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Abstract: FR-PO261

Loss of Intestinal Pkd1 Does Not Alter Epithelial Cell Integrity or Inflammation in Early Autosomal Dominant Polycystic Kidney Disease

Session Information

Category: Genetic Diseases of the Kidneys

  • 1101 Genetic Diseases of the Kidneys: Cystic

Authors

  • Sedaka, Randee S., The University of Alabama at Birmingham, Birmingham, Alabama, United States
  • Yamaguchi, Shinobu, The University of Alabama at Birmingham, Birmingham, Alabama, United States
  • Shinde, Sejal Sanjay, The University of Alabama at Birmingham, Birmingham, Alabama, United States
  • Hsu, Jung-Shan, The University of Alabama at Birmingham, Birmingham, Alabama, United States
  • Saigusa, Takamitsu, The University of Alabama at Birmingham, Birmingham, Alabama, United States
Background

Autosomal dominant polycystic kidney disease (ADPKD) is the most common inherited progressive kidney disorder, manifested by a germline PKD1 mutation in nearly 80% of patients. Polycystin-1 (PC-1), the protein encoded by PKD1, is critical to maintaining renal epithelial cell adhesion. However, its expression along the intestines and its role in intestinal epithelial cell barrier function have yet to be elucidated. Considering the gut is the largest source of inflammatory cells in the body, and macrophage infiltration precedes accelerated cyst growth in kidney-specific Pkd1 knockout (Pkd1KO) mice, we hypothesized that loss of intestinal Pkd1 would lead to decreased intestinal epithelial cell integrity and increased inflammation, potentially preceding renal inflammation.

Methods

Plasma, kidney, and intestines were collected from 9-12 week old male and female conditional Pkd1KO (CAGG-creER; tamoxifen-induced at 5-6 weeks) and flox (control) mice. Intestinal permeability was detected via a fluorescein isothiocyanate–dextran assay. Tissue was utilized for RT-PCR and immunohistochemistry, while plasma was used to measure monocyte chemoattractant protein-1 (MCP-1).

Results

Kidney/body weight ratio was significantly elevated in Pkd1KO compared to flox mice. No genotype differences were observed in colon or small intestine/body weight ratio. Pkd1 expression was significantly decreased in the kidney, duodenum, jejunum, ileum, proximal colon, and distal colon of Pkd1KO compared to flox mice. Despite these deficiencies, there were no differences in kidney, ileum, or colon epithelial integrity genes (Ocln, Ptk2, Cldn1, Tjp1, Dsg2, Cdh1), inflammatory genes (Csf1, Il1b, Ccl2, Il6, Tnfa, Tgfb1, Muc2), intestinal damage, plasma MCP-1, or small intestinal permeability between genotypes. However, colonic endothelial integrity marker, Plvap, was significantly elevated in Pkd1KO compared to flox mice, with a trended increase in Cdh5 and Cgn and decrease in colonic permeability.

Conclusion

Although Pkd1 expression is downregulated along the entire intestinal tract in our ADPKD mouse model, it does not appear that intestinal epithelial integrity or inflammation are altered at this early timepoint preceding renal inflammation. Elevated endothelial integrity marker expression suggests improved colonic barrier function in Pkd1KO mice.

Funding

  • NIDDK Support