Comparative Transcriptomic Analysis of Polycystic Kidneys and Livers from Patients with ADPKD Reveals Organ-Specific Alterations in Transcriptional Profiles and Associated Signaling Pathways

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Background: Autosomal Dominant Polycystic Kidney Disease (ADPKD) and ADPKD-associated Polycystic Liver Disease (PLD) are co-existing monogenic disorders with limited (ADPKD) or no (PLD) FDA-approved therapies. We hypothesize that organ-specific transcriptional profiles in PKD kidneys and PLD livers might determine disparity in renal and hepatic cystogenesis and help identify new therapeutic targets. Methods: Kidney and liver tissues of age- and sex-matched ADPKD patients and healthy individuals (n=3 for each condition) were used to assess transcriptional profiles of cystic renal (PKD-REC) and biliary epithelial cells (PLD-BEC) by applying unbiased discovery-based spatial transcriptomics (ST). KEGG pathway analysis was used to reveal commonly or uniquely dysregulated pathways in cystic kidneys and livers. Results: Results: we found that PKD-REC and PLD-BEC are characterized by multiple differentially expressed genes and affected signaling pathways (ASigP) (Table 1). The top 5 distinctively ASigP in kidneys are: EGF/EGFR, TGF-beta receptor, ROBO receptors and TROP2 signaling, and cellular senescence. The top 5 distinctively ASigP in livers are: cell cycle, ciliary landscape, transcriptional regulation by p53, and HIF-1 and Rap1 signaling. Commonly affected pathways in both organs include cAMP signaling, autophagy, cell cycle, innate immune system and transcriptional misregulation. Conclusion: Comparative transcriptomic profiling of liver and kidney tissues in ADPKD patients demonstrates that pathways underlying PKD and PLD progression are different and organ specific. The overall larger number of differentially expressed genes and affected pathways in PKD compared to PLD might account for more severe phenotype in PKD. Common and uniquely affected signaling pathways in cystic kidneys and liver might serve as targets for concurrent or exclusive treatment of PKD and PLD. Funding: NIDDK Support, Private Foundation Support Table 1 - Kidney Liver Number of differentially expressed genes 2557 1758 Number of affected signaling pathways (ASigP) 78 42 Number of Distinctive ASigP 65 29 Number of Common ASigP 13 13

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