Sphingomyelin and Medullary Sponge Kidney Disease: A Biological Link Identified by Omics Approach

Simona Granata; Maurizio Bruschi; Michela Deiana; Andrea Petretto; Gianmarco Lombardi; Alberto Verlato; Rossella Elia; Giovanni Candiano; Giovanni Malerba; Giovanni Gambaro; Gianluigi Zaza

doi:10.3389/fmed.2021.671798

Sphingomyelin and Medullary Sponge Kidney Disease: A Biological Link Identified by Omics Approach

Front Med (Lausanne). 2021 May 26:8:671798. doi: 10.3389/fmed.2021.671798. eCollection 2021.

Affiliations

¹ Renal Unit, Department of Medicine, University-Hospital of Verona, Verona, Italy.
² Laboratory of Molecular Nephrology, Istituto Pediatrico di Ricovero e Cura a Carattere Scientifico (IRCCS) Istituto Giannina Gaslini, Genova, Italy.
³ Section of Biology and Genetics, Department of Neuroscience, Biomedicine and Movement Sciences, University of Verona, Verona, Italy.
⁴ Core Facilities - Clinical Proteomics and Metabolomics, Istituto Pediatrico di Ricovero e Cura a Carattere Scientifico (IRCCS) Istituto Giannina Gaslini, Genoa, Italy.

Abstract

Background: Molecular biology has recently added new insights into the comprehension of the physiopathology of the medullary sponge kidney disease (MSK), a rare kidney malformation featuring nephrocalcinosis and recurrent renal stones. Pathogenesis and metabolic alterations associated to this disorder have been only partially elucidated. Methods: Plasma and urine samples were collected from 15 MSK patients and 15 controls affected by idiopathic calcium nephrolithiasis (ICN). Plasma metabolomic profile of 7 MSK and 8 ICN patients was performed by liquid chromatography combined with electrospray ionization tandem mass spectrometry (UHPLC-ESI-MS/MS). Subsequently, we reinterrogated proteomic raw data previously obtained from urinary microvesicles of MSK and ICN focusing on proteins associated with sphingomyelin metabolism. Omics results were validated by ELISA in the entire patients' cohort. Results: Thirteen metabolites were able to discriminate MSK from ICN (7 increased and 6 decreased in MSK vs. ICN). Sphingomyelin reached the top level of discrimination between the two study groups (FC: -1.8, p < 0.001). Ectonucleotide pyrophophatase phosphodiesterase 6 (ENPP6) and osteopontin (SPP1) resulted the most significant deregulated urinary proteins in MSK vs. ICN (p < 0.001). ENPP6 resulted up-regulated also in plasma of MSK by ELISA. Conclusion: Our data revealed a specific high-throughput metabolomics signature of MSK and indicated a pivotal biological role of sphingomyelin in this disease.

Keywords: idiopathic calcium nephrolithiasis; medullary sponge kidney; metabolomics; proteomics; sphingomyelin.