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Kidney Week

Abstract: PO1727

The Role of Proteoglycans in Glomerular Physiology and Pathophysiology

Session Information

Category: Glomerular Diseases

  • 1201 Glomerular Diseases: Fibrosis and Extracellular Matrix

Authors

  • Ebefors, Kerstin, Goteborgs universitet Sahlgrenska Akademin, Goteborg, Sweden
  • Khramova, Alina, Goteborgs universitet Sahlgrenska Akademin, Goteborg, Sweden
  • Nystrom, Jenny C., Goteborgs universitet Sahlgrenska Akademin, Goteborg, Sweden
Background

Diabetic kidney disease (DKD) is the leading cause of renal failure in the world. Diabetes is associated with damage to the endothelial glycocalyx (eGCX), the layer of negatively charge molecules, such as proteoglycans (PGs) that cover the cells. The negatively charge restrain the flow of charged molecules, as albumin, over the filtration barrier. Loss of the glomerular eGCX leads to proteinuria without other visible damage to the barrier, but the composition of this structure is still largely unknown. The aim of this study was to gain new knowledge about the composition and role of the eGCX in health and DKD.

Methods

The negatively charged PGs in the eGCX was eluted from rats using 1 M NaCl solution (high salt, HS). 1 M mannitol was used as osmotic control (HO) and 0.15 M NaCl as physiological salt (NS). Solutions were introduced intra-arterially to rat kidneys under anesthesia in vivo. Venous effluent was analyzed using mass spectrometry. Fractional clearance of albumin and GFR was measured. Electron microscopy (EM) was used to investigate morphology. Expression of PGs and PG related genes in glomeruli from patients with DKD was investigated using deep sequencing data from the Swedish DKD cohort (DKD n=19, controls n=20).

Results

We identified 17 PGs in the eluates from rats. PGs were found in in the highest yields in the HS samples. EM demonstrated that the eGCX thickness was significantly reduced in the HS rats compared to NS. Rats perfused with HS had significantly increased fractional clearance of albumin and reduced GFR, compared to NS and HO, 10 minutes after perfusion. In glomeruli from patients with DKD 12 PGs were found to be significantly regulated, and 4 of these PGs were also identified in the eGCX eluates from rats. There was an overall decrease in expression of enzymes responsible for PG side chain synthesis and an increase in proteins involved in PG degradation.

Conclusion

In our study, we identified several PGs novel to the glomerular eGCX. We show that loss of eGCX leads to proteinuria and reduced GFR, strongly suggesting that the eGCX is important for preventing proteinuria. In glomeruli from patients with DKD we found significant changes in the gene expression of PGs, indicating a changed composition of the matrixes in the glomeruli. Further investigation is needed to clarify how these changes are involved in development of DKD, and especially the eGCX.

Funding

  • Private Foundation Support