The role of SLC26A6‐mediated chloride/oxalate exchange in causing susceptibility to nephrolithiasis
Year: 2008
Type: article
Abstract: Solute-linked carrier 26 (SLC26) isoforms are members of a large, conserved family of anion exchangers, which encompasses at least 10 distinct genes or isoforms (SLC26A1–11) (Kere, 2006; Soleimani, 2006; Sindic et al. 2007). A recently identified member of this family is SLC26A6 (human)/Slc26a6 (mouse), also known as putative anion transporter 1 (PAT1) or chloride/formate exchanger (CFEX). SLC26A6/Slc26a6 is abundantly expressed on the apical membrane of small intestinal villi, extending from the duodenum to jejunum and ileum, but shows a remarkable absence in the caecum and colon (Wang et al. 2002). Lower but significant levels of expression of Slc26a6 are also detected on the apical membrane of kidney proximal tubule and in cardiac myocytes (Knauf et al. 2001; Wang et al. 2002; Petrovic et al. 2003; Alvarez et al. 2004). PAT1 can function in chloride/bicarbonate exchange and chloride/oxalate exchange modes (reviewed in Kere, 2006; Soleimani, 2006; Sindic et al. 2007). In either mode, the luminal chloride is exchanged with the intracellular base (oxalate or bicarbonate). Mice deficient in Slc26a6 exhibit enhanced oxalate absorption in the small intestine, with subsequent increase in urine oxalate excretion (Freel et al. 2006) and kidney oxalate stone formation (Jiang et al. 2006). These results demonstrate that Slc26a6 is the main oxalate secreting pathway in the small intestine and its deletion leaves the oxalate uptake pathway unopposed, leading to enhanced oxalate absorption (Freel et al. 2006; Jiang et al. 2006) (Fig. 1). These phenotypes are remarkable in view of the fact that wild-type mice are highly resistant to nephrolithiasis. Studies in human, however, show significant susceptibility to nephrolithiasis, with 5–20% of the US population experiencing at least one kidney stone in their lifetime (Coe et al. 1992). The reason for this difference in susceptibility to nephrolithiasis remains speculative. Schematic model depicting the contribution of Slc26a6 (PAT1) to oxalate transport in mouse ileum Efflux of oxalate (Ox) is mediated by the DIDS sensitive SLC26A6 (labelled PAT1; left panel) whereas the influx of oxalate is a mediated by a DIDS-insensitive unidentified exchanger (Freel et al. 2006). In PAT1 (Slc26a6) null mouse (right panel), Ox secretion across the brush border is reduced, leaving the uptake mechanism(s) unopposed, therefore enhancing net oxalate absorption (Freel et al. 2006). A−, anion. In this issue of The Journal of Physiology, Clark et al. (2008) provide clear evidence that the human SLC26A6 and mouse Slc26a6 have divergent anion transport properties that might in part explain the high human susceptibility and the low wild-type murine susceptibility to oxalate kidney stone. The authors specifically demonstrate that while both orthologues exhibit oxalate efflux in exchange for extracellular chloride influx in oocytes injected with the respective RNA, the affinity for extracellular chloride is significantly lower in human SLC26A6. Indeed, the mouse Slc26a6 has an ∼8-fold increase in its affinity for extracellular chloride over the human SLC26A6, with half-maximal affinity of 8 mm for mouse Slc26a6 compared with 62 mm for human SLC26A6. The authors further expand on their previous work (Chernova et al. 2005) and demonstrate that whereas the mouse oxalate/chloride exchange mode via Slc26a6 is electrogenic the exchange mode via human SLC26A6 is apparently electroneutral. Lastly, the authors identified a human SLC26A6 variant – V185M – which exhibits reduced Cl−/oxalate exchange activity. Given the postprandial luminal chloride concentration of ∼60–70 mm in the distal segment of human small intestine, these results suggest that even a mild reduction in luminal chloride concentration to values close to 40–50 mm can significantly decrease the ability of SLC26A6 to secret oxalate into the intestinal lumen. Such a scenario, which is highly plausible in humans on decreased dietary chloride (salt) intake, can lead to net oxalate absorption, thereby increasing the urine oxalate excretion and predisposing to nephrolithiasis. Given the high affinity of the mouse Slc26a6 for extracellular chloride, a similar reduction in luminal chloride concentration in the mouse small intestine will not significantly affect oxalate secretion via Slc26a6, and hence there will be less susceptibility to nepohrolithiasis. Another plausible scenario, which can explain the increased incidence of oxalate-containing kidney stones in human, is the presence of polymorphic changes in human SLC26A6 cDNA. While the polymorphic SLC26A6 variant V185M, which exhibits reduced oxalate-secreting ability (Clark et al. 2008), has not been linked to nephrolithiasis, it is plausible that a combination of reduced activity and a highly dependent luminal chloride concentration might reduce the SLC26A6-mediated oxalate secretion enough to enhance lithogenecity. It is worth mentioning that SLC26A6 can function in both Cl−/HCO3− exchange and Cl−/oxalate exchange modes, with the Cl−/HCO3− exchange mode predominantly detected in the proximal portion of the small intestine (Wang et al. 2002, 2005; Soleimani, 2006) whereas the Cl−/oxalate exchange mode is predominantly detected in the kidney proximal tubule and the ileum (Wang et al. 2005; Freel et al. 2006), a small intestinal fragment highly adapted for oxalate handling. There are two major players in net oxalate absorption in the luminal membrane of small intestine: the oxalate uptake pathway and the oxalate secreting pathway. SLC26A6 represents the major oxalate secreting transporter, but the molecule(s) that are responsible for oxalate uptake in the small intestine remain unknown (Fig. 1). This much is known that the apical uptake of oxalate is mediated by a DIDS-insensitive, chloride-dependent exchanger (Freel et al. 2006). Unlike PAT1, which mediates the influx of intracellular oxalate in exchange for the luminal chloride, the uptake of oxalate is competed by the luminal chloride (Freel et al. 2006). Identification of molecule(s) that mediate oxalate uptake should be of the utmost importance in regulating oxalate absorption and reducing lithogenecity. The critical review of this manuscript by Dr Hassane Amlal and Marguerite Hatch is greatly appreciated.
Source: The Journal of Physiology
Author: Manoocher Soleimani
Language: English
Subfield: Pulmonary and Respiratory Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W2027360314