Crescentic glomerulonephritis (CGN) and focal segmental glomerusclerosis (FSGS) are characterized by glomerular injury caused by invading parietal epithelial cells (PECs). Now, Carole Henique, Pierre-Louis Tharaux and colleagues report that CD9 contributes to this pathogenic process.
“Having observed that heparin-binding epidermal growth factor-like growth factor (HB-EGF) was critical to mediate severe CGN, we decided to study molecular partners of HB-EGF, such as CD9,” explains Tharaux. “In this new study, when we measured RNA and protein expression it became clear that de novo expression of CD9 occurs primarily and robustly in PECs in various unrelated extracapillary lesions in mice and humans.” Staining of patient samples showed that CD9 colocalized with integrin β1 (ITGB1) and CD44 in extracapillary GN but not in in non-proliferative GN or in healthy kidneys.
Global Cd9–/– mice were protected from CGN, but not mice in which Cd9 was only deleted in platelets, which express high levels of CD9. Irradiated wild-type mice reconstituted with Cd9–/– bone marrow were also susceptible to CGN. “However, selective CD9 deficiency in PECs prevented a large part of glomerular failures in FSGS and crescentic GN models, showing that PECs are not just bystanders but are truly pathogenic,” notes Henique.
PECs in which Cd9 was knocked down proliferated less in response to HB-EGF or platelet-derived growth factor (PDGF) than scramble controls. Using a microfluidic system, the researchers showed that Cd9 knockdown also prevented migration towards a PDGF gradient — loss of Cd9 led to impaired phosphorylation of PDGFRβ, EGFR and focal adhesion kinase 1 (FAK). “CD9 might lower the response threshold of PECs to factors released by the diseased capillary tuft, driving coordinated directional migration, adhesion and sclerosis,” remarks Tharaux.
“Our work indicates that the abnormal behaviour of PECs is a clear therapeutic target for FSGS and CGN,” adds Henique.
Lazareth, H. et al. The tetraspanin CD9 controls migration and proliferation of parietal epithelial cells and glomerular disease progression. Nat. Commun. 10, 3303 (2019)
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Wang, M. CD9 boosts PEC glomerular invasion. Nat Rev Nephrol 15, 594 (2019). https://doi.org/10.1038/s41581-019-0198-4