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Abstract: FR-PO554

Early Transcriptional Changes in Distal Convoluted Tubule Cells Are Evident in PKD1 (Polycystin 1) Mutant Mice Prior to Cyst Development

Session Information

Category: Genetic Diseases of the Kidneys

  • 1201 Genetic Diseases of the Kidneys: Cystic


  • Nguyen, Elizabeth D., University of Washington, Seattle, Washington, United States
  • Mandel, Amrei Maxi, Universitat zu Koln, Koln, Nordrhein-Westfalen, Germany
  • Houghtaling, Scott Robert, Seattle Children's Research Institute, Seattle, Washington, United States
  • Gombart, Sean, Seattle Children's Research Institute, Seattle, Washington, United States
  • Beier, David R., University of Washington, Seattle, Washington, United States

Autosomal dominant polycystic kidney disease (ADPKD) is due to mutations in PKD1 and PKD2 and is not diagnosed in patients until cyst formation has already occurred. Cysts arise mainly from distal portions of renal tubular segments but the mechanism of cyst formation is still unclear, and there are no treatment strategies to prevent formation of cysts. The PKD1 p.R3277C Pkd1tm1.1Pcha knockin mouse (RC/RC) develops gradual cystogenesis mimicking the features of ADPKD (Hopp K et al., JCI 2012). Here, we use this model to identify transcriptional changes at early timepoints; post-natal day 10 (p10), before gross cyst formation and p20, after cystic changes occur in the kidney.


Single nuclei RNA-seq was performed on kidneys from RC/RC and age matched control mice at p10 (n=3) and p20 (n=3). Sequencing data within the same condition were aggregated. Cluster identities were assigned using expression of known cell markers. Differentially expressed genes between p10 and p20 with correlating controls was performed on distal convoluted tubule (DCT) cell clusters using regression analysis with a cutoff of log2 fold change.


Cells with unique molecular identifiers (UMI) > 1000 ranged between 7000 to 10,000 for controls and 25,000 to 31,000 for kidneys from RC/RC mice. There were 20-26 clusters for each condition covering 12 kidney cell types, including >1500 DCT cells per condition. Genes with significant differential expression in the RC/RC mouse at p10 included genes associated with cystic disease (Nek1 and Pde1a) in addition to 34 other genes. Genes with differential expression within DCT cells at p20 include Hsf2bp in addition to 5 other genes.


This work identifies genes within distal convoluted tubule cells implicated in cyst formation in polycystic kidney disease caused by mutations in PKD1. The transcriptional landscape of the pre-cystic kidney is significantly different than control, indicating that molecular pathways are activated at early timepoints before structural changes in the tissue. Further characterization of differentially expressed genes at early timepoints will address an important gap in field of ADPKD by identifying pathways leading to cyst formation and potential targets for therapeutics before cysts occur.


  • NIDDK Support