Polycystin-1 C-terminal tail suppresses cystic phenotype in autosomal dominant polycystic kidney disease in a Pkd genotype-independent manner

Objective: To assess mechanisms by which polycystin-1 C-terminal tail (PC1-CTT) suppresses disease in mouse models of autosomal dominant polycystic kidney disease (ADPKD) caused by disruption of Pkd1 or Pkd2. Hypothesis: PC1-CTT expression suppresses cystic disease through pathways independent of Pkd1 or Pkd2 loss. Methodology: Bulk RNA-seq was performed on kidney lysates of 10-week-old Pkd1-KO models (Pkd1fl/fl;Pax8rtTA;Teto-Cre;C57BL/6N) expressing PC1-CTT (Pkd1-KO+CTT) or not (Pkd1-KO). When induced with oral doxycycline from 4-6 weeks of age, 10-week-old mice show early stages of the cystic phenotype. In addition, mice expressing a flox-stop 2HA-PC1-CTT were crossed with a Pkd2-KO ADPKD orthologous mouse model (Pkd2fl/fl;Pax8rtTA;TetO-Cre) on a C57BL/6N background to generate Pkd2-KO mice expressing CTT or not. Oral doxycycline induction from 4-6 weeks of age leads to PC2 loss in renal epithelial cells. Mice were aged to 16 weeks, at which point later stage cystic disease manifests and compromises renal function in Pkd2-KO. Blood was taken for serum BUN and creatinine measurements, and kidneys were harvested for immunohistochemistry and biochemical analysis to assess PC1-CTT suppression of Pkd2 related cystic disease. Data: Bulk RNA-seq revealed patterns of gene expression in 10-week-old Pkd1-KO+CTT kidneys that were elevated or reduced compared to those in Pkd1-KO kidneys, resembling expression to that of wildtype (WT) kidneys. In addition, patterns of gene expression were observed in Pkd1-KO+CTT kidneys that were elevated or reduced in Pkd1-KO+CTT as compared to both WT and Pkd1-KO. The genes that resembled WT were involved in pathways related to extracellular matrix remodeling, TGF-beta signaling, and chemoattraction, prompting investigation of immune cell populations in proximity to renal cysts. Immunofluorescence performed on kidney sections to detect M2 macrophages, which have been associated with cyst suppression, revealed no differences in total M2 macrophage counts between Pkd1-KO+CTT and Pkd1-KO. This analysis, however, showed significant differences between areas of low cystic index and high cystic index within each model, suggesting M2 macrophages localize to areas of high cystic index independent of PC1-CTT expression. We next evaluated whether PC1-CTT suppressed Pkd2-related cystic disease. In 16-week-old Pkd2-KO mice, PC1-CTT reduced kidney weight/body weight ratio by 30% (9.5% vs 6.8%, p< 0.0099). Ongoing work is exploring details of these apparent shared PC1-CTT-associated suppression mechanisms in both the Pkd1 and Pkd2 KO models. Summary: Bulk RNA-seq revealed effects of PC1-CTT in Pkd1-KO compared to Pkd1-KO+CTT kidneys consistent with Pkd1-independent suppression pathways. Despite reduced expression of chemoattractant genes like Mcp1, M2 macrophage populations were not different between models. Thus, suppression of the ADPKD cystic phenotype by PC1-CTT does not appear to be due to altered immune cell localization. PC1-CTT suppresses cystic phenotype due to loss of Pkd1 or Pkd2, demonstrating that its disease suppression mechanism functions independent of disease-causing genotype in the two most common forms of ADPKD. Conclusions: The PC1-CTT suppresses disease independent of Pkd1 and is effective in suppressing ADPKD caused by loss of Pkd2. Funding sources: NIH R01DK139319 (MJC); NIH F31DK135356 (VR) This abstract was presented at the American Physiology Summit 2026 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.