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Acid‐base regulation of intestinal oxalate transport (LB716)
Author(s) -
Whittamore Jonathan,
Freel Robert,
Hatch Marguerite
Publication year - 2014
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.28.1_supplement.lb716
Subject(s) - bicarbonate , chemistry , carbonic anhydrase , oxalate , secretion , biochemistry , carbonic anhydrase ii , kidney , transporter , enzyme , endocrinology , biology , inorganic chemistry , organic chemistry , gene
Primary Hyperoxaluria (PH) is a rare, inherited disease caused by an absence of specific liver enzyme(s) leading to overproduction of oxalate (Ox 2‐ ), kidney stones and eventual renal failure. Alongside the kidney, the intestine is capable of secreting Ox 2‐ and reducing the systemic Ox 2‐ burden. Preserving renal function in PH is paramount therefore the notion of extra‐renal Ox 2‐ elimination should not be under‐estimated. Identification of chloride/bicarbonate (Cl ‐ /HCO 3 ‐ ) exchangers with an affinity for Ox 2‐ raises the possibility of these membrane‐bound proteins serving as future therapeutic targets for promoting Ox 2‐ secretion in PH. Despite this interest, understanding how these transporters are regulated is not well defined. Components of the HCO 3 ‐ ‐buffering system (pH, CO 2 and HCO 3 ‐ ) are important, but under‐appreciated regulators of Cl ‐ /HCO 3 ‐ exchange. The objective of this study was to determine whether these acid‐base variables, and associated enzyme, carbonic anhydrase (CA), are involved in Ox 2‐ handling. Isolated mouse intestinal preparations were mounted in an Ussing chamber and experiments systematically examined how changes to pH, P CO2 and [HCO 3 ‐ ] impacted Ox 2‐ fluxes. Results showed that Ox 2‐ secretion by the distal colon requires CA activity, is sensitive to changing [HCO 3 ‐ ], but not pH, and can be stimulated > 70 % by increasing P CO2 . In contrast, Ox 2‐ 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 Ox 2‐ handling, being regulated by distinct stimuli in different segments that express a similar suite of Cl ‐ /HCO 3 ‐ 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)