Osmotic regulation of renal betaine transport: transcription and beyond.

Cells in the kidney inner medulla are routinely exposed to high extracellular osmolarity during normal operation of the urinary concentrating mechanism. One adaptation critical for survival in this environment is the intracellular accumulation of organic osmolytes to balance the osmotic stress. Betaine is an important osmolyte that is accumulated via the betaine/gamma-aminobutyric acid transporter (BGT1) in the basolateral plasma membrane of medullary epithelial cells. In response to hypertonic stress, there is transcriptional activation of the BGT1 gene, followed by trafficking and membrane insertion of BGT1 protein. Transcriptional activation, triggered by changes in ionic strength and water content, is an early response that is a key regulatory step and has been studied in detail. Recent studies suggest there are additional post-transcriptional regulatory steps in the pathway leading to upregulation of BGT1 transport, and that additional proteins are required for membrane insertion. Reversal of this adaptive process, upon removal of hypertonic stress, involves a rapid efflux of betaine through specific release pathways, a reduction in betaine influx, and a slower downregulation of BGT1 protein abundance. There is much more to be learned about many of these steps in BGT1 regulation.