Acid‐base regulation of intestinal oxalate transport (LB716)

Abstract

Primary Hyperoxaluria (PH) is a rare, inherited disease caused by an absence of specific liver enzyme(s) leading to overproduction of oxalate (Ox2‐), kidney stones and eventual renal failure. Alongside the kidney, the intestine is capable of secreting Ox2‐ and reducing the systemic Ox2‐ burden. Preserving renal function in PH is paramount therefore the notion of extra‐renal Ox2‐ elimination should not be under‐estimated. Identification of chloride/bicarbonate (Cl‐/HCO3‐) exchangers with an affinity for Ox2‐ raises the possibility of these membrane‐bound proteins serving as future therapeutic targets for promoting Ox2‐ secretion in PH. Despite this interest, understanding how these transporters are regulated is not well defined. Components of the HCO3‐‐buffering system (pH, CO2 and HCO3‐) are important, but under‐appreciated regulators of Cl‐/HCO3‐ exchange. The objective of this study was to determine whether these acid‐base variables, and associated enzyme, carbonic anhydrase (CA), are involved in Ox2‐ handling. Isolated mouse intestinal preparations were mounted in an Ussing chamber and experiments systematically examined how changes to pH, PCO2 and [HCO3‐] impacted Ox2‐ fluxes. Results showed that Ox2‐ secretion by the distal colon requires CA activity, is sensitive to changing [HCO3‐], but not pH, and can be stimulated > 70 % by increasing PCO2. In contrast, Ox2‐ transport by the ileum was impervious to these maneuvers. This sets the foundation for more detailed studies into the identity of the transporter(s) responsible, the role of CA, and the underlying signaling pathway. These findings also highlight the heterogeneity of intestinal Ox2‐ handling, being regulated by distinct stimuli in different segments that express a similar suite of Cl‐/HCO3‐ exchangers.Grant Funding Source: Supported by a Career Development Fellowship from the Rare Kidney Stone Consortium at the Mayo Clinic, Rochester, MN (NIH 5U54 DK083908‐05)