Novel developments in untangling the significance of Epac signaling in the kidney

Exchange proteins directly activated by cAMP (Epac1 and Epac2) are abundantly expressed in the glomerulus and epithelial cells of the renal tubule. Epac activity is rather benign at baseline, but it can be greatly potentiated in response to stress or during disease states. However, the significance of the Epac signaling cascade for kidney function is largely enigmatic. This review analyzes recently published evidence on the reno-protective actions of Epac1 and Epac2 isoforms in the pathology of glomerulonephritis and upon dietary acidification.

Paralog-specific beneficial actions of Epac have been reported recently in the glomerulus and the collecting duct system. Activation of Epac1 promotes glycolysis and increases lactate production, thereby augmenting podocyte survival in an experimental model of glomerulonephritis. Dietary acidification greatly enhances renal Epac2, but not Epac1, expression to stimulate urinary acid excretion. Epac2 deficiency produces a distal renal tubule acidosis (RTA)-like phenotype associated with the inability to acidify urine due to impaired H + secretion by A-type intercalated cells.

Activation of Epac1 and Epac2 isoforms is instrumental for defensive and adaptive responses in the pathophysiology of glomerulonephritis and metabolic acidosis. Further characterization and subsequent implementation of pharmacology-based treatments targeting individual Epac isoforms might be of considerable clinical importance.