Hypertonicity in kidney medullary interstitium is essential for urinary concentration. Osmolality in the papillary interstitium can reach up to 1200 mOsm/kg. How do cells in the renal medullary interstitium survive this hypertonic stress?
Virtually all cells respond to hypertonicity by the accumulation of organic osmolytes (i.e. myo-inositol, betaine, taurine, glycerophosphorylcholine, sorbitol) and renal medullary interstitial cells are not the exception.
Hypertonicity upregulates the transcription of certain genes involved in organic osmolyte transport or synthesis such as SMIT (sodium-myo-inositol cotransporter), BGT1 (sodium chloride/betaine cotransporter), TauT (sodium chloride/taurine cotransporter), NTE (neuropathy target esterase, enzyme responsible for the synthesis of glycerophosphorylcholine) and AR (aldose reductase, enzyme responsible for the synthesis of sorbitol).
This increase in gene transcription is mediated by TonE (Tonicity-responsive Enhancer) located in the promoter region of these osmoprotective genes. TonEBP (Tonicity-responsive Enhancer Binding Protein), also known as NFAT5, has been identified as the transcription factor that binds TonE and stimulate transcription. Severe atrophy of renal medulla was observed in TonEBP knockout mice.
Urea is one of the main solutes responsible for renal medullary hypertonicity. However, high urea concentrations have been shown to cause cell cycle delay and apoptosis in renal medullary cells. HSP70 is a heat-shock protein found to play an important role in the protection against the deleterious effects of urea. TonEBP has also been shown to increase the expression of HSP70.
In summary, TonEBP is the master regulator of renal medulla for cellular protection against hypertonicity and high urea concentrations via accumulation of organic osmolytes and increased expression of protective heat shock proteins.