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PDGF-D Is Dispensable for the Development and Progression of Murine Alport Syndrome
Emilia Anouk Margo Firat1, Eva Miriam Buhl2, Nassim Bouteldja1
1Institute of Pathology, RWTH Aachen University Hospital, Aachen, Germany.
Insights
Platelet-derived growth factor-D (PDGF-D) is upregulated in Alport syndrome kidney disease. However, inhibiting PDGF-D did not improve kidney function or disease markers in a mouse model, suggesting it doesn't drive disease progression without activation.
Area of Science:
- Nephrology
- Molecular Biology
- Genetics
Background:
- Alport syndrome is an inherited kidney disease causing glomerulosclerosis and fibrosis.
- Platelet-derived growth factor-D (PDGF-D) is implicated in kidney fibrosis in various models.
- PDGF-D's role in Alport syndrome pathogenesis requires investigation.
Purpose of the Study:
- To investigate the role of PDGF-D in a mouse model of Alport syndrome.
- To evaluate the therapeutic potential of PDGF-D inhibition in Alport syndrome.
Main Methods:
- In vitro studies using human parietal epithelial cells.
- In vivo studies using Col4a3-/- mice treated with PDGF-D neutralizing antibody.
- Analysis of Col4a3-/- mice with genetic deletion of Pdgfd (Col4a3-/-Pdgfd-/-).
Main Results:
- PDGF-D was significantly upregulated in Col4a3-/- mice.
- PDGF-D antibody treatment did not affect renal function, glomerulosclerosis, or fibrosis.
- Genetic deletion of Pdgfd in Col4a3-/- mice showed no difference in pathology or kidney function.
Conclusions:
- PDGF-D does not appear to mediate the development or progression of Alport syndrome in mice.
- Lack of proteolytic activation of PDGF-D may explain the observed in vivo effects.
- Targeting PDGF-D may not be a viable therapeutic strategy for Alport syndrome without considering its activation status.
Abstract:
Alport syndrome is an inherited kidney disease, which can lead to glomerulosclerosis and fibrosis, as well as end-stage kidney disease in children and adults. Platelet-derived growth factor-D (PDGF-D) mediates glomerulosclerosis and interstitial fibrosis in various models of kidney disease, prompting investigation of its role in a murine model of Alport syndrome. In vitro, PDGF-D induced proliferation and profibrotic activation of conditionally immortalized human parietal epithelial cells. In Col4a3-/- mice, a model of Alport syndrome, PDGF-D mRNA and protein were significantly up-regulated compared with non-diseased wild-type mice. To analyze the therapeutic potential of PDGF-D inhibition, Col4a3-/- mice were treated with a PDGF-D neutralizing antibody. Surprisingly, PDGF-D antibody treatment had no effect on renal function, glomerulosclerosis, fibrosis, or other indices of kidney injury compared with control treatment with unspecific IgG. To characterize the role of PDGF-D in disease development, Col4a3-/- mice with a constitutive genetic deletion of Pdgfd were generated and analyzed. No difference in pathologic features or kidney function was observed in Col4a3-/-Pdgfd-/- mice compared with Col4a3-/-Pdgfd+/+ littermates, confirming the antibody treatment data. Mechanistically, lack of proteolytic PDGF-D activation in Col4a3-/- mice might explain the lack of effects in vivo. In conclusion, despite its established role in kidney fibrosis, PDGF-D, without further activation, does not mediate the development and progression of Alport syndrome in mice.
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