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Abstract: PO0525

Leaky Intestinal Epithelium Causes Hyperoxaluria in CA-MLCK Mice

Session Information

Category: Bone and Mineral Metabolism

  • 401 Bone and Mineral Metabolism: Basic

Authors

  • Hassan, Hatim A., The University of Chicago, Chicago, Illinois, United States
  • Bashir, Mohamed Elfatih, The University of Chicago, Chicago, Illinois, United States
  • Alshaikh, Altayeb, The University of Chicago, Chicago, Illinois, United States
  • Jung, Daniel Y., The University of Chicago, Chicago, Illinois, United States
  • Turner, Jerrold R., Harvard Medical School, Boston, Massachusetts, United States
  • Asplin, John R., Litholink Corporation, Chicago, Illinois, United States
Background

Most kidney stones are composed of calcium oxalate, and very small increases in urine oxalate enhance the stone risk. The intestine plays a crucial role in oxalate homeostasis, and intestinal oxalate absorption is largely passive and paracellular. To evaluate whether enhanced intestinal paracellular permeability can increase urinary oxalate excretion, mice with augmented small and large intestinal paracellular leak (transgenic mice expressing intestinal constitutively active myosin light chain kinase = CA-MLCK) were used.

Methods

Described under Results.

Results

CA-MLCK mice have significantly higher (1.27-fold) urine oxalate compared to controls (µM/mg creatinine; Controls = 10.15±0.48; CA-MLCK = 12.86±0.65), reflecting that primary intestinal barrier dyscfuntion is sufficient by itself to cause hyperoxaluria. This 27% increase in urinary oxalate concentration is significant since minor increases enhance the stone risk. To see if the observed hyperoxaluria is due to enhanced passive paracellular intestinal oxalate absortion, jejunal and ileal tissues were isolated from control and CA-MLCK mice and mounted in Ussing chambers, and unidirectional 14C-oxalate and 3H-mannitol absorptive fluxes were assessed. CA-MLCK mice have signifincatly higher ileal 14C-oxalate (1.65-fold) and 3H-mannitol (1.70-fold) absorptive fluxes. CA-MLCK also have a statistically insignifcant higher jejunal 14C-oxalate (1.31-fold) absorptive flux. To determine whether enhanced intestinal oxalate absorption is also active in vivo as observed ex vivo, control and CA-MLCK mice were orally gavaged with a single dose of 13C-oxalate, followed by urine collection x 6 h. CA-MLCK mice have a statistically insignifcant higher (1.40-fold) 13C-oxalate excreted in the urine compated to Controls in preliminary studies, suggesting that they absorbed higher amount of the administered 13C-oxalate, which is likely due to the underlying intestinal barrier dysfunction leading to enhanced passive paracellular oxalate absorption.

Conclusion

CA-MLCK mice have significant hyperoxaluria due to mechanisms including enhanced small intestinal passive paracellular oxalate absorption. These findings are of significant interest since they provide new understanding into the role of leaky intestinal epithelium and hyperoxaluria, a feature of diseases such as obesity, DM, IBD, and celiac disease.

Funding

  • NIDDK Support