TABLE 1.
ENaC channel‐activating proteases tested in animal models and their associated epithelial phenotypes
| Serine proteases | Rodent model & study condition | Phenotype (effect) | Identified in vivo substrate(s) | Ref. |
|---|---|---|---|---|
| CAP1/Prss8 (prostasin) | Constitutive KO, unchallenged | Placenta – syncytialization defect (impaired differentiation and signal transduction) | Not reported; CAP3/St14 | 40, 41 |
| Epidermal‐specific KO, unchallenged | Skin – orthokeratotic hyperkeratosis, hair follicle dysmaturation, tight junction leakiness (impaired barrier function/integrity) | Profilaggrin, occludin | 42 | |
| Colon‐specific KO, unchallenged, low Na+ diet | Colon – colonic pseudohypoaldosteronism type 1 (impaired ion transport) | ENaC | 43 | |
| Colon‐specific KO, DSS‐induced colitis | Colon – inflammation (altered signal transduction) | TLR4 | 44 | |
| Alveolar‐specific KO, unchallenged, acute volume overload | Lung – decreased alveolar fluid clearance hydrostatic oedema (impaired ion transport) | ENaC | 45 | |
| Liver‐specific KO, high fat diet | Liver – insulin resistance | TLR4 | 46 | |
| Spontaneous mutation frV170D, unchallenged | Reduced embryonic vitality; skin – dehydration, hyperkeratosis; colon – reduced ENaC activity (impaired ion transport) | ENaC (colon) | 47 | |
| Spontaneous mutation frCR (rats), unchallenged | Reduced embryonic vitality; skin – baldness, dehydration, hyperkeratosis; colon – reduced ENaC activity, diarrhea (impaired ion transport) | ENaC (colon) | 47 | |
| Spontaneous mutation frCR (rats), DSS‐induced colitis | Colon – epithelial remodelling; intestinal inflammation (impaired signal transduction and differentiation) | ENaC not confirmed | 48 | |
| Knockin Prss8R44Q (zymogen‐locked), unchallenged | Skin – impaired/delayed whisker and pelage hair formation (altered signal transduction) | CAP3/St14 suspected | 49 | |
| Knockin Prss8R44Q (zymogen‐locked), low Na+ (high K+) diet, triamterene |
Kidney – normal Na+ conservation; hypokalaemia; hyperaldosteronism Na+ wasting, weight loss (impaired ion transport) |
ENaC not confirmed, ENaC suspected |
50 | |
| Knockin Prss8S238A (catalytically inactive), unchallenged | Skin – delayed whisker and pelage hair formation (altered signal transduction) | Not reported | 51 | |
| Knockin Prss8S238A (catalytically inactive), low Na+ (high K+) diet, triamterene | Kidney – normal Na+ conservation; no obvious phenotype | ENaC not confirmed | 50 | |
| Adenovirus‐induced Prss8wt overexpression, unchallenged | Kidney – induced mineralocorticoid production (hypertension, impaired electrolyte homoeostasis) | Kallikrein | 52 | |
| Epidermal‐specific transgenic mice (Prss8wt), unchallenged | Skin – hyperkeratosis, dehydration, inflammation (altered signal transduction) | PAR2; nexin‐1 | 53, 54 | |
| Epidermal‐specific transgenic mice (Prss8 S238A), unchallenged | Skin – hyperkeratosis, dehydration, inflammation (altered signal transduction) | PAR2, nexin‐1 | 53 | |
| CAP2/ TMPRSS4 | Constitutive KO, low Na+ diet | No obvious phenotype; kidney | ENaC excluded | 55 |
| Constitutive KO, low K+ diet | Skin – ichthyosis; impaired water handling | HKA2, Nr3c1, AC6 | 56 | |
| CAP3/ St14 (matriptase) | Constitutive KO, unchallenged | Skin, thymus – postnatal lethality, ichthyosis, thymocyte apoptosis (impaired epithelial barrier function and thymus development) | Not reported | 57, 58 |
| Tamoxifen‐induced | Skin, intestine – loss of tight junction, ichthyosis, enlarged colon (impaired integrity of tight junctions) | Occludin, ZO‐1, claudin‐1 | 59 | |
| Adenoviral‐induced salivary gland KO, virus‐induced | Salivary glands – altered tight junction distribution (Sjögren's syndrome‐like disease) | Claudin‐3 | 60 | |
| Salivary‐gland KO, unchallenged | (Impaired gland function) | Not reported | 59 | |
| Intestinal‐specific KO, unchallenged | Colon – failed terminal differentiation, colitis, adenocarcinoma, (altered signal transduction, impaired epithelial integrity) | E‐cadherin, ZO‐1, occluding, β‐catenin and laminin suspected | 59 | |
| Hypomorphic mice, unchallenged | Skin – ichthyosis with hypotrichosis‐like syndrome (impaired epidermal barrier) | CAP1/Prss8, profilaggrin, claudin‐2 | 61 | |
| Epidermal‐specific transgenic mice, unchallenged, DMBA‐induced | Skin – carcinogenesis (malignant transformation, altered differentiation) | Ras | 62 | |
| uPA (uro‐kinase‐type plasminogen activator) | Anti‐uPA targeting anti‐body; induced podocin KO, tamoxifen‐induced, ± amiloride | Kidney – attenuation of sodium retention (impaired ion transport) | ENaC | 63 |
| Constitutive KO, amiloride, doxorubicin‐induced nephrotic syndrome | Kidney – phenotype not different from control | ENaC suspected | 64 | |
| Plasminogen | Constitutive KO; inducible podocin KO, doxycycline‐induced nephrotic syndrome | Kidney – phenotype not different from control | ENaC not confirmed | 65 |
| Tissue Kallikrein | KO, aldosterone infusion or low Na+ diet | Kidney, colon, lung – decreased ENaC activity in kidney and colon, but not in lung (partly impaired ion transport) | ENaC | 18 |
| Plasma kallikrein | KO, doxorubicin‐induced nephrotic syndrome | Kidney – phenotype not different from control | ENaC not confirmed | 19 |
| Tmprss3 | Constitutive KO, unchallenged | Ear – organ of Corti and hair cell degeneration, deafness (impaired ion transport) | ENaC not confirmed | 66, 67 |
| Tmprss2 | Constitutive KO, unchallenged | No obvious phenotype | Not reported | 68 |
| FSAP | Constitutive KO, doxorubicin‐induced nephrotic syndrome | Kidney – no obvious phenotype | ENaC not confirmed | 22 |
Unchallenged, no specific pretreatment.
Abbreviations: AC6, adenylate cyclase 6; FSAP, factor VII‐activating protease.; HKA2, H+, K+‐ATPase type 2; KO, knockout; Nr3c1, nuclear receptor subfamily 3 group C member 1; TLR4, toll‐like receptor 4; ZO‐1, zona occludens 1.