Exploring the urinary metabolome of polycystic kidney disease

Elena Sánchez-López, Human Genetics, Leiden University Medical Center, Leiden, The Netherlands (E.Sanchez_Lopez@lumc.nl)
Aswin Verhoeven, Center For Proteomics And Metabolomics, Leiden University Medical Center, Leiden, The Netherlands
Dorien J. M. Peters, Human Genetics, Leiden University Medical Center, Leiden, The Netherlands
Oleg A. Mayboroda, Center For Proteomics And Metabolomics, Leiden University Medical Center, Leiden, The Netherlands

Autosomal dominant polycystic kidney disease (ADPKD) is a genetic disorder affecting 1 in 2500 individuals worldwide. In the majority of patients ADPKD is caused by a mutation in the PKD1-gene resulting in the formation of many fluid-filled cysts, leading to kidney enlargement, fibrosis, and progressive loss of renal function. PKD accounts to be one of the major leading causes of renal failure, in which patients around 55 years old require renal transplantation [1]. PKD has no cure, but a Vasopressin V2 receptor antagonist has been licensed as a treatment that slows down its progression. Unfortunately, this drug has several side effects, such as an abnormal excretion of urine (polyuria). Therefore, the search for alternative therapies is still ongoing and metabolic regulation in PKD is considered as one of the promising topics. Moreover, unraveling what metabolites are affected in PKD will also help understanding the mechanisms of this disease.

In previous reports we performed the analysis of kidney tissue sections of a PKD mouse model by liquid chromatography- and capillary electrophoresis-mass spectrometry [2,3], which enabled us to pinpoint a subset of metabolites affected in this disease. However, in practice, an assessment of the disease status in experimental models and patients requires a noninvasive approach based on the metabolic profiling of body fluids, mainly urine. Nuclear magnetic resonance (NMR) was chosen as the main analytical platform thanks to the quantitative nature of the technology and the reproducible data generated. Here, we applied targeted, quantitative metabolic profiling using the semi-automatic KIMBLE workflow [4]. A tamoxifen-inducible kidney-specific Pkd1-deletion mouse model was used. Urine samples were collected at different time points (3, 6, 9 and 11 weeks after tamoxifen administration) and concentrations of about 30 urinary metabolites were compared between PKD and wild type (control) mice. Some of these metabolites displayed a longitudinal pattern. The quantitative data generated by NMR offers a window in the insight of the underlying mechanisms of PKD.

Acknowledgments: This project has received funding from the European Union’s H2020 research and innovation programme under the Marie Sklodowska-Curie grant agreement No. 707404 (LEaDing Fellows programme).

References

[1] Torres et al. Lancet, 369, 2007, 1287.

[2] Sánchez-López et al. Molecular BioSystems,13, 2017, 1940.

[3] Sánchez-López et al. Scientific Reports, 9, 2019, 806.

[4] Verhoeven et al. Analytica Chimica Acta, 1044, 2018, 66.

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Abstract Reference & Short Personal Biography of Presenting Author

Elena Sánchez López (1990) obtained her PhD at the University of Alcalá (Madrid, Spain) in 2017 supervised by Dr. María Luisa Marina and Dr. Antonio L. Crego. Her thesis dealt with chiral separations and metabolomic analysis, both by means of (micro)-separative techniques coupled to mass spectrometry. During her PhD she carried out two internships in the Center of Proteomics and Metabolomics of the Leiden University Medical Center (Leiden, the Netherlands), under supervision of Dr. Oleg A. Mayboroda. There she developed analytical strategies based on capillary electrophoresis and liquid chromatography coupled to mass spectrometry to obtain the metabolic profile of 20 µm-thick sections of mouse kidney.

Her first postdoc was conducted at the University of Alcalá where she was involved in the metabolomics study of an in vitro model of high glucose under Dr. María Castro and Dr. María Luisa Marina's supervision. Since November 2018 she is a Marie Sklodowska-Curie postdoctoral fellow (LEaDing fellows programme) working in the Human Genetics department of the Leiden University Medical Center, supervised by Dr. Dorien Peters. Her current project involves the metabolomics study of polycystic kidney disease, a genetic disorder characterized by the development of large fluid cysts in kidneys. She has published 15 research articles and has contributed with 5 book chapters. She obtained the best young scientist oral communication award at the PBA2016 conference in Guangzhou (China).