Kidney cell survival in high tonicity

Abstract

The kidney medulla of mammals undergoes large changes in tonicity in parallel with the tonicity of the final urine that emerges from the kidney at the tip of the medulla. When the medulla is hypertonic, its cells accumulate the compatible osmolytes myo-inositol, betaine, taurine, sorbitol and glycerophosphorylcholine. The mechanisms by which the compatible osmolytes are accumulated have been explored extensively in kidney-derived cells in culture. Myo-inositol, betaine and taurine are accumulated by increased activity of specific sodium-coupled transporters, sorbitol by increased synthesis of aldose reductase that catalyses the synthesis of sorbitol from glucose. Glycerophosphorylcholine accumulates primarily because its degradation is reduced in cells in hypertonic medium. cDNAs for the cotransporters and for aldose reductase have been cloned and used to establish that hypertonicity increases the transcription of the genes for the cotransporters for myo-inositol, betaine and for aldose reductase. The region 5' to the promoter of the gene for the betaine cotransporter and for aldose reductase confer osmotic responsiveness to a heterologous promoter. The 12-bp sequence responsible for the transcriptional response to hypertonicity has been identified in the 5' region of the gene for the betaine cotransporter.