Abstract
Focal segmental glomerulosclerosis is a major cause of end stage renal disease. Many patients prove unresponsive to available therapies. An improved understanding of the molecular basis of the disease process could provide insights leading to novel therapeutic approaches. In this study we carried out an RNA-seq analysis of the altered gene expression patterns of podocytes, mesangial cells and glomerular endothelial cells of the bigenic Cd2ap+/-, Fyn-/- mutant mouse model of FSGS. In the podocytes we observed upregulation of many genes related to the Tgfβ family/pathway, including Gdnf, Tgfβ1, Tgfβ2, Snai2, Vegfb, Bmp4, and Tnc. The mutant podocytes also showed upregulation of Acta2, a marker of smooth muscle and associated with myofibroblasts, which are implicated in driving fibrosis. GO analysis of the podocyte upregulated genes identified elevated protein kinase activity, increased expression of growth factors, and negative regulation of cell adhesion, perhaps related to the observed podocyte loss. Both podocytes and mesangial cells showed strong upregulation of aldehyde dehydrogenase genes involved in the synthesis of retinoic acid. Similarly, the Cd2ap+/-, Fyn-/- mesangial cells, as well as podocytes in other genetic models, and the glomeruli of human FSGS patients, all show upregulation of the serine protease Prss23, with the common thread suggesting important functionality. Another gene with strong upregulation in the Cd2ap+/-, Fyn-/- mutant mesangial cells as well as multiple other mutant mouse models of FSGS was thrombospondin, which activates the secreted inactive form of Tgfβ. The Cd2ap+/-, Fyn-/- mutant endothelial cells showed elevated expression of genes involved in cell proliferation, angioblast migration, angiogenesis, and neovasculature, all consistent with the formation of new blood vessels in the diseased glomerulus. The resulting global definition of the perturbed molecular pathways in the three major cell types of the mutant glomerulus provide deeper understanding of the molecular pathogenic pathways.
Highlights
Focal segmental glomerulosclerosis (FSGS) is a histologic pattern that is the most common glomerular cause of end stage renal disease (ESRD) in the United States [1]
In this report we further study the Cd2ap+/, Fyn-/- bigenic murine model of FSGS, examining gene expression changes that take place in the glomerular podocyte, mesangial and endothelial cells
We examined the FSGS altered gene expression patterns of all three major glomerular cell types using RNA-seq to begin to better understand the underlying pathogenic molecular pathways
Summary
Focal segmental glomerulosclerosis (FSGS) is a histologic pattern that is the most common glomerular cause of end stage renal disease (ESRD) in the United States [1]. It is characterized by sclerosis of parts (segmental) of some (focal) glomeruli. There are high penetrance genetic causes, with over 38 genes identified, where homozygous mutation of a single gene results in FSGS [7] These are more likely seen in childhood nephrotic syndrome (~60%) than in older children or adolescents (~5%), with still lower rates in adults [8, 9]. Causative genes include Actn, Inf, Trpc, and Nphs, to name a few [7]
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