Abstract: FR-PO0056
The C-Terminal Tail of Polycystin-1 (PC1-CTT) Suppresses Cystic Disease in a Pkd2-KO ADPKD Orthologous Mouse Model
Session Information
- ADPKD and Cystic Kidney Disease - 2
October 23, 2026 | Location: Exhibit Hall A, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Genetic Diseases of the Kidneys
- 1201 Genetic Diseases of the Kidneys: Cystic (Monogenic)
Authors
- Rai, Victoria, Yale University, New Haven, Connecticut, United States
- Onuchic, Laura, Yale University, New Haven, Connecticut, United States
- Reyna-Neyra, Marcela Andrea, Yale University, New Haven, Connecticut, United States
- Caplan, Michael J., Yale University, New Haven, Connecticut, United States
Background
Autosomal dominant polycystic kidney disease (ADPKD) is the most prevalent life-threatening monogenic disorder. Mutations in PKD2 account for ~15% of cases. We have previously shown that transgenic expression of PC1-CTT, a protein corresponding to the final 200 aa residues of PC1, can suppress cystic phenotype in Pkd1-KO murine models. This suppression is dependent upon the interaction between PC1-CTT and mitochondrial enzyme nicotinamide nucleotide transhydrogenase (NNT). Herein, we performed RNA-seq in PC1-CTT-expressing Pkd1-KO mice and observed profound NNT-dependent changes to transcriptional regulation. This suggests that PC1-CTT-mediated disease suppression occurs entirely through effects exerted at the mitochondrial level, which led us to hypothesize that PC1-CTT effects on cystogenesis could be observed in ADPKD models attributable to other mutations, provided that they share a similar metabolic signature with Pkd1-KOs.
Methods
Bulk RNA-seq was performed on kidney lysates of PC1-CTT-expressing 10-week (w) Pkd1-KO mice on both NNT-deficient C57BL/6J and NNT-expressing C57BL/6N backgrounds. PC1-CTT-expressing Pkd2-KO mice were generated by crossing mice expressing flox-stop 2HA-PC1-CTT with Pkd2fl/fl;Pax8rtTA;TetO-Cre mice.
Results
Bulk RNA-seq shows that 10w Pkd1-KO mice expressing both NNT and PC1-CTT have over 2000 differentially expressed genes (DEGs) relative to Pkd1-KO mice that lack PC1-CTT. In contrast, comparing NNT-deficient Pkd1-KO mice with and without PC1-CTT shows only 2 DEGs. The NNT/PC1-CTT interaction reduces expression of genes associated with matrix remodeling and increases expression of genes associated with metabolic pathways. In pre-cystic 10w mice, kidney weight/body weight ratio (KW/BW) are comparable between Pkd2-KO mice that do or do not express PC1-CTT (2.2%). In cystic 16w Pkd2-KO mice, PC1-CTT expression reduces KW/BW by 30% (9.5% vs 6.8%, p<0.0099). Immunoblotting shows PC1-CTT localizes to the mitochondrial fraction of kidney homogenates in Pkd2-KO mice and increased PC1-CTT expression levels may correlate with improved phenotype.
Conclusion
PC1-CTT suppresses cystic phenotype in Pkd2-KO mice. Ongoing work explores details of the shared PC1-CTT-associated suppression mechanisms in both Pkd1-KO and Pkd2-KO models. These studies open the doors to exploring the therapeutic potential of the PC1-CTT in the added context of PKD2 mutations.
Funding
- NIDDK Support