PDGF-D is dispensable for the development and progression of murine Alport syndrome.

Alport syndrome is an inherited kidney disease, which can lead to glomerulosclerosis and fibrosis, and end-stage kidney disease in children and adults. Platelet-derived growth factor (PDGF)-D was shown to mediate glomerulosclerosis and interstitial fibrosis in different models of kidney disease, prompting us to investigate 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 (ciPECs). In Col4a3-/- mice, a model of Alport syndrome, PDGF-D mRNA and protein were significantly upregulated compared to non-diseased wild-type mice. To analyze 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 to 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 pathological features or kidney function was observed in Col4a3-/- Pdgfd-/- mice compared to 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.