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Open AccessArticle

Proteomic Analysis of Urinary Extracellular Vesicles Reveals a Role for the Complement System in Medullary Sponge Kidney Disease

1
Laboratory of Molecular Nephrology, IRCCS Istituto Giannina Gaslini, 16147 Genova, Italy
2
Renal Unit, Department of Medicine, University/Hospital of Verona, Piazzale A. Stefani 1, 37126 Verona, Italy
3
Laboratory of Mass Spectrometry—Core Facilities, IRCCS Istituto Giannina Gaslini, 16147 Genova, Italy
4
Division of Nephrology, Dialysis and Transplantation, IRCCS Istituto Giannina Gaslini, 16147 Genova, Italy
*
Author to whom correspondence should be addressed.
These authors contributed equally to the study.
Int. J. Mol. Sci. 2019, 20(21), 5517; https://doi.org/10.3390/ijms20215517
Received: 12 September 2019 / Revised: 15 October 2019 / Accepted: 4 November 2019 / Published: 5 November 2019
Medullary sponge kidney (MSK) disease is a rare and neglected kidney condition often associated with nephrocalcinosis/nephrolithiasis and cystic anomalies in the precalyceal ducts. Little is known about the pathogenesis of this disease, so we addressed the knowledge gap using a proteomics approach. The protein content of microvesicles/exosomes isolated from urine of 15 MSK and 15 idiopathic calcium nephrolithiasis (ICN) patients was investigated by mass spectrometry, followed by weighted gene co-expression network analysis, support vector machine (SVM) learning, and partial least squares discriminant analysis (PLS-DA) to select the most discriminative proteins. Proteomic data were verified by ELISA. We identified 2998 proteins in total, 1764 (58.9%) of which were present in both vesicle types in both diseases. Among the MSK samples, only 65 (2.2%) and 137 (4.6%) proteins were exclusively found in the microvesicles and exosomes, respectively. Similarly, among the ICN samples, only 75 (2.5%) and 94 (3.1%) proteins were exclusively found in the microvesicles and exosomes, respectively. SVM learning and PLS-DA revealed a core panel of 20 proteins that distinguished extracellular vesicles representing each clinical condition with an accuracy of 100%. Among them, three exosome proteins involved in the lectin complement pathway maximized the discrimination between MSK and ICN: Ficolin 1, Mannan-binding lectin serine protease 2, and Complement component 4-binding protein β. ELISA confirmed the proteomic results. Our data show that the complement pathway is involved in the MSK, revealing a new range of potential therapeutic targets and early diagnostic biomarkers. View Full-Text
Keywords: medullary sponge kidney; idiopathic calcium nephrolithiasis; complement system; proteomics medullary sponge kidney; idiopathic calcium nephrolithiasis; complement system; proteomics
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Bruschi, M.; Granata, S.; Candiano, G.; Fabris, A.; Petretto, A.; Ghiggeri, G.M.; Gambaro, G.; Zaza, G. Proteomic Analysis of Urinary Extracellular Vesicles Reveals a Role for the Complement System in Medullary Sponge Kidney Disease. Int. J. Mol. Sci. 2019, 20, 5517.

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