Signalling and gene regulation by urea and NaCl in the renal medulla

1. Cells of the mammalian renal medulla are routinely subjected to an enormously elevated and labile ambient osmolality as a consequence of the renal concentrating mechanism. The present review focuses on the most recent advances in hyperosmotic solute-mediated signal transduction and regulation of gene transcription in cells of the kidney medulla. 2. On the basis of osmolality alone, NaCl and urea are the principal renal medullary solutes. 3. Urea, which is membrane permeant, activates transcription of immediate-early genes via an extracellular signal-regulated kinase (ERK)/Elk-1-dependent pathway. Urea also activates multiple effectors characteristic of a receptor tyrosine kinase-like signalling cascade. 4. In contrast, the functionally impermeant solute NaCl activates transcription of tonicity responsive genes (principally genes encoding proteins essential for osmolyte uptake or synthesis) via a unique consensus element contained within their 5' flanking sequences. 5. An activity exhibiting tonicity inducible sequence-specific interaction with this DNA element has been identified. 6. Hypertonicity, like thermal stress, activates transcription of genes encoding heat shock proteins. The relationship between signalling events leading to tonicity mediated and heat shock-mediated gene transcription remains to be established.