Podocyte Epac1 promotes glycolysis and protects against glomerulonephritis
The second messenger cyclic AMP (cAMP) is involved in many aspects of renal physiology and disease. Epac is an effector of cAMP and its pathophysiological role in the development of chronic kidney diseases (CKD) has yet to be determined. Here, we show that total Epac1 isoform genetic deletion does not cause any baseline renal abnormalities but remarkably potentiates the deterioration of renal structure and function during the progression of the nephrotoxic serum (NTS)-induced glomerular nephritis (GN). Similarly, podocyte Epac1 deletion in podocytes exacerbated GN development. Global gene expression profile in mouse glomeruli using RNAseq analysis indicates a transcriptomic signature of GN related to immune system, extracellular matrix, and cytoskeleton gene dysregulation at the onset of the disease. Furthermore, glomeruli with podocyte Epac1 deletion display altered mitochondrion and metabolic processes in nephritic mice. Consistently, mechanistic analysis demonstrates that Epac1 activation increases human podocyte mitochondrial function to cope with extra energy demand in stress condition. Of particular importance, Epac1 increases aerobic glycolysis to ameliorate podocyte viability and motility. Therefore, the metabolic flexibility mediated by Epac1 constitutes a protective mechanism against podocyte injury. Altogether these data highlight the potential of Epac1 as a therapeutic approach for CKD treatment. Overall design: To investigate the role of podocyte Epac1 in GN progression, glomerulonephritis (GN) was induced in conditional knockdown 3-month-old female mice with specific Epac1 deletion in podocytes (NPHS2Cre: Epac1fl/fl) and in the littermate (Epac1fl/fl), by 2 consecutive days' intravenous administration of decomplemented nephrotoxic serum (NTS; 18,5 µl/gBW), while the control mice were injected with PBS. We examined RNA glomerular extracts from 21 female mice at two stages of the disease: early (day 4) and late (day 11).: - PBS: 3 Epac1fl/fl; 3 NPHS2Cre: Epac1fl/fl - NTS D4: 3 Epac1fl/fl; 4 NPHS2Cre: Epac1fl/fl - NTS D11: 4 Epac1fl/fl; 4 NPHS2Cre: Epac1fl/fl In order to perform comparative gene expression profilling analysis.