Calcineurin-NFATc Signaling Pathway Regulates AQP2 Expression in Response to Calcium Signals and Osmotic Stress

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Title: Calcineurin-NFATc Signaling Pathway Regulates AQP2 Expression in Response to Calcium Signals and Osmotic Stress
Authors: Li, Song-Zhe; McDill, Bradley; Kovach, Paul; Ding, Li; Go, William Y.; Ho, Steffan N.; Chen, Feng
Publisher: American Journal of Physiology: Cell Physiology
Date Published: December 13, 2006
Reference Number: 715
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The aquaporin 2 (AQP2) channel mediates the reabsorption of water in renal collecting ducts in response to arginine vasopressin (AVP) and hypertonicity. Here we show that AQP2 expression was induced not only by the TonEBP/NFAT5-mediated hypertonic stress response, but also by the calcium-dependent calcineurin-NFATc pathway. The induction of AQP2 expression by the calcineurin-NFATc pathway can occur in the absence of TonEBP/NFAT5. Mutational and chromatin immunoprecipitation analyses revealed the existence of functional NFAT binding sites within the proximal AQP2 promoter responsible for regulation of AQP2 by NFATc proteins and TonEBP/NFAT5. Contrary to the notion that TonEBP/NFAT5 is the only Rel/NFAT family member regulated by tonicity, we found that hypertonicity promotes the nuclear translocation of NFATc proteins for the subsequent induction of AQP2 expression. Calcineurin activity was also found to be involved in the induction of TonEBP/NFAT5 expression by hypertonicity, thus further defining the signaling mechanisms that underlie the TonEBP/NFAT5 osmotic stress response pathway. The coordinate regulation of AQP2 expression by both osmotic stress and calcium signaling appears to provide a means to integrate diverse extracellular signals into optimal cellular responses. Key words: Aquaporin, NFAT, calcineurin , osmotic response, TonEBP.
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This translation by the NDI Foundation is to assist the lay reader. To provide a clear, accessible interpretation of the original article, we eliminated or simplified some technical detail and complicated scientific language. We concentrated our translation on those aspects of the article dealing directly with NDI. The NDI Foundation thanks the researchers for their work toward understanding and more effectively treating this disorder.
© Copyright NDI Foundation 2007 (JC)

In genetics, the term expression refers to the process by which a gene’s DNA sequence is converted into proteins. For example, the principal cell of the kidney collecting duct expresses many different proteins that perform necessary functions for the cell. Aquaporin-2 (AQP2) is one such protein. It helps the principal cell absorb water in the kidney by traveling to the cell membrane when signaled by a chemical sequence initiated when the hormone, arginine vasopressin (AVP) links with the vasopressin 2 receptor (V2R) on the principal cell’s membrane. When so signaled, AQP2 travels from the cell interior to the cell membrane and acts as a channel through which water can enter the cell.

The signal generated by the linking of AVP and V2R help regulate the long term expression of AQP2 in the cell. In other words, it signals the cell to make more AQP2s. However, AVP/V2R signaling is not the only mechanism in the cell that regulates AQP2 expression. Li, et al., investigated two other cellular pathways that they hypothesized could induce AQP2 to express: the TonEBP/NFAT5-mediated hypertonic stress response and by the calcineurin-NFATc pathway.

The kidneys require a hypertonic environment in order to reabsorb water, a necessary aspect of maintaining body water balance. However, if the kidney did not have the ability to balance the hypertonic state, it would prove detrimental to kidney health. TonEBP/NFAT5 activates in response to hypertonic stress. It helps to regulate the transcription of genes that code for solutes that establish water balance within a hypertonic environment. (Transcription is a process that uses DNA as a template to produce messenger RNA for the subsequent protein synthesis.)

Calcineurin is a protein phosphatase, which is an enzyme that removes phosphate groups (dephosphorylates) from its substrate (i.e., the molecule specific to the enzyme). NFATc proteins are a substrate for calcineurin. Li, et al.’s, extensive research not only revealed that AQP2 can be induced by both the TonEBP/NFAT5-mediated hypertonic stress response and by the calcineurin-NFATc pathway, but that these two pathways can affect this in an independent yet coordinated manner. By helping to regulate the expression of AQP2 in the principal cells of the kidney collecting duct, TonEBP/NFAT5 and calcineurin-NFATc can help the movement of water through these cells, and thus help promote body water balance.