Contributions of the anion exchangers SLC26A1, SLC26A2, SLC26A3, and SLC26A6 to intestinal oxalate transport in human Caco2-BBE cells.

Abstract

Kidney stones affect ~1 in 5 men and 1 in 11 women, with 70%-80% being composed of calcium oxalate. Knowing the contributions of anion exchangers SLC26A2 (A2), A3, and A6 to apical and A1 to basolateral oxalate transport in human intestinal Caco2-BBE (C2) cells is important since enhancing intestinal oxalate secretion (A6/2/?A1) and reducing intestinal oxalate absorption (A3) are potential therapeutic targets. We previously showed A6 contributes > A2 to oxalate transport in C2 cells. Here, we report the contributions of combined A2+A6, A1, and A3 to oxalate transport in C2 cells using siRNA knockdown. A2 (74% reduced mRNA expression), A6 (64% reduced protein abundance), and A2+A6 (combined knockdown utilizing same A2 or A6 C2 silencing batches) mediate 31.1%, 57%, and 78% of apical oxalate transport, respectively. A1 mediates 30.9% (59.5% reduced protein abundance) of basolateral oxalate transport. A3 (78.7% reduced protein abundance) has no significant contribution to apical oxalate transport. In conclusion, most apical oxalate transport in C2 cells is mediated by A2+A6 (with no significant contribution from A3) while A1 contributes to basolateral oxalate transport. Thus, C2 cells can be used for screening/testing novel drugs targeting these transporters, which will have significant potential therapeutic implications for oxalate-related disorders.