#4904 EPAC1- MEDIATED CAMP SIGNALLING PROMOTES CELLULAR ENERGY ADAPTATIONS IN PODOCYTES TO PROTECT FROM GLOMERULONEPHRITIS

Abstract Background and Aims Many efforts are made to identify new therapeutic targets slow down, prevent or even reverse Chronic Kidney Disease (CKD) progression. One of the approaches is activating renoprotective cAMP pathway, especially by stimulation its downstream effector, protein kinase A (PKA). PKA was considered as unique however, exchange factor directly activated 1 (EPAC1) has been recently identified a novel, PKA-independent, mediator signalling. EPAC1 guanidine that promotes GDP for GTP regulating important cellular functions. Epac1 activation exerts effect during acute kidney injury, via maintenance epithelial adhesion protection from oxidative stress. However, role in CKD remains poorly understood. Here we aim determine Method Nephrotoxic serum glomerulonephritis (NTS-GN) induced genetically modified mice with total conditional deletion. Then isolated glomeruli deletion podocytes analysed RNA-sequencing. The main metabolic energy pathways studied vitro under stress exposure presence absence an agonist. Results Following induction NTS-GN, genetic show aggravated renal disease, characterized increased proteinuria, glomerular damage, tissue inflammation fibrosis compared wild-type mice. Conversely, pharmacological EPAC1, agonist 8-pCPT-2-OMe-cAMP, delays NTS-GN Since human wild type mouse tissues observe expression podocytes, (Nphs2Cre:epac) generated. Similar whole-body knockout, damage worsened disease progression control RNA-sequencing analysis these gene proteins linked pathway glycolysis abolished early stage (day 4). These data suggest EPAC1-mediated essential limit GN This substantiated experiments which production independently mitochondrial respiration. protected increasing cell viability, decreasing LDH release AKT pathway. Conclusion Our results protective podocytes-derived against development through energetic adaptations based on switch glycolysis. Activating cAMP-EPAC1 signalling axis could represent option delay CKD. Further investigations needed define relevance