Adaptation of cells to hypertonicity often involves changes in gene ex
pression. Since the concentration of salt in the interstitial fluid su
rrounding renal inner medullary cells varies with operation of the ren
al concentrating mechanism and generally is very high, the adaptive me
chanisms of these cells are of special interest. Renal medullary cells
compensate for hypertonicity by accumulating variable amounts of comp
atible organic osmolytes, including sorbitol, myo-inositol, glycine be
taine, and taurine. In this review we consider how these solutes help
relieve the stress of hypertonicity and the nature of transporters and
enzymes responsible for their variable accumulation. We emphasize rec
ent developments concerning the molecular basis for osmotic regulation
of these genes, including identification and characterization of osmo
tic response elements. Although osmotic stresses are much smaller in o
ther parts of the body than in the renal medulla, similar mechanisms o
perate throughout, yielding important physiological and pathophysiolog
ical consequences.