Regulation of the myo-inositol and betaine cotransporters by tonicity.

Cells of the hypertonic renal medulla accumulate high concentrations of the non-perturbing osmolytes myo-inositol, betaine, and taurine, and are thereby protected from the perturbing effects of hypertonicity. Kidney-derived MDCK cells accumulate high levels of these three non-perturbing osmolytes when cultured in hypertonic medium and have been used to study their accumulation. The increase in the intracellular concentration of these non-perturbing osmolytes is the result of an increase in the abundance of the mRNA for the specific cotransporter for each osmolyte and the ensuing increase in the activity of the three specific sodium coupled transporters. The increased abundance of mRNA for the myo-inositol and the betaine cotransporters is driven by an increase in the rate of transcription of their genes. We have identified a 13 basepair cis-acting element in the 5' flanking region of the gene for the betaine cotransporter. The element is an enhancer that mediates the transcriptional response to hypertonicity. The protein(s) that binds to the tonicity responsive element is much more active in hypertonic than in isotonic cells, and is in all likelihood the mediator of the transcriptional response to changes in tonicity.