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  • P-III-1059

Global proteomic profiling of a patient-derived 3D cyst model and reference tissue from polycystic kidney disease

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Human Health Insights (Neurobiology, Cardiovascular, Liver, Kidney etc.)

Poster

Global proteomic profiling of a patient-derived 3D cyst model and reference tissue from polycystic kidney disease

Thema

  • Human Health Insights (Neurobiology, Cardiovascular, Liver, Kidney etc.)

Mitwirkende

Alina Meyer (Uppsala / SE), Bola Khalil (Beerse / BE; Leiden / NL), Margarita Iljin (Leiden / NL), Hester Bange (Leiden / NL), Leo Price (Leiden / NL), Dorien Peters (Leiden / NL), Per Artursson (Uppsala / SE)

Abstract

Autosomal dominant polycystic kidney disease (ADPKD) is the most common hereditary kidney disease eventually leading to end-stage renal disease. The progressively expanding, fluid-filled renal cysts are associated with proliferation, inflammation, fibrosis and Warburg-like metabolic reprogramming. Despite the relatively high prevalence, treatment options are currently limited to a single approved drug. While transcriptomic studies have elucidated deregulated pathways and potential drug targets, comprehensive proteomic profiling of human patient-derived samples remains largely unexplored. Here, we investigated the utility of human healthy and late-stage ADPKD patient-derived three-dimensional cyst cultures used in phenotypic drug screens as an in vitro model for ADPKD research. First, we analyzed the proteomes of 3D cyst cultures derived from healthy and diseased tissues using mass spectrometry-based quantitative global proteomic profiling. We then compared the protein expression profiles with those of reference tissues derived mainly from the same patients. We complemented our enrichment analyses with a database-based knowledge graph that links our differentially expressed proteins with diseases, pathways, biological processes and drugs. In addition, we quantified proteins affecting drug disposition in ADPKD as well as proposed drug targets for treatment of ADPKD. Our results show that proteomic profiling of human 3D cyst cultures reflects previously reported pathophysiological alterations, including aberrant protein expression in inflammation and metabolism. In addition, downregulated protein synthesis was observed in ADPKD. The knowledge graph allowed us to explore differentially expressed proteins in a multidimensional network and facilitated the biological interpretation of the data. While the 3D cyst cultures partially recapitulated the disease phenotype in vitro, transporter expression was notably reduced compared to in vivo conditions. Finally, known target proteins for promising drug repurposing candidates such as the AMP-activated protein kinase showed similar expression in vitro and in tissues, supporting the suitability of the 3D cyst model for ADPKD drug screenings. In summary, our results provide a multifaceted insight into the ADPKD proteome and offer a starting point for further research to improve treatment options for affected individuals.

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