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Urinary proteomics reveals key markers of salt sensitivity in hypertensive patients during saline infusion

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Abstract

Background

Hypertension is a complex disease and is the major cause of cardiovascular complications. In the vast majority of individuals, the aetiology of elevated blood pressure (BP) cannot be determined, thus impairing optimized therapies and prognosis for individual patients. A more precise understanding of the molecular pathogenesis of hypertension remains a pressing priority for both basic and translational research. Here we investigated the effect of salt on naive hypertensive patients in order to better understand the salt intake-blood pressure relationship.

Methods

Patients underwent an acute saline infusion and were defined as salt-sensitive or salt-resistant according to mean blood pressure changes. Urinary proteome changes during the salt load test were analysed by a label-free quantitative proteomics approach.

Results

Our data show that salt-sensitive patients display equal sodium reabsorption as salt-resistant patients, as major sodium transporters show the same behaviour during the salt load. However, salt-sensitive patients regulate the renin angiotensin system (RAS) differently from salt-resistant patients, and upregulate proteins, as epidermal growth factor (EGF) and plasminogen activator, urokinase (PLAU), involved in the regulation of epithelial sodium channel ENaC activity.

Conclusions

Salt-sensitive and salt-resistant subjects have similar response to a saline/volume infusion as detected by urinary proteome. However, we identified glutamyl aminopeptidase (ENPEP), PLAU, EGF and Xaa-Pro aminopeptidase 2 precursor XPNPEP2 as key molecules of salt-sensitivity, through modulation of ENaC-dependent sodium reabsorption along the distal tubule.

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Availability of data and material

Proteomic datasets produced in this study are available in the following database: Peptide Atlas repository, https://www.peptideatlas.org/. Accession number PASS00383 for T0 samples; accession number PASS01405 for T120 and T240 samples.

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Acknowledgements

We thank Mrs Brioni Elena, research nurse in OSR, for performing the saline load tests on patients.

Funding

This work was supported by PRIN 2006 no 2006065339.

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Authors and Affiliations

  1. IFOM-FIRC Institute of Molecular Oncology, Via Adamello 16, 20139, Milan, Italy

    Vittoria Matafora & Angela Bachi

  2. Chair of Nephrology, Genomics of Renal Diseases and Hypertension Unit, IRCCS San Raffaele Scientific Institute, Università Vita Salute San Raffaele, Via Olgettina 60, 20132, Milan, Italy

    Chiara Lanzani, Laura Zagato, Paolo Manunta & Marco Simonini

  3. Department of Translational Medical Science, University of Campania Luigi Vanvitelli, Naples, Italy

    Miriam Zacchia, Francesco Trepiccione & Giovambattista Capasso

  4. Biogem S.c.a.r.l., Ariano Irpino, Italy

    Francesco Trepiccione & Giovambattista Capasso

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  1. Vittoria Matafora
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  3. Laura Zagato
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Contributions

CL and PM performed visits of patients and acute salt load test, VM performed the proteomic experiments, VM and AB analysed the data, participated in the discussion on data interpretation and wrote the manuscript, LZ collected biological samples and implemented the clinical database, LZ, CL and PM revised the manuscript. GC proposed the experiments, followed the project in its phases and reviewed the manuscript, FT and MZ participated in the discussion on data interpretation.

Corresponding authors

Correspondence to Chiara Lanzani or Angela Bachi.

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The authors declare no competing interests.

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The study was approved by the Ethics Committee of the San Raffaele Hospital, Milan (Italy).

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Matafora, V., Lanzani, C., Zagato, L. et al. Urinary proteomics reveals key markers of salt sensitivity in hypertensive patients during saline infusion. J Nephrol 34, 739–751 (2021). https://doi.org/10.1007/s40620-020-00877-z

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