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A Possible Zebrafish Model of Polycystic Kidney Disease: Knockdown of wnt5a Causes Cysts in Zebrafish Kidneys
Published on: December 2, 2014
VEGF receptor 2 blockade leads to renal cyst formation in mice
S McGrath-Morrow1, C Cho, R Molls
1Department of Pediatrics, Johns Hopkins University, Baltimore, Maryland 21287, USA. smorrow@jhmi.edu
Abstract:
Polycystic kidney disease (PKD) is associated with mutations in PKD1 and PKD2 and vascular abnormalities. The links between the epithelial and vascular defects, however, are poorly understood. Vascular endothelial growth factor (VEGF) has been shown to be critical for normal kidney development. In animal models, blockade of VEGF in the perinatal period can lead to abnormal glomerular development, impaired nephrogenesis, proteinuria, and renal failure. We hypothesized that brief blockade of VEGF signaling during early postnatal kidney development can lead to renal cyst development. On days 2 and 4 of life, CD-1 mice were treated with antibodies generated against the extracellular portion of the VEGF receptor 2 (DC101), the area of the receptor where VEGF binding occurs. Mice developed renal cysts between 2 and 3 weeks. The DC101-treated mice also had increased cell proliferation in the renal tubule epithelium. In addition, mice receiving DC101 developed abnormal glomeruli, proteinuria, and patchy cellular infiltrates. Early disruption of VEGFR-2 signaling during the perinatal period results in renal cyst formation, impaired glomerulogenesis, and inflammation. VEGF could be a key link between vascular and cystic changes in kidney cyst formation.
Insights
Blocking vascular endothelial growth factor (VEGF) signaling in early life can cause kidney cysts. This disruption impacts kidney development, leading to polycystic kidney disease (PKD)-like symptoms.
Area of Science:
- Nephrology
- Developmental Biology
- Vascular Biology
Background:
- Polycystic kidney disease (PKD) involves genetic mutations and vascular abnormalities, but the link between epithelial and vascular defects is unclear.
- Vascular endothelial growth factor (VEGF) is crucial for kidney development; its blockade in animal models causes glomerular abnormalities and renal failure.
Purpose of the Study:
- To investigate if brief blockade of VEGF signaling during early postnatal kidney development can induce renal cyst formation.
Main Methods:
- CD-1 mice were treated with antibodies against VEGF receptor 2 (DC101) on postnatal days 2 and 4.
- Kidney development, cyst formation, cell proliferation, glomerular structure, and proteinuria were assessed in treated mice.
Main Results:
- DC101-treated mice developed renal cysts between 2 and 3 weeks of age.
- Increased renal tubule epithelium cell proliferation, abnormal glomeruli, proteinuria, and inflammation were observed.
- Early disruption of VEGFR-2 signaling leads to renal cyst formation, impaired glomerulogenesis, and inflammation.
Conclusions:
- VEGF signaling disruption during the perinatal period is a potential cause of renal cyst formation.
- VEGF may serve as a critical link between vascular and cystic changes in kidney development.
- This study highlights the role of VEGF in preventing cystogenesis and maintaining normal kidney structure.
