Abstract: FR-PO1028
Pathophysiology of Hyperoxaluria in SAMP1/YitFc Mice
Session Information
- CKD Mechanisms: From Mendel to Mars
November 03, 2023 | Location: Exhibit Hall, Pennsylvania Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: CKD (Non-Dialysis)
- 2303 CKD (Non-Dialysis): Mechanisms
Authors
- Zaidan, Nadim, NYU Langone Health, New York, New York, United States
- Ho, Melody, NYU Langone Health, New York, New York, United States
- Cardozo, Lila, NYU Langone Health, New York, New York, United States
- Xiong, Xiaozhong, NYU Langone Health, New York, New York, United States
- Mital, Vibha, NYU Langone Health, New York, New York, United States
- Nair, Ambika, NYU Langone Health, New York, New York, United States
- Goldfarb, David S., NYU Langone Health, New York, New York, United States
- Nazzal, Lama, NYU Langone Health, New York, New York, United States
Background
Enteric hyperoxaluria (EH) is postulated to arise from increased oxalate (Ox) bioavailability in the gastrointestinal (GI) tract secondary to fat malabsorption. This could lead to chronic kidney disease progression or recurrent kidney stones. Crohn’s disease (CD) is one of the most prevalent conditions causing EH. The SAMP1/YitFc (SAMP1) mouse model develops spontaneous ileal inflammation mimicking human CD pathology. In this ileitis mouse model, we aim to confirm the development of the EH phenotype and explore the different factors underlying EH pathophysiology.
Methods
We compared adult SAMP1 mice and their closest genetic control (AKR mice) on three different fat-containing diets (10%, 45%, and 60%), all supplemented with 1% Ox. Urine (U), plasma (P), and fecal samples were collected during the study and GI segments were harvested at sacrifice at week 5. We measured Ox and creatinine (Cr) levels in the blood and urine. We performed lipidomics assessments of fecal fats to assess malabsorption. Tight junction proteins are important determinants of gut permeability. Occludin and ZO1 were assessed in the ileum using qPCR and Western Blots (WB), respectively.
Results
UOx increased with the percentage of dietary fat, an increase marked in the SAMP1 mice compared with AKR. At sacrifice comparing SAMP1 to AKR, UOx/UCr was 0.40±0.01 vs 0.28±0.01 µmol/mg on 45% fat and 0.45±0.04 vs 0.28±0.02 µmol/mg on 60% fat (both p<0.0001). At sacrifice, POx and PCr were higher in SAMP1 mice compared to AKR. The SAMP1 mice had a higher abundance of lipid species in the feces. Specifically, increased amounts of diacylglycerols and free fatty acids in SAMP1 stool samples suggest fat malabsorption. ZO1 and Occludin levels were lower in SAMP1 as compared to AKR mice.
Conclusion
After confirming the EH phenotype, we were able to characterize important factors underlying EH in this model. Decreased TJ in SAMP1's ileum, suggesting increased gut permeability, and a higher bioavailability of Ox arising from fat malabsorption contribute to increased passive Ox reabsorption. Next steps will include exploring the microbiome of these mouse models and characterizing the determinants of kidney injury in these models.
Funding
- NIDDK Support