Adenosinergic signaling inhibits oxalate transport by human intestinal Caco2-BBE cells through the A2B adenosine receptor

Am J Physiol Cell Physiol. 2018 Nov 1;315(5):C687-C698. doi: 10.1152/ajpcell.00024.2017. Epub 2018 Jul 18.


Most kidney stones (KS) are composed of calcium oxalate, and small increases in urine oxalate affect the stone risk. Intestinal oxalate secretion mediated by anion exchanger SLC26A6 (PAT1) plays a crucial role in limiting net absorption of ingested oxalate, thereby preventing hyperoxaluria and related KS, reflecting the importance of understanding regulation of intestinal oxalate transport. We previously showed that ATP and UTP inhibit oxalate transport by human intestinal Caco2-BBE cells (C2). Since ATP is rapidly degraded to adenosine (ADO), we examined whether intestinal oxalate transport is regulated by ADO. We measured [14C]oxalate uptake in the presence of an outward Cl gradient as an assay of Cl-oxalate exchange activity, ≥49% of which is PAT1-mediated in C2 cells. We found that ADO significantly inhibited oxalate transport by C2 cells, an effect completely blocked by the nonselective ADO receptor antagonist 8- p-sulfophenyltheophylline. ADO also significantly inhibited oxalate efflux by C2 cells, which is important since PAT1 mediates oxalate efflux in vivo. Using pharmacological antagonists and A2B adenosine receptor (A2B AR) siRNA knockdown studies, we observed that ADO inhibits oxalate transport through the A2B AR, phospholipase C, and PKC. ADO inhibits oxalate transport by reducing PAT1 surface expression as shown by biotinylation studies. We conclude that ADO inhibits oxalate transport by lowering PAT1 surface expression in C2 cells through signaling pathways including the A2B AR, PKC, and phospholipase C. Given higher ADO levels and overexpression of the A2B AR in inflammatory bowel disease (IBD), our findings have potential relevance to pathophysiology of IBD-associated hyperoxaluria and related KS.

Keywords: A adenosine receptor; PKC; SLC26A6; inflammation; intestinal oxalate transport; phospholipase C.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adenosine / administration & dosage
  • Adenosine / metabolism*
  • Adenosine A2 Receptor Antagonists / administration & dosage
  • Adenosine Triphosphate / metabolism
  • Amino Acid Transport Systems / genetics*
  • Biological Transport / genetics
  • Caco-2 Cells
  • Humans
  • Hyperoxaluria / genetics
  • Hyperoxaluria / metabolism
  • Hyperoxaluria / pathology
  • Inflammatory Bowel Diseases / genetics*
  • Inflammatory Bowel Diseases / metabolism
  • Inflammatory Bowel Diseases / pathology
  • Intestinal Mucosa / metabolism
  • Intestines / drug effects
  • Kidney Calculi / genetics
  • Kidney Calculi / metabolism
  • Kidney Calculi / pathology
  • Oxalates / metabolism
  • Receptor, Adenosine A2B / genetics*
  • Receptor, Adenosine A2B / metabolism
  • Risk Factors
  • Signal Transduction / drug effects
  • Symporters / genetics*
  • Theophylline / administration & dosage
  • Type C Phospholipases / genetics


  • Adenosine A2 Receptor Antagonists
  • Amino Acid Transport Systems
  • Oxalates
  • Receptor, Adenosine A2B
  • SLC36A1 protein, human
  • Symporters
  • Adenosine Triphosphate
  • Theophylline
  • Type C Phospholipases
  • Adenosine