Granata Simona, Bruschi Maurizio, Deiana Michela, Petretto Andrea, Lombardi Gianmarco, Verlato Alberto, Elia Rossella, Candiano Giovanni, Malerba Giovanni, Gambaro Giovanni, Zaza Gianluigi
Renal Unit, Department of Medicine, University-Hospital of Verona, Verona, Italy.
Laboratory of Molecular Nephrology, Istituto Pediatrico di Ricovero e Cura a Carattere Scientifico (IRCCS) Istituto Giannina Gaslini, Genova, Italy.
Front Med (Lausanne). 2021 May 26;8:671798. doi: 10.3389/fmed.2021.671798. eCollection 2021.
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. 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. 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, < 0.001). Ectonucleotide pyrophophatase phosphodiesterase 6 (ENPP6) and osteopontin (SPP1) resulted the most significant deregulated urinary proteins in MSK vs. ICN ( < 0.001). ENPP6 resulted up-regulated also in plasma of MSK by ELISA. Our data revealed a specific high-throughput metabolomics signature of MSK and indicated a pivotal biological role of sphingomyelin in this disease.
分子生物学最近为理解髓质海绵肾疾病（MSK）的病理生理学提供了新的见解，髓质海绵肾疾病是一种罕见的肾脏畸形，其特征为肾钙质沉着症和复发性肾结石。与这种疾病相关的发病机制和代谢改变仅得到了部分阐明。收集了15例MSK患者和15例特发性钙肾结石（ICN）对照患者的血浆和尿液样本。对7例MSK患者和8例ICN患者进行了液相色谱结合电喷雾电离串联质谱分析（UHPLC-ESI-MS/MS），以检测其血浆代谢组学特征。随后，我们重新分析了之前从MSK和ICN患者尿液微泡中获得的蛋白质组学原始数据，重点关注与鞘磷脂代谢相关的蛋白质。通过酶联免疫吸附测定法（ELISA）在整个患者队列中对组学结果进行了验证。13种代谢产物能够区分MSK和ICN（与ICN相比，MSK中有7种代谢产物增加，6种代谢产物减少）。鞘磷脂在两个研究组之间的区分度最高（FC：-1.8，<0.001）。外核苷酸焦磷酸酶磷酸二酯酶6（ENPP6）和骨桥蛋白（SPP1）是MSK与ICN相比尿液中最显著失调的蛋白质（<0.001）。通过ELISA检测发现，MSK患者血浆中的ENPP6也上调。我们的数据揭示了MSK的一种特定的高通量代谢组学特征，并表明鞘磷脂在这种疾病中具有关键的生物学作用。
