Cells initially respond to hypertonicity by regulatory volume increase in which transporters convey inorganic ions into the cells, followed by an osmotic influx of water that restores cell volume. Although cell volume is corrected, intracellular ionic strength remains elevated, and high ionic strength perturbs the structure and function of cellular macromolecules (Yancey et al., 1982). Cells compensate by replacing excess inorganic ions with compatible organic osmolytes, which allows maintenance of cell volume along with less perturbation of macromolecules. Tonicity is normally higher in the renal inner medulla than elsewhere in the body. The principal organic osmolytes in cells of the renal medulla are sorbitol, glycine betaine (betaine), myo-inositol (inositol), taurine, and glycerophospho-choline (GPC) (Burg et al., 1997). Several enzymes and transporters are responsible for accumulation of these osmolytes. Aldose reductase (AR) converts glucose to sorbitol. The betaine/g-aminobutyric acid transporter, the sodium inositol cotransporter, and the taurine transporter, respectively, mediate the cellular accumulation ofbetaine, inositol, and taurine (Burg et al., 1997). The phospholipase, neuropathy target esterase, catalyzes the synthesis of GPC from phosphatidylcholine (Gallazzini et al., 2006). Hypertonicity causes each of these proteins to increase in abundance by increasing the transcription of its gene (Burg etal., 1997; Gallazzini etal., 2006). The increase results from activation of the transcription factor, TonEBP/OREBP.
Other genes that are central to osmoprotection and urinary concentration are also transactivated by TonEBP/OREBP. These genes code for heat shock protein 70 (Woo et al., 2002), vasopressin-activated urea transporters [UT-A1 (Nakayama et al., 2000) and possibly UT-A2 (Lam et al., 2004)], as well as aquaporin 2 (AQP2)(Hasler et al., 2006). TonEBP/ OREBP activates its target genes by binding to one or more consensus DNA elements in the regulatory regions of these genes. The TonEBP/OREBP-binding sites are called osmotic response elements (OREs) (Ferraris et al., 1994; Ko etal., 1997) ortonicity-responsive enhancers (TonEs) (Takenaka etal., 1994).
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