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Updated: Jul 17, 2026
Assessment of Kidney Function in Mouse Models of Glomerular Disease
Published on: June 30, 2018
Impaired glomerular maturation and lack of VEGF165b in Denys-Drash syndrome
Valérie Anne Schumacher1, Stefanie Jeruschke, Frank Eitner
1Institute of Human Genetics and Anthropology, Duesseldorg, Germany. valerie.schumacher@childrens.harvard.edu
Abstract:
Individuals with Denys-Drash syndrome (DDS) develop diffuse mesangial sclerosis, ultimately leading to renal failure. The disease is caused by mutations that affect the zinc finger structure of the Wilms' tumor protein (WT1), but the mechanisms whereby these mutations result in glomerulosclerosis remain largely obscure. How WT1 regulates genes is likely to be complex, because it has multiple splice forms, binds both DNA and RNA, and associates with spliceosomes. Herein is described that in DDS podocytes, the ratio of both WT1 +KTS isoforms C to D differs considerably from that of normal child and adult control podocytes and more closely resembles fetal profiles. Aside from the delay in podocyte maturation, DDS glomeruli show swollen endothelial cells, reminiscent of endotheliosis, together with incompletely fused capillary basement membranes; a dramatic decrease in collagen alpha4(IV) and laminin beta2 chains; and the presence of immature or activated mesangial cells that express alpha-smooth muscle actin. Because appropriate vascular endothelial growth factor A (VEGF-A) expression is known to be essential for the development and maintenance of glomerular architecture and function, this article addresses the question of whether VEGF-A expression is deregulated in DDS. The data presented here show that DDS podocytes express high levels of the proangiogenic isoform VEGF165, but completely lack the inhibitory isoform VEGF165b. The VEGF165/VEGF165b ratio in DDS resembles that of fetal S-shaped bodies, rather than that of normal child or adult control subjects. The alteration in VEGF-A expression presented here may provide a mechanistic insight into the pathogenesis of DDS.
Insights
Denys-Drash syndrome (DDS) podocytes exhibit altered Wilms' tumor protein (WT1) isoform ratios and abnormal vascular endothelial growth factor A (VEGF-A) expression. This suggests a potential mechanism for glomerulosclerosis in DDS pathogenesis.
Area of Science:
- Nephrology
- Developmental Biology
- Molecular Genetics
Background:
- Denys-Drash syndrome (DDS) causes renal failure due to diffuse mesangial sclerosis, linked to Wilms' tumor protein (WT1) mutations.
- The precise mechanisms by which WT1 mutations lead to glomerulosclerosis are not fully understood.
- WT1's complex regulatory role involves multiple splice forms, DNA/RNA binding, and spliceosome association.
Purpose of the Study:
- To investigate the alterations in WT1 isoform ratios and vascular endothelial growth factor A (VEGF-A) expression in Denys-Drash syndrome (DDS) podocytes.
- To explore the potential role of these molecular changes in the pathogenesis of DDS-related glomerulosclerosis.
Main Methods:
- Analysis of WT1 isoform ratios (specifically +KTS isoforms C and D) in DDS podocytes compared to normal controls.
- Assessment of VEGF-A isoform expression (VEGF165 and VEGF165b) in DDS podocytes.
- Histological examination of DDS glomeruli for structural abnormalities.
Main Results:
- DDS podocytes show altered WT1 +KTS isoform ratios, resembling fetal profiles rather than adult or child controls.
- DDS glomeruli exhibit delayed podocyte maturation, swollen endothelial cells, incomplete capillary basement membranes, and reduced collagen alpha4(IV) and laminin beta2.
- DDS podocytes display an elevated ratio of proangiogenic VEGF165 to inhibitory VEGF165b, similar to fetal S-shaped bodies.
Conclusions:
- Altered WT1 isoform balance and dysregulated VEGF-A expression (specifically the VEGF165/VEGF165b ratio) in DDS podocytes may contribute to glomerulosclerosis.
- These findings offer mechanistic insights into the pathogenesis of Denys-Drash syndrome.
- The study highlights the importance of WT1 and VEGF-A in glomerular development and disease.
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