Abstract
In the renal collecting duct, intercalated cells regulate acid-base balance by effluxing protons through the v-H+-ATPase, and bicarbonate via apical pendrin or the basolateral kidney anion exchanger 1 (kAE1). Additionally, collecting duct cells play an essential role in transepithelial absorption of sodium and chloride. Expression of kAE1 in polarized MDCK I cells was previously shown to decrease trans-epithelial electrical resistance (TEER), suggesting a novel role for kAE1 in paracellular permeability. In our study, we not only confirmed that inducible expression of kAE1 in mIMCD3 cells decreased TEER but we also observed (i) increased epithelial absolute permeability to both sodium and chloride, and (ii) that this effect was dependent on kAE1 activity. Further, kAE1 regulated tight junction properties through the tight junction protein claudin-4, a protein with which it physically interacts and colocalizes. These findings unveil a novel interaction between the junctional protein claudin-4 and the kidney anion exchanger, which may be relevant to ion and/or pH homeostasis.
Highlights
We provide evidence that the increased leakiness of kidney anion exchanger 1 (kAE1)-expressing mIMCD3 cells is mediated by an effect on claudin-4, a paracellular pore to chloride ions that is expressed in principal cells and intercalated cells of the collecting duct and which physically interacts with kAE1 protein
Cells, Toye and colleagues reported that stably expressing kAE1 protein resulted in an increased leakiness of the epithelial monolayer to fluorescently labelled biotin when added to the luminal side of the monolayer[15]
We observed that kAE1 protein was located at the basolateral membrane, and carried complex oligosaccharides (Fig. 1A,B), supporting a similar processing as in other cell lines and in mouse kidney as previously described[15,18,20]
Summary
In this manuscript we provide evidence that kAE1 expression and function alters tight junction permeability in renal epithelial cells. Toye and colleagues reported that the functional dRTA mutant kAE1 R901X which was mis-trafficked to the apical membrane in MDCK I cells, did not alter the epithelium tightness[15] This finding indicates that the function of an active chloride/bicarbonate transporter in another location than either the basolateral membrane or tight junction is not sufficient to affect renal epithelial tightness. We propose that in dRTA patients where kAE1 function is abnormal due to a mutation in the SLC4A1 gene, the functional interaction between kAE1 and claudin-4 is altered, resulting in a tighter collecting duct epithelium preventing sodium and chloride reabsorption[45] and loss of urinary ions This loss of urinary electrolytes would not be improved by sustained correction of metabolic acidosis as it would be caused by a defective ability of kAE1 to reduce the trans-epithelial resistance, a hypothesis that will need to be tested in further studies
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