Abstract
The membrane-bound serine protease CAP2/Tmprss4 has been previously identified in vitro as a positive regulator of the epithelial sodium channel (ENaC). To study its in vivo implication in ENaC-mediated sodium absorption, we generated a knockout mouse model for CAP2/Tmprss4. Mice deficient in CAP2/Tmprss4 were viable, fertile, and did not show any obvious histological abnormalities. Unexpectedly, when challenged with sodium-deficient diet, these mice did not develop any impairment in renal sodium handling as evidenced by normal plasma and urinary sodium and potassium electrolytes, as well as normal aldosterone levels. Despite minor alterations in ENaC mRNA expression, we found no evidence for altered proteolytic cleavage of ENaC subunits. In consequence, ENaC activity, as monitored by the amiloride-sensitive rectal potential difference (ΔPD), was not altered even under dietary sodium restriction. In summary, ENaC-mediated sodium balance is not affected by lack of CAP2/Tmprss4 expression and thus, does not seem to directly control ENaC expression and activity in vivo.
Highlights
The regulation of sodium balance throughout the body is important to maintain blood volume and blood pressure
CAP2/Tmprss4loxneo/+ mice were mated with Cre- or Flp-deleter mouse strains [31,30], and floxed CAP2/Tmprss4 (CAP2/ Tmprss4lox/+, CAP2/Tmprss4loxlox), CAP2/Tmprss4 heterozygous mutant (CAP2/Tmprss4Δ/+) and knockout (CAP2/Tmprss4Δ/Δ) mice were obtained as evidenced by Southern blot (Fig 2C) and DNA-based PCR analyses (Fig 2D)
The knockout mice seemed healthy and we detected no obvious effects on embryonic development or after birth (Fig 3), in contrary to the phenotype described for CAP2/Tmprss4 knockdown experiments in zebrafish embryos which exhibit severe defects in tissue development and cell differentiation including disturbed skeletal muscle formation, decelerated heartbeat, a degenerated vascular system, and impaired epidermal keratinocytes [39]
Summary
The regulation of sodium balance throughout the body is important to maintain blood volume and blood pressure. In tight epithelia as in kidney and colon, aldosterone promotes sodium reabsorption through the amiloride-sensitive epithelial sodium channel ENaC [1]. This channel was initially identified in the colon of rats challenged with a low salt diet [2,3]. CAP2/Tmprss and ENaC Activity collection and analysis, decision to publish, or preparation of the manuscript
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