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A Cyclic‐AMP Dependent Pathway Regulates Intestinal Oxalate Secretion
Author(s) -
Whittamore Jonathan,
Hatch Marguerite
Publication year - 2017
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.31.1_supplement.1007.30
Subject(s) - oxalate , calcium oxalate , cotransporter , secretion , kidney stones , chemistry , apical membrane , biochemistry , intracellular , microbiology and biotechnology , ussing chamber , biophysics , endocrinology , medicine , biology , membrane , sodium , inorganic chemistry , organic chemistry
A primary constituent of kidney stones is calcium oxalate, where elevated urinary oxalate (hyperoxaluria) is a major risk factor. Oxalate is a waste metabolite, and dietary component, with the kidney largely responsible for its excretion. However, the intestine also has a pivotal role, capable of actively secreting oxalate and reducing the endogenous burden. Molecular identification of the membrane‐bound intestinal anion exchangers (AEs) which transport oxalate has raised the possibility of the intestine serving as potential therapeutic target. Despite these advances, the signals and pathways regulating oxalate handling remain largely undefined. Our recent finding that oxalate secretion by the mouse cecum can be dramatically stimulated by the intracellular 2 nd messenger cyclic AMP (cAMP) is therefore particularly significant. The objective of this study was therefore focused on identifying the apical transporter and characterizing the corresponding basolateral process involved. At the apical membrane, the Slc26a6 anion exchanger PAT1 ( P utative An ion Tr ansporter 1), is a prospective candidate since previous work has demonstrated PAT1 mediates oxalate secretion in the adjacent small intestine. Utilizing in vitro tissue preparations mounted in Ussing chambers, experiments compared ceca from wild‐type and PAT1‐knockout mice. We determined that PAT1 was not directly involved in oxalate secretion, and subsequent experiments revealed evidence for another AE, as well as the cAMP‐stimulated chloride (Cl − ) channel, CFTR. At the basolateral membrane, the rate‐limiting step for secretion did not require a Cl − ‐dependent AE, as hypothesized, rather our data revealed a novel finding – the involvement of a cation‐Cl − cotransporter – supporting oxalate secretion in response to cAMP. Support or Funding Information NIH NIDDK DK‐088892 (M. Hatch)