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Kidney Week

Abstract: SA-PO780

Novel Regulatory Networks of CFTR in the Kidneys

Session Information

Category: Genetic Diseases of the Kidneys

  • 1201 Genetic Diseases of the Kidneys: Cystic

Authors

  • Miszczuk, Mateusz, University of Virginia School of Medicine, Charlottesville, Virginia, United States
  • Swiatecka-Urban, Agnieszka, University of Virginia, Charlottesville, Virginia, United States
Background

Cystic fibrosis (CF) is an autosomal recessive genetic disorder arising from mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene and leads to impaired ion transport across epithelial cell membranes. While the most affected organs in people with CF (PwCF) are the lungs and digestive system, advancements in clinical care and novel high efficiency CFTR modulator therapy have increased life expectancy for most PwCF, unveiling impacts on other organs, including the kidneys. Adult PwCF have up to 20-fold higher risk of end stage kidney disease. In vitro studies suggest that CFTR may regulate renal metabolic pathways and protect from fibrosis, but nothing is known about such role in vivo. We performed single-nuclei (sn) multiomic analysis to elucidate the molecular mechanisms underlying CFTR role in the kidney.

Methods

Kidneys from 7–9-week-old male and female C57BL/6J mice expressing wild-type (WT) CFTR or CFTR G542X (CFTR KO [1]; N=1/group/sex) were subjected to nuclei isolation, Chromium Single Cell Multiome Assay, and snRNA-seq and ATAC-seq profiling. We annotated clusters and assigned cell types based on the expression pattern of knowledge-based cell type marker genes. We assessed the linkage between differentially expressed genes and accessible chromatin regions. This enabled the identification of potential regulatory elements and molecular changes in CFTR KO kidneys.

Results

We detected 27K of high-quality cells in both snRNA-seq and snATAC-seq. In WT and KO groups we identified reads corresponding to Cftr region, predominantly in the proximal tubuleepithelial (PTE) cells. Feature linkage plots corresponding with ATAC accessibility peaks (1Mbrange) and expression of CFTR gene across different cell types showed a robust positive and negative correlation network in the proximity of CFTR gene along with higher overall peak strength in KO groups.

Conclusion

The novel transcriptional and epigenetic CFTR regulatory networks suggest a novel role of CFTR in the kidney and emphasize that CFTR dysfunction may predispose PwCF to CKD.

Funding

  • Other NIH Support