Abstract: FR-OR38
Setting a Pig Model of Crescentic Glomerulonephritis and Testing a Heparin-Binding Epidermal Growth Factor-Like Growth Factor (HB-EGF) Antagonist as a New Treatment
Session Information
- Glomerular Diseases: Mechanisms and More
October 25, 2024 | Location: Room 1, Convention Center
Abstract Time: 04:40 PM - 04:50 PM
Category: Glomerular Diseases
- 1401 Glomerular Diseases: Mechanisms, including Podocyte Biology
Authors
- Tharaux, Pierre-Louis, Paris Centre de Recherche Cardiovasculaire, Paris, Île-de-France, France
- Mahtal, Nassim, Paris Centre de Recherche Cardiovasculaire, Paris, Île-de-France, France
- Dang, Julien, Paris Centre de Recherche Cardiovasculaire, Paris, Île-de-France, France
- Pichard, Sylvain, Commissariat a l'energie atomique et aux energies alternatives Direction de la recherche fondamentale, Gif-sur-Yvette, Île-de-France, France
- Resmini, Léa, Paris Centre de Recherche Cardiovasculaire, Paris, Île-de-France, France
- Gillet, Daniel, Commissariat a l'energie atomique et aux energies alternatives Direction de la recherche fondamentale, Gif-sur-Yvette, Île-de-France, France
Background
Current crescentic glomerulonephritis (CGN) treatments are based only on drugs targeting the immune compartment responsible for glomerular injury. Despite state-of-the-art immunosuppression, many patients develop CKD and, ultimately, ESRD. Glomerular destruction following immune aggression is due to dedifferentiation and proliferation of parietal epithelial cells (PECs) and podocytes. These events are mediated by de novo expression of HB-EGF, a growth factor activating EGF receptor (EGFR) signaling (Bollée et al., Nat Med 2011). We developed an HB-EGF antagonizing strategy to prevent glomerular destruction during CGN.
We described previously DTR8, an antagonist of HB-EGF derived by molecular evolution from the receptor-binding domain of the diphtheria toxin, a natural and highly selective binder of HB-EGF (Gillet et al., Patent WO/2013/140335). We engineered DTR8 to reach a pM affinity and reduce immunogenicity and antigenicity.
Methods
A model of CGN was induced in pigs by injection of decomplemented nephrotoxic serum (NTS) from sheep immunized against pig glomerular basement membrane. Ten pigs received intramuscular injections of 0.3 mg.kg-1 of DTR8 twice daily for 20 days, and 12 pigs received vehicle only. Five normal control animals received pre-immune sheep serum. On day 21, the kidneys were harvested for histopathological observations.
Results
Pigs receiving NTS developed nephritic syndrome with high proteinuria, hypoalbuminemia, edema, and crescentic lesions typical of CGN. Their glomerular cells displayed immunoreactive HB-EGF, loss of podocyte differentiation markers, and exhibited phosphorylation of the EGFR. Periglomerular lymphocyte infiltration and interstitial fibrosis were observed. All these features were absent in control pigs receiving pre-immune sheep serum. Group-blinded comparison of DTR8-treated pigs showed a significant reduction of crescentic lesions (p=0.037), nephrin loss (p=0.003), EGFR phosphorylation (p=0.016), and interstitial fibrosis (p=0.031) compared to vehicle-treated animals.
Conclusion
We developed a valid model of CGN in pigs. Treatment with the HB-EGF antagonist DTR8 significantly reduced the histopathological damage. Reduction of EGFR phosphorylation highly suggests that DTR8 acts by inhibiting the HB-EGF/EGFR cascade.