Lessons learned about epithelial sodium channels from transgenic mouse models

Figures

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  Box 1. no caption available

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  FIGURE 1. Renal phenotype of mice with global altered ENaC expression. Global knockouts of α-, β-, and γ-ENaC subunits and their major renal phenotype under various diet conditions (SD, standard, 0.17–0.25% Na+; LNa, low sodium, 0.01% Na+; HNa, high sodium, 4% Na+; HK, high potassium diet, 5–6% K+). KO, knockout mouse; + to ++, presence and severity of the trait; –, absence of trait, not different from control mice. ∗ Mice with hypokalemia. a130 mM KCl infusion. ENaC, epithelial sodium channel.

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  FIGURE 2. Renal phenotype of mice with nephron segment specific altered ENaC expression. Constitutive and/or inducible knockouts of α-, β-, and γ-ENaC subunits and their major renal phenotype under various diet conditions (SD, standard diet, 0.17–0.25% Na+; LNa, low sodium, 0.01Na+; HNa, high sodium 4% Na+; HNa, LK, high sodium, low potassium 3.5% Na+, 0.1% K+; LK, low potassium, 0.1% K+; HK, high potassium, 5–6% K+). KO, knockout mouse; + to +++, presence and severity of the trait; –, absence of trait, not different from control mice. CCD, collecting duct; CNT, connecting tubule; DCT, distal convoluted tubule; ENaC, epithelial sodium channel; IMCD, inner medullary collecting duct; OMCD, outer medullary collecting duct.

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  FIGURE 3. Rescue of global ENaC subunit knockout mice on various diet conditions. Supplementation with sodium and potassium-containing diet rescues the lethal phenotype of global α-, β-, and γ-ENaC knockout mice. SD, standard diet 0.17Na+; HNa, LK, high sodium, low potassium, 3.5% Na+,0.2% K+; LK, low potassium, 0.1% K+; kayexalate 0.96 μl/day/g of body weight. n.d., not determined. ENaC, epithelial sodium channel; KO, knockout mouse.

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  FIGURE 4. Selected recently identified regulators of ENaC function. Confirmed (full) and hypothetical (dashed line) pathways of ENaC regulation. Please note that only selected canonical and novel pathways are illustrated integrating recently identified in vivo regulators. Lys, lysosome; HIF1α, hypoxia-inducible factor 1-alpha; Ankrd36, ankyrin repeat domain 36; GRP170, glucose-regulated protein 170 (Hyou1); MST3, mammalian St20-like protein kinase 3 (Stk24); WNK4, WNK lysin deficient protein kinase 4; mTOR, mammalian target of rapamycin; MR, mineralocorticoid (Nr3C2); SGK1, serum and glucocorticoid-regulated kinase 1; pNedd4–2, neural precursor cell expressed developmentally down-regulated 4-like; RAS, renin-angiotensin system; cAMP, cyclic adenosine monophosphate; Epac1–2-, Exchange proteins directly activated by cAMP (Rapgef3, Rapgef4), Ank3, ankyrin-3; CKII, casein kinase II; CAPs, channel activating proteases; ENaC, epithelial sodium channel .