J Am Soc Nephrol
Department of Medicine, The University of Chicago, Chicago, Illinois;
Published: March 2017
Hyperoxaluria is a major risk factor for kidney stones and has no specific therapy, although colonization is associated with reduced stone risk. interacts with colonic epithelium and induces colonic oxalate secretion, thereby reducing urinary oxalate excretion, an unknown secretagogue. The difficulties in sustaining colonization underscore the need to identify the derived factors inducing colonic oxalate secretion. We therefore evaluated the effects of culture conditioned medium (CM) on apical C-oxalate uptake by human intestinal Caco-2-BBE cells. Compared with control medium, CM significantly stimulated oxalate uptake (>2.4-fold), whereas CM from did not. Treating the CM with heat or pepsin completely abolished this bioactivity, and selective ultrafiltration of the CM revealed that the -derived factors have molecular masses of 10-30 kDa. Treatment with the protein kinase A inhibitor H89 or the anion exchange inhibitor 4,4'-diisothiocyano-2,2'-stilbenedisulfonic acid completely blocked the CM-induced oxalate transport. Knockdown of the oxalate transporter SLC26A6 also significantly restricted the induction of oxalate transport by CM. In a mouse model of primary hyperoxaluria type 1, rectal administration of CM significantly reduced (>32.5%) urinary oxalate excretion and stimulated (>42%) distal colonic oxalate secretion. We conclude that -derived bioactive factors stimulate oxalate transport in intestinal cells through mechanisms including PKA activation. The reduction in urinary oxalate excretion in hyperoxaluric mice treated with CM reflects the retention of biologic activity and the therapeutic potential of these factors.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5328155 | PMC |
http://dx.doi.org/10.1681/ASN.2016020132 | DOI Listing |
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