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Int J Mol Sci. 2020 Mar 18;21(6). pii: E2095. doi: 10.3390/ijms21062095.

ECM Characterization Reveals a Massive Activation of Acute Phase Response during FSGS.

Author information

1
Institute of Translational Medicine, Semmelweis University Budapest, Tűzoltó u 37-47, 1094 Budapest, Hungary.
2
Clinical Institute for Pathology, Medical University Vienna, Währinger Gürtel 18-20, 1090 Vienna, Austria.
3
Clinical Division of Hematology and Hemostaseology, Department of Internal Medicine I, Medical University Vienna, Währinger Gürtel 18-20, 1090 Vienna, Austria.
4
Vetcore Facility for Research, University of Veterinary Medicine Vienna, Veterinärplatz 1, 1210 Vienna, Austria.
5
Christian Doppler Laboratory for Molecular Stress Research in Peritoneal Dialysis, Department of Pediatrics and Adolescent Medicine, Medical University of Vienna, 1210 Vienna, Austria.
6
Division of Pediatric Nephrology and Gastroenterology, Department of Pediatrics and Adolescent Medicine, Medical University of Vienna, 1210 Vienna, Austria.

Abstract

The glomerular basement membrane (GBM) and extra-cellular matrix (ECM) are essential to maintain a functional interaction between the glomerular podocytes and the fenestrated endothelial cells in the formation of the slit diaphragm for the filtration of blood. Dysregulation of ECM homeostasis can cause Focal segmental glomerulosclerosis (FSGS). Despite this central role, alterations in ECM composition during FSGS have not been analyzed in detail yet. Here, we characterized the ECM proteome changes in miR-193a-overexpressing mice, which suffer from FSGS due to suppression of Wilms' tumor 1 (WT1). By mass spectrometry we identified a massive activation of the acute phase response, especially the complement and fibrinogen pathways. Several protease inhibitors (ITIH1, SERPINA1, SERPINA3) were also strongly increased. Complementary analysis of RNA expression data from both miR-193a mice and human FSGS patients identified additional candidate genes also mainly involved in the acute phase response. In total, we identified more than 60 dysregulated, ECM-associated genes with potential relevance for FSGS progression. Our comprehensive analysis of a murine FSGS model and translational comparison with human data offers novel targets for FSGS therapy.

KEYWORDS:

ECM; FSGS; acute phase response; complement system; fibrinogen; sclerosis

PMID:
32197499
DOI:
10.3390/ijms21062095
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