Keratins modulate colonocyte electrolyte transport via protein mistargeting.
The function of intestinal keratins is unknown, although keratin 8 (K8)-null mice develop colitis, hyperplasia, diarrhea, and mistarget jejunal apical markers. We quantified the diarrhea in K8-null stool and examined its physiologic basis. Isolated crypt-units from K8-null and wild-type mice have similar viability. K8-null distal colon has normal tight junction permeability and paracellular transport but shows decreased short circuit current and net Na absorption associated with net Cl secretion, blunted intracellular Cl/HCO3-dependent pH regulation, hyperproliferation and enlarged goblet cells, partial loss of the membrane-proximal markers H,K-ATPase-beta and F-actin, increased and redistributed basolateral anion exchanger AE1/2 protein, and redistributed Na-transporter ENaC-gamma. Diarrhea and protein mistargeting are observed 1-2 d after birth while hyperproliferation/inflammation occurs later. The AE1/2 changes and altered intracellular pH regulation likely account, at least in part, for the ion transport defects and hyperproliferation. Therefore, colonic keratins have a novel function in regulating electrolyte transport, likely by targeting ion transporters to their cellular compartments.
Toivola
Diana M
DM
Palo Alto VA Medical Center, 3801 Miranda Ave., Mail code 154J, Palo Alto, CA 94304, USA.
Krishnan
Selvi
S
Binder
Henry J
HJ
Singh
Satish K
SK
Omary
M Bishr
MB
D000367:Age Factors; D000818:Animals; D001639:Bicarbonates / Q000378:metabolism; D015415:Biomarkers; D002034:Bumetanide / Q000494:pharmacology; D002712:Chlorides / Q000378:metabolism; D003106:Colon / Q000033:anatomy & histology* / Q000378:metabolism; D000242:Cyclic AMP / Q000378:metabolism; D004232:Diuretics / Q000494:pharmacology; D004573:Electrolytes / Q000378:metabolism*; D004594:Electrophysiology; D005260:Female; D006863:Hydrogen-Ion Concentration; D007249:Inflammation / Q000378:metabolism; D007413:Intestinal Mucosa / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D017136:Ion Transport / Q000502:physiology; D053533:Keratin-8; D007633:Keratins / Q000378:metabolism*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009579:Nitrobenzoates / Q000494:pharmacology; D010641:Phenotype; D012964:Sodium / Q000378:metabolism
D001639:Bicarbonates; D015415:Biomarkers; D002712:Chlorides; D004232:Diuretics; D004573:Electrolytes; D053533:Keratin-8; C486595:Krt8 protein, mouse; D009579:Nitrobenzoates; D002034:Bumetanide; C058176:5-nitro-2-(3-phenylpropylamino)benzoic acid; D007633:Keratins; D012964:Sodium; D000242:Cyclic AMP