Kidney Week

Abstract: FR-PO273

A Quantitative Proteomic Study of Tolvaptan Treatment in an Orthologous Mouse Model of Autosomal Dominant Polycystic Kidney Disease: What Remains Altered?

Session Information

• Genetic Diseases of the Kidneys: Cystic - II
  November 04, 2022 | Location: Exhibit Hall, Orange County Convention Center‚ West Building
  Abstract Time: 10:00 AM - 12:00 PM

Category: Genetic Diseases of the Kidneys

• 1101 Genetic Diseases of the Kidneys: Cystic

Authors

• Nuñez-Gonzalez, Laura, Genetics and Developmental Biology of Kidney Diseases. Health Research Institute of Santiago de Compostela (IDIS), Santiago de Compostela Clinical Hospital Complex (CHUS), Santiago de Compostela, Spain

Laura Nuñez-Gonzalez,

• Cordido, Adrian, Genetics and Developmental Biology of Kidney Diseases. Health Research Institute of Santiago de Compostela (IDIS), Santiago de Compostela Clinical Hospital Complex (CHUS), Santiago de Compostela, Spain

Adrian Cordido,

• Vizoso, Marta, Genetics and Developmental Biology of Kidney Diseases. Health Research Institute of Santiago de Compostela (IDIS), Santiago de Compostela Clinical Hospital Complex (CHUS), Santiago de Compostela, Spain

Marta Vizoso,

• Gómez García, Fernando, Genetics and Developmental Biology of Kidney Diseases. Health Research Institute of Santiago de Compostela (IDIS), Santiago de Compostela Clinical Hospital Complex (CHUS), Santiago de Compostela, Spain

Fernando Gómez García,

• Bravo, Susana, Proteomic Platform. Health Research Institute of Santiago de Compostela (IDIS), Santiago de Compostela Clinical Hospital Complex (CHUS), Santiago de Compostela, Spain

Susana Bravo,

• Rodríguez, Cándido Díaz, Genetics and Developmental Biology of Kidney Diseases. Health Research Institute of Santiago de Compostela (IDIS), Santiago de Compostela Clinical Hospital Complex (CHUS), Santiago de Compostela, Spain

Cándido Díaz Rodríguez,

• Ortiz, Alberto, Jimenez Diaz foundation. School of Medicine, Autonomous University of Madrid (UAM), Madrid, Spain

Alberto Ortiz,

• Garcia-Gonzalez, Miguel A., Genetics and Developmental Biology of Kidney Diseases. Health Research Institute of Santiago de Compostela (IDIS), Santiago de Compostela Clinical Hospital Complex (CHUS), Santiago de Compostela, Spain

Miguel A. Garcia-Gonzalez,

Background

Autosomal Dominant Polycystic Kidney Disease (ADPKD) is a monogenic inherited disorder caused by mutations in PKD1 and PKD2 genes, with a prevalence of 1:800 live births. It Is characterized by the presence and progressive development of fluid-filled cysts leading to end-stage renal disease. A specific antagonist of vasopressin receptor type 2 in the distal tubules of the nephron (Tolvaptan) has been approved for ADPKD treatment. Although Tolvaptan mechanism of action has been described, its underlying molecular mechanisms are not well characterized. Our study is mainly focused on the understanding of those Tolvaptan hidden molecular mechanisms, in order to also understand, the remain altered pathways.

Methods

Quantitative proteomics based on SWATH–MS technology were performed comparing proteomes of kidneys from polycystic kidney disease (PKD) murine model: Pkd1cond/cond;Tam-Cre−/+. Mice were subdivided in three groups: Wild Type, Mutant and Tolvaptan-treated mutant animals.

Results

In this study, tolvaptan showed an amelioration of renal function measured by BUN, as well as diminution in cystic index and number of cysts. Through quantitative proteomics, we identified a list of 327 proteins with and adjusted p-value below 0.05 and two-fold cut-off which were found to be modified after tolvaptan treatment in comparison to mutant animals and 433 proteins in tolvaptan-treated group in comparison with wild type animals. In both differential proteomes tolvaptan treatment has shown a differential expression in the cluster of respiratory electron transport and ATP synthesis by proteins of the inner membrane of mitochondria, which could indicate a reduction in the oxygen necessities after the treatment. This effect can reduce hypoxia in cystic environment, which in turn can be responsible for some of the beneficial effects of the drug.

Conclusion

This work identified novel molecular pathways modified after tolvaptan treatment such as diminution in oxygen necessities and downregulation of proteins responsible for ATP synthesis. These modifications elucidate crucial aspects of tolvaptan treatment, unmasking novel alternative or complementary treatment strategies for ADPKD.