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Abstract: FR-PO526

Characterization of Oxalobacter Formigenes-Derived Factors as Potential Novel Therapeutic Agents for Hyperoxalemia, Hyperoxaluria, and Related Kidney Stones

Session Information

Category: Bone and Mineral Metabolism

  • 401 Bone and Mineral Metabolism: Basic

Authors

  • Hassan, Hatim A., University of Chicago, Chicago, Illinois, United States
  • Arvans, Donna L., University of Chicago, LEMONT, Illinois, United States
  • Chang, Changsoo, Argonne National Laboratory, Argonne, Illinois, United States
  • Tesar, Christine, Argonne National Lab, Argonne, Illinois, United States
  • Babnigg, Gyorgy, Argonne National Laboratory, Argonne, Illinois, United States
  • Alshaikh, Altayeb, University of Chicago, Chicago, Illinois, United States
  • Musch, Mark W., U Chicago, Chicago, Illinois, United States
  • Chang, Eugene B., University of Chicago, Chicago, Illinois, United States
  • Joachimiak, Andrzej, Argonne National Laboratory, Argonne, Illinois, United States
Background

Most kidney stones are composed of calcium oxalate, and small increases in urine oxalate significantly enhance the risk for stone formation. Hyperoxaluria is a major risk factor for calcium oxalate kidney stones (COKS) and it has no specific therapy. The gut bacterium Oxalobacter formigenes (Of) induces colonic oxalate secretion and reduces urinary oxalate excretion via an unknown secretagogue. Given the difficulties with recolonization, Of alone is not therapeutically feasible and underscores the need to identify the secretagogue inducing colonic oxalate secretion. We previously identified Of-derived factors secreted in its culture conditioned medium (CM) that stimulate (>2.8-fold) oxalate transport by human intestinal Caco2-BBE (C2) cells, and reduce (>32.5%) urinary oxalate excretion in hyperoxaluric mice by stimulating (>42%) distal colonic oxalate secretion. The in vivo retention of biologic activity reflects the therapeutic potential of these factors and support the pursuit of their characterization.

Methods

Using Mass spectrometry we identified multiple protiens in a family of a regulatory protein as the major Of-derived factors, and we have obtained the crystal structures for 5 of these proteins.

Results

The identified proteins closely recapitulate the effects of the Of-derived factors and stimulate (1.4-2.4-fold) oxalate transport by C2 cells via PKA and stimulation of the oxalate transporters SLC26A6 and SLC26A2 similar to CM. We also identified 35-amino acid peptides (P8+9) within one of these proteins that significantly stimulate (>2.4-fold) oxalate transport by C2 cells. P8+9 peptides also stimulated oxalate transport by human sigmoid colon (1.8-fold) and ileum (2-fold) organoids (ex vivo intestinal epithelia models fully mimicking the in vivo physiological responses), strongly suggesting that P8+9 peptides will stimulate oxalate transport in human colonic and ileal epithelia in vivo.

Conclusion

We identifed Of-derived peptides with singificant potential to stimulate oxalate transport in human colonic and ileal epithelia in vivo. Future studies will evaluate the therapeutic potential of these peptides in reducing urine and plasma oxalate levels in hyperoxaluric and hyperoxalemic mice, respectively.

Funding

  • NIDDK Support