Loss of Slc26a9 anion transporter alters intestinal electrolyte and HCO3 - transport and reduces survival in CFTR-deficient mice

Abstract

Slc26a9 is an anion transporter that is strongly expressed in the stomach and lung. Slc26a9 variants were recently found associated with a higher incidence of meconium ileus in cystic fibrosis (CF) infants, raising the question whether Slc26a9 is expressed in the intestine and what its functional role is. Slc26a9 messenger RNA (mRNA) was found highly expressed in the mucosae of the murine and human upper gastrointestinal tract, with an abrupt decrease in expression levels beyond the duodenum. Absence of SLC26a9 expression strongly increased the intestinally related mortality in cystic fibrosis transmembrane conductance regulator (CFTR)-deficient mice. Proximal duodenal JHCO3− and fluid secretion were reduced in the absence of Slc26a9 expression. In the proximal duodenum of young Slc26a9 KO mice, the glands and villi/crypts were elongated and proliferation was enhanced. This difference was lost with ageing, as were the alterations in fluid movement, whereas the reduction in JHCO3- remained. Laser dissection followed by qPCR suggested Slc26a9 expression to be crypt-predominant in the duodenum. In summary, deletion of Slc26a9 caused bicarbonate secretory and fluid absorptive changes in the proximal duodenal mucosa and increased the postweaning death rates in CFTR-deficient mice. Functional alterations in the duodenum were most prominent at young ages. We assume that the association of meconium ileus and Slc26a9 variants may be related to maldigestion and impaired downstream signaling caused by loss of upper GI tract digestive functions, aggravating the situation of lack of secretion and sticky mucus at the site of obstruction in CF intestine.Electronic supplementary materialThe online version of this article (doi:10.1007/s00424-014-1543-x) contains supplementary material, which is available to authorized users.

Targeting ion channels in cystic fibrosis

“…First, recent studies in CFTR-deficient mice demonstrated that concomitant lack of SLC26A9 causes a significant increase in GI-related mortality suggesting that SLC26A9-mediated chloride secretion alleviates the severe meconium ileus-like intestinal obstruction in CF mice [81]. Second, studies in mice with experimental asthma demonstrated that similar to TMEM16A, SLC26A9 function was increased in Th2-mediated airway inflammation in parallel with goblet cell metaplasia and mucin hypersecretion [82,83].…”

The role of intestinal oxalate transport in hyperoxaluria and the formation of kidney stones in animals and man

“…It is conceivable that DRA does not participate in oxalate absorption in the proximal small intestine, even though it is prominently expressed there and responsible for 50–60% of baseline duodenal HCO 3 − secretion [25–28]. In the Ussing chamber, the duodenum, unlike more distal segments, deteriorates rapidly with observable damage to the villi after 2 h followed by their near-complete destruction at 4 h [29].…”

“…This could not be explained by a transcriptional upregulation of DRA [16], but may be evidence of a direct functional coupling between DRA and PAT1 [38, 89–91]. This is not surprising given that they are both apical Cl − /HCO 3 − exchangers with an overlapping distribution along the crypt–villus axis of the small intestine [25, 28, 30, 31, 80, 92]. In the absence of DRA, there was no corresponding increase in (PAT1-mediated) $J_{\mathrm{sm}}^{\mathrm{Ox}}$ by the distal ileum [17], suggesting PAT1 does not compensate in terms of oxalate secretion in the DRA-KO ileum.…”

Variants in Solute Carrier SLC26A9 Modify Prenatal Exocrine Pancreatic Damage in Cystic Fibrosis

“…Lohi et al report expression of SLC26A9 in the human pancreas 35 . Pancreatic expression was not reported in a study of adult human tissues 34 , although the importance of SLC26A9 function in the gastrointestinal tract of very young mice has been reported 36 . SLC26A9 encodes an anion transporter that can mediate chloride-bicarbonate exchange and sodium-coupled transport 37 .…”