Abstract: PO2473
EPAC1-Mediated cAMP Signaling in Podocytes Protects Kidneys from the Progression of Glomerulonephritis
Session Information
- CKD: Inflammation, Endothelial Dysfunction, and Signaling
November 04, 2021 | Location: On-Demand, Virtual Only
Abstract Time: 10:00 AM - 12:00 PM
Category: CKD (Non-Dialysis)
- 2103 CKD (Non-Dialysis): Mechanisms
Authors
- Abbad, Lilia, Inserm UMR 1155, Paris, France
- Kavvadas, Panagiotis, Inserm UMR 1155, Paris, France
- Detrait, Maximin, Inserm UMR S 1297, Toulouse, France
- Prakoura, Niki, Inserm UMR 1155, Paris, France
- Chadjichristos, Christos E., Inserm UMR 1155, Paris, France
- Lezoualch, Frank, Inserm UMR S 1297, Toulouse, France
- Chatziantoniou, Christos, Inserm UMR 1155, Paris, France
Background
Many efforts are made to identify new therapeutic targets to slow down, prevent or even reverse Chronic Kidney Disease (CKD) progression. One of the therapeutic approaches is the targeting of the renoprotective cAMP pathway, especially by stimulation of its downstream effector, the protein kinase A (PKA). PKA was considered as the unique cAMP effector, however, the exchange factor directly activated by cAMP 1 (EPAC1) has been recently identified as a novel, PKA-independent, mediator of cAMP signaling. Epac1 is a guanidine exchange factor that promotes the exchange of GDP for GTP regulating important cellular functions. Of the two isoforms described, Epac1 is the most expressed in the kidney. Epac1 activation exerts a renoprotective effect during acute kidney injury, via maintenance of epithelial adhesion and protection from oxidative stress. However, the role of EPAC1 in CKD remains poorly understood.
Methods
Here we aim to determine the role of EPAC1 in CKD progression, by inducing nephrotoxic serum glomerulonephritis (NTS-GN) in genetically modified mice with total and conditional EPAC1 deletion.
Results
Following the induction of NTS-GN, genetic deletion of EPAC1 aggravates renal disease, characterized by increased proteinuria, glomerular damage, tissue inflammation and fibrosis compared to wild-type mice. Conversely, pharmacological activation of Epac1, with the agonist 8-pCPT-2-OMe-cAMP, delays NTS-GN progression. Since in normal mouse kidney tissues we have observed EPAC1 expression in podocytes, mice with conditional deletion of EPAC1 in podocytes (Nphs2Cre:epacfl/fl) are generated. Similar to the whole-body knockout, mice with EPAC1 deletion in podocytes show increased renal damage and worsened disease progression compared to control mice.
Conclusion
Our results suggest a protective role of podocytes-derived EPAC1 against the development of GN. Targeting the cAMP-EPAC1 signaling axis could represent a new therapeutic option to delay the development of CKD. Further investigations are needed to better define the molecular mechanisms involved, and to define its relevance in human CKD.
Funding
- Government Support – Non-U.S.