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Abstract: TH-PO426

Adaptive Remodeling of Mesangial Matrix Proteoglycan Composition During IgA Nephropathy

Session Information

Category: Glomerular Diseases

  • 1301 Glomerular Diseases: Fibrosis and Extracellular Matrix

Authors

  • Ebefors, Kerstin, Goteborgs universitet Sahlgrenska Akademin, Goteborg, Sweden
  • Johansson, Alva, Goteborgs universitet Sahlgrenska Akademin, Goteborg, Sweden
  • Boi, Roberto, Goteborgs universitet Sahlgrenska Akademin, Goteborg, Sweden
  • Nystrom, Jenny C., Goteborgs universitet Sahlgrenska Akademin, Goteborg, Sweden
Background

IgA nephropathy (IgAN) is characterized by galactose deficient IgA (gd-IgA1) containing immune complexes in the mesangium, leading to activation of the cells, proliferation, matrix expansion and local inflammation. The exact composition of the mesangial matrix and its role in disease progression is not fully known. One important group of proteins in matrixes are proteoglycans (PGs). PGs are composed of a core protein to which glycosaminoglycan (GAG) side chains are attached. The most common GAGs are heparan sulfate (HS) and chondroitin sulfate (CS). Both the core protein and GAGs determine the properties of PGs and changes in PG composition could be of importance for disease progression. In this study, we aimed to elucidate the role of changes in the PG expression in IgAN.

Methods

Human MCs expression of PGs after stimulation with gd-IgA1 was investigated using a glycoproteomics which gives information about both the core protein identity and the the GAGs attached. Immunoflourescens was used for quantification of GAGs. ELISA was used to investigate specific PGs. In vivo and in vitro validation was done using a previously published transcriptomic data set of glomeruli from patients with IgAN in combination with a proteomic data set of HMCs treated with gd-IgA (Liu et al JASN 2017).

Results

Glycoproteomics identified 13 PGs in the medium and 5 in the cell lysate and their corresponding GAGs, of which the majority was CS PGs. More PGs were identified in the cells treated with control IgA (cIgA) or gd-IgA1 than the controls. Immunohistochemistry revealed that gd-IgA1 treatment of MCs does not lead to a total increase in GAGs, but rather to a switch from HS to CS GAGs. This was found to be true also in the already published proteomic data set on MCs treated with gd-IgA1. In vivo validation revealed that in IgAN there are more CS upregulated than HS in IgAN. Bikunin, the most upregulated CS PG, expression was validated using ELISA, and found to not be expressed by cells before stimulation with IgA, but then highly upregulated.

Conclusion

In conclusion, this study gives a comprehensive view of the PGs expressed by MCs and their alterations in response to gd-IgA1 as part of the expansion of the mesangium in IgAN. The switch of HS GAGs to CS GAGs could be involved in driving inflammation/proliferation but the role of this switch needs further investigation.

Funding

  • Private Foundation Support