Increased Renal Responsiveness to Vasopressin and Enhanced V2 Receptor Signaling in RGS2-/- Mice
|Title:||Increased Renal Responsiveness to Vasopressin and Enhanced V2 Receptor Signaling in RGS2-/- Mice|
|Authors:||Zuber, Annie Mercier; Singer, Dustin; Penninger, Josef; Rossier, Bernard; Firsov, Dmitri|
|Publisher:||Journal of American Society of Nephrology|
|Date Published:||June 01, 2007|
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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)
The hormone, arginine vasopressin (AVP), regulates the body’s ability to balance its internal water supply. It does this by binding to the vasopressin 2 receptor (V2R), located on the membrane of the principal cells of the kidney collecting duct. When AVP and V2R bind, V2R sends a signal that initiates the following chemical sequence: adenylyl cyclase is activated via the stimulatory G protein, Gs. This increases intracellular levels of cyclic adenosine monophosphate (cAMP), which activates protein kinase A (PKA). This leads to a process called phosphorylation wherein a phosphate group is added to aquaporin 2 (AQP2). This stimulates AQP2 to travel from the cell interior to the apical portion of the cell membrane. Once inserted in the cell membrane, it acts as a channel through which water can enter the cell.
The research team of Zuber, et al., recently observed and described the vasopressin-dependent gene network of the principal cell of the mouse cortical collecting duct, a part of the kidney involved in body water absorption. The vasopressin-dependent gene network is a set of genes that require the presence of AVP to begin synthesizing the proteins whose blueprint they contain. One of these genes is called the regulator of G protein signaling 2 (RGS2). The RGS2 protein controls both the strength and length of signaling (communication) that takes place through G protein-coupled receptors (GPCR). Zuber, et al., sited data indicating that RGS2 may play a role in how the kidney balances body water. Experiments with laboratory cell cultures indicate that RGS2 can inhibit four types of adenylyl cyclase as well as several types of GPCR. (As mentioned in the first paragraph, adenylyl cyclase and Gs, a GPCR, are both involved in the chemical sequence that results in absorption of body water from the kidney into the blood.)
Thus, Zuber, et al., conducted a series of experiments to determine the role played by RGS2 in the kidney’s water balancing process. They knew that AVP stimulated RGS2 expression (i.e., the process by which the RGS2 gene’s DNA sequence is converted into the RGS2 protein). They hypothesized that RGS2 interferes with V2R’s signaling ability, thereby acting as a negative feedback regulator that, by interfering with V2R’s signal, helps bring the water absorption process that V2R signals through the Gs protein to an end.
- RSG2 is found only in those parts of the kidney that are AVP sensitive.
- AVP rapidly increases the amount of RSG2 expression.
- RGS2 negative mice have significantly higher amounts of cAMP in their kidney collecting ducts than do mice with RGS2. (In the collecting duct, the accumulation of cAMP is regulated by AVP.)
- The kidneys of RGS2 negative mice are significantly more responsive to AVP than mice with intact RGS2.
These results suggest that RGS2 acts as a negative feedback regulator to AVP’s effect in the kidney. That is, it attenuates the water reabsorbing process initiated when AVP binds with V2R. By negatively regulating V2R signaling, RGS2 helps reestablish equilibrium in the kidney’s water absorption process. The work of Zuber, et al., provides the first evidence of the role RGS2 plays in the water balancing function of the kidney.