MOLECULAR ALTERATIONS OF PODOCYTES IN PRIMARY FOCAL SEGMENTAL GLOMERULOSCLEROSIS AND IMMUNOGLOBULIN A NEPHROPATHY: AN EXPLORATORY STUDY

7 Feb 2025 12 a.m. 12 a.m.
WCN25-AB-3085, Poster Board= FRI-484

Introduction:

This exploratory study was based on the premise that the molecular phenotype of podocytes is altered in immune glomerulopathies, with particular emphasis on the expression of molecules of epithelial and mesenchymal phenotypes.

Methods:

A quantitative immunomorphological study of Wilms' tumour protein (WT1), podocin (Nphs2) and podocyte mesenchymal markers (desmin, vimentin, nestin) glomerular expression was performed on all kidney samples from 14 cases of morphologically confirmed primary FSGS (pFSGS), 12 cases of IgA nephropathy (IgAN) and 12 negative controls (NC). NC included samples of unaltered renal cortex obtained during laparoscopic nephrectomy in patients with malignant neoplasms of the kidney and bladder without proteinuria.

Results:

pFSGS cases showed nephrotic syndrome and typical glomerular alterations by light microscopy and ultrastructural analysis; in IgAN, proteinuria was less severe (Fig 1). eGFR in pFSGS and IgAN was similar (Fig 1).

Figure 1 – Clinical parameters and quantitative morphometry in study groups

Compared to groups with less proteinuria, pFSGS showed a lower prevalence of glomerular WT1, Nphs2 Fig 1, 2) and higher glomerular expression of intermediate filament (IF) desmin, and nestin (Fig 1, 3).

Figure 2 – Representative microphotographs and quantitative morphometry of protein glomerular expression; NC – negative control, IgAN – IgA nephropathy, pFSGS – primary focal segmental glomerular sclerosis; scale bar 50 μm.

Figure 3 – Representative microphotographs and quantitative morphometry of protein glomerular expression; NC – negative control, IgAN – IgA nephropathy, pFSGS – primary focal segmental glomerular sclerosis; scale bar 50 μm.

In both pFSGS and IgAN, there was a reduction in glomerular Nphs2 expression compared to NC (Fig 1, 2).

WT1 and Nphs2 were directly correlated (r=0.51, p<0.05). In the common group of cases, their expression was not associated with eGFR, while it was negatively associated with proteinuria (-0.45 and -0.50, respectively; p<0.05).

In pFSGS, WT1 was negatively correlated with desmin (-0.74, p<0.05), which was predominantly localized in WT1-negative glomerular areas by confocal microscopy (Figure 4).

Figure 4 – Confocal microscopy of WT1 and desmin glomerular expression in a patient with pFSGS and proteinuria of 7.0 g: (a) WT1 expression in podocytes, (b) desmin expression (green) in WT1-negative areas, (c) co-expression of WT1 (red) and desmin (granular staining, yellow) in individual podocytes.

Decreased WT1 and increased desmin in the parietal epithelium were also found to characterize pFSGS (Fig 1).

Conclusions:

Bidirectional alterations in the glomerular expression of podocyte markers (WT1, Nphs2) and intermediate filament proteins are apparent in pFSGS. These findings are suggestive for the genomic reprogramming of podocytes and the parietal epithelium of the glomerulus as part of the epithelial-mesenchymal transition, determining the structural and functional disorders of these cells, more prominent in pFSGS.

I have no potential conflict of interest to disclose.

I did not use generative AI and AI-assisted technologies in the writing process.