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

1. Cells of the mammalian renal medulla are routinely subjected to an enorm ously elevated and labile ambient osmolality as a consequence of the renal concentrating mechanism. The present review focuses on the most recent adva nces 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-e arly genes via an extracellular signal-regulated kinase (ERK)/Elk-1-depende nt pathway. Urea also activates multiple effecters characteristic of a rece ptor tyrosine kinase-like signalling cascade. 4. In contrast, the functionally impermeant solute NaCl activates transcrip tion of tonicity responsive genes (principally genes encoding proteins esse ntial for osmolyte uptake or synthesis) via a unique consensus element cont ained 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 enc oding heat shock proteins. The relationship between signalling events leadi ng to tonicity mediated and heat shock-mediated gene transcription remains to be established.