The cellular response to osmotic stress ensures that the concentration of water inside the cell is maintained within a range that is compatible with biologic function. Single cell organisms are particularly dependent on mechanisms that permit adaptation to osmotic stress because each individual cell is directly exposed to the external environment. Mammals, however, limit osmotic stress by establishing an internal aqueous environment in which intravascular water and electrolytes are subject to sensitive and dynamic, organism-based homeostatic regulation. NFAT5/TonEBP is an essential mammalian osmoregulatory transcription factor, and this invention demonstrates the unexpected yet critical significance of cell-based osmotic regulation in vivo. The invention highlights the fundamental importance of maintaining intracellular water homeostasis in the face of varying cellular metabolic activity and distinct tissue microenvironments. Methods for treating, preventing, or inhibiting human diseases using the osmotic stress pathway have been provided.