Suppression of Autosomal Dominant Polycystic Kidney Disease Influences Epithelial Cell Transcription Program

Objective: To identify transcriptional differences in autosomal dominant polycystic kidney disease (ADPKD) using mouse models that lead to suppressed and non-suppressed cystic phenotypes and to define differential cells states that may be associated with stages of disease progression. Hypothesis: Expression of the 200 amino acid C-terminal tail (CTT) portion of the larger polycystin-1 protein, encoded by the Pkd1 gene whose loss causes ADPKD, alters epithelial cell transcriptional profile in early stages of disease, which subsequently influences downstream suppression of cystic phenotype compared to the non-suppressed model. Methodology: Orthologous doxycycline-inducible mouse models (Pkd1fl/fl;Pax8rtTA;Teto-Cre;C57BL/6N) expressing CTT (Pkd1-KO+CTT) or not (Pkd1-KO) were induced between 4-6 weeks of age and aged to 10 weeks, a time at which early stages of the cystic phenotype are evident. We performed single cell RNA sequencing (scRNA-seq) on single cell kidney suspensions from biological replicates that were pooled and processed for cDNA synthesis and library preparation with 10X Chromium technology. Reads were aligned using the 10X Genomics CellRanger pipeline and further processed using the gene cell-inverse cell frequency pipeline. Data: Several clusters were identified in the Pkd1-KO model that were absent or sparsely populated in the Pkd1-KO+CTT model. These clusters expressed markers of multiple tubule segments as well as novel transcripts, suggesting that cells in different tubule segments possess a shared cell transcriptional profile due to loss of Pkd1. These clusters are not shared between the Pkd1-KO and Pkd1-KO+CTT models, suggesting that CTT expression influences the transcriptional program of renal epithelial cells. RNA velocity and pseudotime analysis identify a transition state between healthy cells and likely cystic cells, and, in the PKD-KO+CTT model, cells are maintained in this transition state. At this early timepoint, there are no significant differences in disease endpoints between the Pkd1-KO and Pkd1-KO+CTT models, supporting a cell-autonomous CTT influence on epithelial cell transcription program. Summary: scRNA-seq at an early ADPKD timepoint reveals novel transcriptional markers whose significance are being interrogated at spatial and functional levels. Early transcriptional differences in epithelial cells of Pkd1-KO and Pkd1-KO+CTT models reveal a transition state that may be associated with progression and suppression of cystic disease. Conclusion: These results reveal that CTT regulates a transcriptional program of epithelial cells in early ADPKD that may participate in the mechanism that determines disease progression or suppression. NIH F31 DK135356, NIH RC2 DK120534-01, PR191158 Department of Defense, and PKD 905682 Foundation for Research in Polycystic Kidney Disease Research Grant This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.