Abstract
Loss of podocyte differentiation can cause nephrotic-range proteinuria and Focal and Segmental Glomerulosclerosis (FSGS). As specific therapy is still lacking, FSGS frequently progresses to end-stage renal disease. The exact molecular mechanisms of FSGS and gene expression changes in podocytes are complex and widely unknown as marker changes have mostly been assessed on the glomerular level. To gain a better insight, we isolated podocytes of miR-193a overexpressing mice, which suffer from FSGS due to suppression of the podocyte master regulator Wt1. We characterised the podocytic gene expression changes by RNAseq and identified many novel candidate genes not linked to FSGS so far. This included strong upregulation of the receptor tyrosine kinase EphA6 and a massive dysregulation of circadian genes including the loss of the transcriptional activator Arntl. By comparison with podocyte-specific changes in other FSGS models we found a shared dysregulation of genes associated with the Wnt signaling cascade, while classical podocyte-specific genes appeared widely unaltered. An overlap with gene expression screens from human FSGS patients revealed a strong enrichment in genes associated with extra-cellular matrix (ECM) and metabolism. Our data suggest that FSGS progression might frequently depend on pathways that are often overlooked when considering podocyte homeostasis.
Highlights
Focal and Segmental Glomerulosclerosis (FSGS) is a clinico-pathological syndrome referring to sclerotic lesions in some areas of some kidney glomeruli and nephrotic range proteinuria [1,2]
The strongest upregulation for a protein-coding gene was found for the trans-membrane receptor tyrosine kinase Ephrin receptor A6 (EphA6), which integrates extra-cellular signals and has never been linked to FSGS before
We found strongly increased levels of Serine Protease 23 (Prss23) and Sphingolipid Transporter 2 (Spns2), which has been associated with kidney fibrosis before [21]
Summary
Focal and Segmental Glomerulosclerosis (FSGS) is a clinico-pathological syndrome referring to sclerotic lesions in some areas of some kidney glomeruli and nephrotic range proteinuria [1,2]. In healthy individuals, interdigitating podocyte foot processes together with the basal lamina and underlying, fenestrated endothelial cells form a sieve-like structure thereby enabling the filtration of blood. A high number of specific genes is necessary to maintain the complex three-dimensional structure of podocytes. The impacts initiating FSGS are heterogeneous and include gene mutations, circulating factors, drugs, viruses and hypertension [1,2]. These very different etiologies lead to a common final path characterised by foot process effacement and loss of podocytes concomitant with nephrotic syndrome, fibrosis and scarring
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