The nephrotic syndrome is a frequent clinical condition characterized by fluid and salt retention. Although several theories have been put forward to explain the salt-retaining status, recent data have confirmed previous renal micropuncture observations indicating that the distal nephron is the site for increased salt reabsorption, eventually leading to sodium retention. Target proteomic approaches and immunocytochemistry experiments have identified the epithelial sodium channel (ENaC) and basolateral Na+,K+-ATPase as the main transport proteins responsible for increased transepithelial sodium reabsorption in various forms of experimental nephrotic syndrome. Although the fine-tuning for the up-regulation of these transporters has not been so far elucidated, it is clear from clinical studies that the use of amiloride, a selective, dose-dependent ENaC inhibitor, is an appropriate tool to reduce distal sodium reabsorption and thus to offset edema formation.