Coordinate regulation of organic osmolytes in renal cells

Abstract

Adaptation of cells to prolonged hypertonicity generally involves accumulation of compatible organic osmolytes. Renal medullary cells in vivo and in tissue culture accumulate several different organic osmolytes, including sorbitol, inositol, betaine, and glycerophosphocholine (GPC) in response to hypertonicity. For the total concentration of these organic osmolytes to be appropriate for the ambient tonicity, an increase in one should cause the others to fall, minimizing changes in their total concentration. The experiments presented here demonstrate this in tissue culture and investigate the mechanisms involved. Sorbitol is synthesized from glucose, catalyzed by aldose reductase. Betaine is transported into the cells. Hypertonicity increases transcription of the aldose reductase and betaine transporter genes, ultimately elevating cell sorbitol and betaine. If aldose reductase is inhibited, which prevents accumulation of sorbitol, betaine transporter gene expression increases, resulting in a higher cell betaine that compensates for the lower sorbitol. Conversely, when cell betaine is altered by changing its concentration in the medium, aldose reductase transcription changes reciprocally, resulting in compensating changes in cell sorbitol. Hypertonicity increases GPC by inhibiting GPC:choline phosphodiesterase (GPC:PDE), an enzyme that degrades GPC. When cell betaine or inositol is increased by raising its concentration in the medium, GPC:PDE activity rises, reducing cell GPC. Thus, the total of the osmolytes, rather than the level of any individual one, is maintained.