Abstract: SA-PO591
Collagen IV Receptor Blockade as Add-On Therapy in Alport Syndrome
Session Information
- Noncystic Mendelian Diseases
November 04, 2017 | Location: Hall H, Morial Convention Center
Abstract Time: 10:00 AM - 10:00 AM
Category: Genetic Diseases of the Kidney
- 802 Non-Cystic Mendelian Diseases
Authors
- Rubel, Diana, University Medicine Goettingen, Goettingen, Germany
- Girgert, Rainer, University Medicine Goettingen, Goettingen, Germany
- Mueller, Gerhard A., University Medicine Goettingen, Goettingen, Germany
- Gross, Oliver, University Medicine Goettingen, Goettingen, Germany
Background
Alport Syndrome (AS) is caused by a lack or misfolding of collagen IV alpha 3, 4 and 5 due to a mutation in one of these genes. Podocytes sense this abnormal glomerular basement membrane (GBM) by collagen receptors such as discoidin domain receptor 1 and Integrin α2. In our present study, we evaluated the nephron-protective effect of knocking-out both receptors in AS (TripleKO) with and without standard ACE-inhibition (ACEi). We hypothesized that the loss of collagen-receptors could inhibit recognition of the altered GBM in AS and improve the renal phenotype. ACEi as the standard off-label therapy delays renal failure until aldosterone escape. Therefore, it is important to evaluate new therapies on top of ACEi.
Methods
Here, we analyze the effect of ACEi and collagen receptor blockade as possible new therapy in wildtype (WT), mice with AS, TripleKO and ACEi treated mice. Mode of action was characterized by real-time PCR, light and electron microscopy with immunogold reactions.
Results
TripleKO mice showed a significant longer survival, less matrix accumulation and fibrosis compared to Alport mice. Additionally, the foot processes were preserved until later stages of disease and splitting of the GBM was considerably less.
The relative expression of podocin in Alport mice was significant reduced compared to WT. In contrast, the TripleKO mice showed a podocin expression which was comparable to WT. Nephrin expression was slightly reduced in TripleKO mice compared to WT, but significant elevated in ACEi treated mice. In Alport mice, the immunogold reactions revealed a podocin accumulation in the areas of podocyte effacement in an age-dependent manner. TripleKO mice showed the same ultrastructural changes, but at a later stage of disease. Nephrin aggregated in TripleKO mice in areas where footprocesses were still preserved.
Conclusion
ACEi and loss of collagen receptors both delay progression of AS in a similar manner, but have different ways of action. In contrast to ACEi therapy for example, podocin expression in TripleKO mice seemed to be maintained, but the protein was mislocated. This confirms a different mode of action resulting in a considerable add-on effect on delaying renal failure. Thus, these additive effects of collagen receptor blockade on top of ACEi should be in the focus of further studies.
Funding
- Private Foundation Support