regulation of renal sodium handling through the interaction between serine proteases and serine protease inhibitors.
Sodium balance, extracellular fluid volume, and ultimately blood pressure are maintained by precise regulation of the activity of epithelial sodium channels (ENaC). Multiple mechanisms such as hormones, intracellular factors, and other regulatory factors contribute to regulation of ENaC activity. Prostasin, a glycosylphosphatidylinositol-anchored serine protease, has been identified as an activator of ENaC that increases its open probability. Furin cleaves αENaC at two sites and γENaC at one site at the Golgi. Prostasin cleaves γENaC at one site that is distinct from the furin site at the plasma membrane. Dual cleavage of α- and γ-subunit releases inhibitory segments from ENaC, leading to channel activation. Protease nexin-1 (PN-1), an endogenous prostasin inhibitor, inhibits ENaC activity through suppression of prostasin activity. Aldosterone and transforming growth factor-β1 reciprocally regulate expression of prostasin, PN-1, and ENaC in renal epithelial cell, resulting in sodium retention or natriuresis, respectively. These findings strongly suggest the possibility that coordinated regulation of serine protease, serpin, and ENaC expression plays a key role in sodium handling in the kidney.
Kitamura
Kenichiro
K
Department of Nephrology, Kumamoto University Graduate School of Medical Sciences, 1-1-1 Honjo, Kumamoto, 860-8556, Japan, ken@gpo.kumamoto-u.ac.jp
Tomita
Kimio
K
D000818:Animals; D053503:Epithelial Sodium Channels / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D007668:Kidney / Q000378:metabolism*; D008958:Models, Molecular; D012697:Serine Endopeptidases / Q000302:isolation & purification / Q000378:metabolism; D057057:Serine Proteases / Q000378:metabolism*; D015842:Serine Proteinase Inhibitors / Q000378:metabolism*; D058258:Serpin E2 / Q000378:metabolism; D012964:Sodium / Q000378:metabolism*; D000099271:Prostasin
D053503:Epithelial Sodium Channels; D012697:Serine Endopeptidases; D057057:Serine Proteases; D015842:Serine Proteinase Inhibitors; D058258:Serpin E2; D012964:Sodium; D000099271:Prostasin