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Towards the Definition of the Molecular Hallmarks of Idiopathic Membranous Nephropathy in Serum Proteome: A DIA-PASEF Approach.

ABSTRACT: Idiopathic membranous nephropathy (IMN) is a pathologically defined disorder of the glomerulus, primarily responsible for nephrotic syndromes (NS) in nondiabetic adults. The underlying molecular mechanisms are still not completely clarified. To explore possible molecular and functional signatures, an optimised mass spectrometry (MS) method based on next-generation data-independent acquisition combined with ion-mobility was applied to serum of patients affected by IMN (n = 15) or by other glomerulopathies (PN) (n = 15). The statistical comparison highlighted a panel of 57 de-regulated proteins with a significant increase in lipoprotein-related proteins (APOC1, APOB, APOA1, APOL1 and LCAT) and a substantial quantitative alteration of key serpins (including A4, D1, A7, A6, F2, F1 and 1) possibly associated with IMN or NS and podocyte stress. A critical dysregulation in metabolisms of lipids (e.g., VLDL assembly and clearance) likely to be related to known hyperlipidemia in IMN, along with involvement of non-classical complement pathways and a putative enrolment of ficolin-2 in sustaining the activation of the lectin-mediated complement system have been pinpointed. Moreover, mannose receptor CD206 (MRC1-down in IMN) and biotinidase (BTD-up in IMN) are able alone to accurately distinguish IMN vs. PN. To conclude, our work provides key proteomic insights into the IMN complexity, opening the way to an efficient stratification of MN patients.

SUBMITTER: Previtali P

PROVIDER: S-EPMC10380405 | biostudies-literature | 2023 Jul

REPOSITORIES: biostudies-literature

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Towards the Definition of the Molecular Hallmarks of Idiopathic Membranous Nephropathy in Serum Proteome: A DIA-PASEF Approach.

Previtali Paolo P Pagani Lisa L Risca Giulia G Capitoli Giulia G Bossi Eleonora E Oliveira Glenda G Piga Isabella I Radice Antonella A Trezzi Barbara B Sinico Renato Alberto RA Magni Fulvio F Chinello Clizia C

International journal of molecular sciences 20230721 14

Idiopathic membranous nephropathy (IMN) is a pathologically defined disorder of the glomerulus, primarily responsible for nephrotic syndromes (NS) in nondiabetic adults. The underlying molecular mechanisms are still not completely clarified. To explore possible molecular and functional signatures, an optimised mass spectrometry (MS) method based on next-generation data-independent acquisition combined with ion-mobility was applied to serum of patients affected by IMN (n = 15) or by other glomeru ...[more]

PMID: 37511514

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Project description:Idiopathic Membranous Nephropathy (IMN) is a pathologically defined disorder of the glomerulus, primarily responsible for nephrotic syndromes (NS) in nondiabetic adults. The underlying molecular mechanisms are still not completely clarified. To explore possible molecular and functional signatures, an optimised MS-method based on next-generation data-independent-acquisition combined with ion-mobility was applied to serum of patients affected by IMN (n=15) or by other glomerulopathies (PN) (n=15). The statistical comparison highlighted a panel of 57 de-regulated proteins with a significant increase of lipoprotein-related-proteins (APOC1, APOB, APOA1, APOL1 and LCAT) and a substantial quantitative alteration of key serpins (including A4, D1, A7, A6, F2, F1 and 1) possibly associated to IMN or NS and podocyte stress. A critical dysregulation in metabolisms of lipids (e.g.VLDL assembly and clearance) likely to be related to known hyperlipidemia in IMN, along with involvement of non-classical complement pathways and a putative enrolment of ficolin-2 in sustaining the activation of the lectin-mediated complement system have been pinpointed. Moreover, Mannose Receptor CD206 (MRC1-down in IMN) and biotinidase (BTD-up in IMN) are able alone to accurately distinguish IMN vs PN. To conclude, our work provides key proteomic insights into the IMN complexity, opening the way to an efficient stratification of MN patients. Herein, a tailor-made DIA-PASEF method was applied to quali-quantitatively portray undepleted serum proteome collected from 15 IMN patients and 15 gender- and age-matched nephropathic subjects having a similar presentation but a different aetiology (PN). For each sample, 400 ng of peptides were injected in duplicate into Evosep One (Evosep Biosystems, Odense, Denmark) LC system coupled online with timsTOF fleXTM (Bruker Daltonics, Bremen, Germany) mass spectrometer (60runs in total). Raw data were elaborated by using SpectronautTM (v.17, https://biognosys.com) following a library-free processing method.

Project description:Introduction: Minimal change disease (MCD) is a major cause of nephrotic syndrome. With a substantial number of patients requiring long-term immunosuppression leading to significant morbidity, the study aim was to determine MCD glomerular transcriptome to serve as a basis for biomarker discovery and novel drug target identification. Animal work showed podocyte injury induced by IL-7/IL-7R signaling (Zhai S, BBRC, 2018). Methods: Renal biopsies from adult patients representing the following groups were selected from the Norwegian Kidney Biopsy Registry: MCD (n=14), as well as normal tissue (n=8) and primary membranous nephropathy (MN; n=12) as the two reference groups. RNA for 75 base-pair paired-end RNASeq was obtained by dissecting glomeruli via laser capture microdissection (LCM) from FFPE cross-sections. Systematic delineation of condition-specific alteration in transcriptional landscapes was achieved by combining pathway-centered analyses with methodologies derived from network science and integrating multiple bioinformatics resources. Results: Compared to normal glomeruli, glomeuli from MCD displayed an inflammatory signature that appeared to be predominantly governed by the IL1 and IL7 systems. While enrichment of IL1 production and secretion was a shared feature of MCD and MN compared to normal tissue, responses involving IL7 pathway activation were unique to MCD. Indeed, IL7R expressed by glomeruli was the most up-regulated gene of to the interleukin-family in MCD vs normal controls. IL7 pathway activation was paralleled by significant enrichment in adaptive immune system processes and transcriptional regulation and depletion in pathways related to energy metabolism and transcription. Downregulation of these organ function-related themes again occurred predominately in MDC and were significantly less pronounced in MN. Conclusion: Our results demonstrate that archival FFPE-biopsies can be used to generate glomeruli-specific gene expression profiles suitable for systematic delineation of kidney-associated diseases. Here the latter provides a data-driven rationale to experimentally address these MCD-specific features as biomarkers and as novel drug targets. In this context inhibiting activation of the IL7 pathway may be particularly promising.

Dataset Information

Towards the Definition of the Molecular Hallmarks of Idiopathic Membranous Nephropathy in Serum Proteome: A DIA-PASEF Approach.

Publications

Towards the Definition of the Molecular Hallmarks of Idiopathic Membranous Nephropathy in Serum Proteome: A DIA-PASEF Approach.

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