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Glomerular proteomic profiling of kidney biopsies with hypertensive nephropathy reveals a signature of disease progression

Hypertension Research volume 46, pages 144–156 (2023)Cite this article

Abstract

Hypertensive nephropathy (HN) requires a kidney biopsy as diagnostic gold-standard but histological findings are unspecific and specific prognostic markers are missing. We aimed at identifying candidate prognostic markers based on glomerular protein signatures. We studied adult patients (n = 17) with eGFR >30 ml/min/1.73m2 and proteinuria <3 g/d from the Norwegian Kidney Biopsy Registry, including subjects non progressing (NP, n = 9), or progressing (P, n = 8) to end-stage renal disease (ESRD) within an average follow-up of 22 years. Glomerular cross-sections from archival kidney biopsy sections were microdissected and processed for protein extraction. Proteomic analyses were performed using Q-exactive HF mass spectrometer and relative glomerular protein abundances were compared between P and NP patients. Immunohistochemistry (IHC) was used to validate selected data. Amongst 1870 quality filtered proteins, 58 were differentially expressed in P and NP patients’ glomeruli, with absolute fold changes (FC) ≥1.5, p ≤ 0.05. Supervised classifier analysis (K nearest neighbor) identified a set of five proteins, including Gamma-butyrobetaine dioxygenase (BBOX1, O75936) and Cadherin 16 (CDH16, O75309), overexpressed in P, and Eosinophil peroxidase (EPX, P11678), DnaJ homolog subfamily B member 1 (DNAJB1, P25685) and Alpha-1-syntrophin (SNTA1, Q13424), overexpressed in NP glomeruli, correctly classifying 16/17 kidney biopsy samples. Geneset Enrichment Analysis (GSEA), showed that metabolic pathways were generally enriched in P, and structural cell pathways in NP. Pathway analysis identified Epithelial Adherens Junction Signaling as most affected canonical pathway. IHC analysis confirmed overexpression of BBOX1 and Cadherin 16 in glomeruli from P patients. In conclusion, glomerular proteomic profiling can be used to discriminate P from NP HN patients.

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Data availability

Data are available via ProteomeXchange with identifier PXD026709.

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Acknowledgements

We are thankful to Giulio Spagnoli, PhD, University of Basel, Switzerland, for correction of the manuscript and to Dagny Ann Sandnes for help with the immunohistological analyses as well as to Mohammad Ibrahim from our institution for his initial work of microdissection and sample preparation.

Funding

This work was supported by an open project grant (number F-12559) to Hans-Peter Marti and an open project grant (number 911968) to Bjørn Egil Vikse both from the Western Norway Regional Health Authority.

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Authors and Affiliations

  1. Department of Clinical Medicine, University of Bergen, Bergen, Norway

    Håvard Mikkelsen, Bjørn E. Vikse, Oystein Eikrem, Kenneth Finne, Tarig Osman & Hans-Peter Marti

  2. Department of Medicine, Haugesund Hospital, Haugesund, Norway

    Bjørn E. Vikse

  3. Department of Medicine, Haukeland University Hospital, Bergen, Norway

    Oystein Eikrem & Hans-Peter Marti

  4. Spheromics, Kontiolahti, Finland

    Andreas Scherer

  5. Institute for Molecular Medicine Finland, University of Helsinki, Helsinki, Finland

    Andreas Scherer

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  1. Håvard Mikkelsen
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Correspondence to Hans-Peter Marti.

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All patients provided written informed consent. The study was performed in accordance with principles of the Declaration of Helsinki and was approved by the Ethics Review Boards of the Universities of Bergen (REK vest 2013/553).

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Mikkelsen, H., Vikse, B.E., Eikrem, O. et al. Glomerular proteomic profiling of kidney biopsies with hypertensive nephropathy reveals a signature of disease progression. Hypertens Res 46, 144–156 (2023). https://doi.org/10.1038/s41440-022-01066-0

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