The apical anion exchanger Slc26a6 promotes oxalate secretion by murine submandibular gland acinar cells

Abstract

The solute carrier family 26 () gene family encodes at least 10 different anion exchangers. SLC26 member 6 (SLC26A6 or CFEX/PAT-1) and the cystic fibrosis transmembrane conductance regulator (CFTR) co-localize to the apical membrane of pancreatic duct cells, where they act in concert to drive HCO and fluid secretion. In contrast, in the small intestine, SLC26A6 serves as the major pathway for oxalate secretion. However, little is known about the function of Slc26a6 in murine salivary glands. Here, RNA sequencing-based transcriptional profiling and Western blots revealed that is highly expressed in mouse submandibular and sublingual salivary glands. Slc26a6 localized to the apical membrane of salivary gland acinar cells with no detectable immunostaining in the ducts. CHO-K1 cells transfected with mouse exchanged Cl for oxalate and HCO, whereas two other anion exchangers known to be expressed in salivary gland acinar cells, Slc4a4 and Slc4a9, mediated little, if any, Cl/oxalate exchange. Of note, both Cl/oxalate exchange and Cl/HCO exchange were significantly reduced in acinar cells isolated from the submandibular glands of mice. Oxalate secretion in submandibular saliva also decreased significantly in mice, but HCO secretion was unaffected. Taken together, our findings indicate that Slc26a6 is located at the apical membrane of salivary gland acinar cells, where it mediates Cl/oxalate exchange and plays a critical role in the secretion of oxalate into saliva.

The Handling of Oxalate in the Body and the Origin of Oxalate in Calcium Oxalate Stones

“…SLC26A6/PAT1 is expressed on the apical membrane in many gastrointestinal tissues, including the pancreas and the small intestine [19]. SLC26A6/PAT1 is expressed at high levels in the small intestine (at equivalent levels in the duodenum and jejunum and at lower levels in the ileum), with far lower levels of expression in the large intestine [21]. Recently, it was observed that SLC26A6-knockout mice have a reduced (50-75%) enteric secretion of oxalate and an increased net amount of oxalate absorbed in the gastrointestinal tract rather than a net proximal tubular secretion of oxalate, elevating plasma oxalate and causing hyperoxaluria.…”

“…SCL26A6 is an anion exchanger expressed on the apical membrane in many tissues, including the kidneys and intestines [17][18][19][20]. Among its transport activities, SLC26A6 serves as the major pathway for oxalate secretion [21]. Mice lacking SLC26A6 have a defect in intestinal oxalate secretion resulting in an enhanced net absorption of oxalate [22].…”

The apical Na+–HCO3− cotransporter Slc4a7 (NBCn1) does not contribute to bicarbonate transport by mouse salivary gland ducts

“…Five-micrometer-thick sections of paraformaldehyde-fixed mouse SMG were deparaffinized and antigen retrieval was performed as described previously (Mukaibo, Munemasa, George et al, 2018 stained with hematoxylin-eosin, and images were captured with a DS-Fit1 Nikon camera mounted on a Nikon Eclipse 50i microscope and Leica Aperio CS2 x20 objective. The ductal cross-sectional area was calculated using Image-J software (https://imagej.nih.gov/ij/), and the acinar cross-sectional area subsequently was estimated as previously described by subtracting the duct cross-sectional area from the stromalomitted gland cross-sectional area (Mukaibo, Munemasa, Masaki et al, 2018).…”

“…Quantitative PCR was performed as previously described (Mukaibo, Munemasa, George et al, 2018 (Table 3).…”

Slc4a11disruption causes duct cell loss and impairs NaCl reabsorption in female mouse submandibular glands

“…qPCR was performed as previously described (Mukaibo et al ). Briefly, submandibular glands were removed and immediately immersed in liquid nitrogen and shipped to MyOmicsDx (Towson, MD).…”