Osomolality of the mammalian kidney medulla is very high. The high osmolality provides driving force for water reabsorption and urinary concentration, a key function of the kidney for maintaining proper body fluid volume and blood pressure. Salt and urea are major solutes in the renal medullary interstitium. Unfortunately, high salt (hypertonicity) causes DNA damage and high urea causes cell death. For the successful function of the kidney, the renal medullary cells have to overcome the deleterious effects of hyperomolality. The cells adapt to the hypertonicity by accumulating compatible osmolytes. We have shown that TonEBP transcriptional activator play a central role in the compatible osmolyte accumulation via stimulating genes whose products either actively transport or synthesize compatible osmolytes. In addition, TonEBP plays significant roles in building up the high urea as well as protecting the cells from the high urea. TonEBP stimulates the vasopressin regulated urea transporters that play a critical role in the counter current recycling of urea in the renal medulla. Our preliminary data show that expression of many genes in the renal medulla is dependent on the hyperosmolality. In addition, we detected a number of signaling pathways activated by hyperosmolality in the renal medulla. Central hypothesis is that hyperosmolality is an important local signal for differentiation of the renal medulla. Hyperosmolality in the renal medulla activates cellular signaling pathways to stimulate transcription of a group of genes. Products of these genes play essential roles in maintaining and supporting differentiation of the renal medulla.
Aim 1 is to test whether TonEBP regulates genes in the renal medulla in response to local osmolality. Osmolality will be changes by inducing diuresis or antidiuresis and the activity of TonEBP will be investigated. TonEBP deficient mice will be examined to investigate functional significance of TonEBP in the renal medulla.
Aim 2 is to test whether there are other genes transcriptionally stimulated by hyperosmolality. Functional genomic screening will be performed to uncover them. Role of TonEBP will be investigated using TonEBP deficient mice and cultured ceils.
Aim 3 is to uncover signaling pathways involved in the osmotic regulation of transcription. Activation of protein kinases that are activated by hypertonicity-induced DNA damage will be investigated using specific antibodies. These studies are likely to uncover a new paradigm of signal transduction unique to the kidney medulla.
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