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Abstract: SA-PO1001

EPAC1-Mediated cAMP Signaling Promotes Cellular Energy Adaptations and Glycolytic Metabolic Shift in Podocytes to Protect from Glomerulonephritis

Session Information

Category: Glomerular Diseases

  • 1403 Podocyte Biology

Authors

  • Abbad, Lilia, Inserm U1155, Paris, France
  • Detrait, Maximin, Inserm U1297, Toulouse, France
  • Kavvadas, Panagiotis, Inserm U1155, Paris, France
  • Melis, Lisa, Inserm U1155, Paris, France
  • Lezoualc'h, Frank, Inserm U1297, Toulouse, France
  • Chatziantoniou, Christos, Inserm U1155, Paris, France
Background

Many efforts are made to identify new therapeutic targets to slow down, prevent Chronic Kidney Disease (CKD) progression. One of the therapeutic approaches is activating the renoprotective cAMP pathway. The exchange factor directly activated by cAMP 1 (EPAC1) has been identified as a novel, PKA-independent, mediator of cAMP signalling. EPAC1 is a guanidine exchange factor that regulates important cellular functions. Here we aim to determine the role of EPAC1 in CKD progression.

Methods

An immunostaining of EPAC1 is performed on biopsies of patients with glomerulonephritis. Nephrotoxic serum glomerulonephritis (NTS-GN) is induced in genetically modified mice with total and conditional EPAC1 deletion in podocytes. Then isolated glomeruli from the conditional mice are analysed by RNA-sequencing. The main metabolic energy pathways are studied in podocytes in vitro under oxidative stress exposure in the presence/absence of an EPAC1 agonist.

Results

EPAC1 is expressed in different GN disease and localized in glomeruli. Following the induction of NTS-GN, mice with genetic deletion of EPAC1 show aggravated renal disease, characterized by increased proteinuria, tissue inflammation and fibrosis compared to control mice. Conversely, pharmacological activation of EPAC1, with the agonist 8-pCPT-2-OMe-cAMP, delays NTS-GN progression. Since in human and mouse kidney tissues we observe EPAC1 expression in podocytes, mice with conditional deletion of EPAC1 in podocytes are generated. Similar to the whole-body knockout, conditional mice show worsened disease progression compared to control mice. RNA-sequencing analysis of glomeruli isolated from these mice show that gene expression of proteins linked to the pathway of glycolysis are abolished in early stage of NTS-GN. EPAC1 activation under oxidative stress in podocytes In vitro, promotes glycolysis with cellular energy production independently from mitochondrial respiration. The EPAC1-mediated glycolysis protected podocytes by increasing cell viability.

Conclusion

Podocytes-derived EPAC1 plays a protective role against the development of GN through cellular energetic adaptations based on metabolic shift to glycolysis. Activating the cAMP-EPAC1 signalling axis could represent a therapeutic option to delay CKD.

Funding

  • Government Support – Non-U.S.