Fig. 1. Cartoon illustrating the hypertonic stress response of animal cells. Exposure to hypertonic media causes rapid water loss and cell shrinkage. Cells respond to shrinkage by activating regulatory volume increase (RVI) salt uptake mechanisms. Osmotically obliged water follows salt uptake and cell volume returns to its original value. Over a period of several hours, cells replace inorganic ions accumulated during RVI with organic osmolytes. Accumulation of organic osmolytes is mediated either by energy-dependent transport from the external medium or by changes in the rates of osmolyte synthesis and degradation. Hypertonic stress typically increases the expression of both organic osmolyte transporters and key enzymes involved in their synthesis. Cells also repair molecular damage including DNA breaks and protein denaturation induced by the initial cell shrinkage and elevation cell inorganic ion levels.