Mechanism of Vasopressin Action in the Renal Collecting Duct
| Title: | Mechanism of Vasopressin Action in the Renal Collecting Duct |
|---|---|
| Authors: | Knepper, Mark; Nielsen, Soren; Chou, Chung-Lin; DiGiovanni, Susan R. |
| Publisher: | Seminars in Nephrology |
| Date Published: | July 01, 1994 |
| Reference Number: | 379 |
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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)
Researchers recognize 5 distinct segments of the kidney CD: the initial collecting tubule (ICT), the cortical collecting duct (CCD), the outer medullary collecting duct (OMCD), the initial part of the inner medullary collecting duct (initial IMCD) and the terminal part of the inner collecting duct (terminal IMCD).
The antidiuretic hormone, arginine vasopressin (AVP) initiates a molecular sequence in the principal cells of all segments of the CD that makes their apical membranes more water permeable. This increase in cell membrane water permeability (Pf) is what allows the kidneys to reabsorb the water flowing through the CDs.
AVP also regulates urea permeability (Purea). Urea is the principal end product of protein breakdown and makes up about half the total urinary solids. Unlike AVP regulation of Pf which occurs throughout the CD, AVP only regulates urea transport in the terminal IMCD (via an increase of apical membrane Purea).
Researchers have investigated how AVP increases Pf and Purea. They discovered an intrinsic membrane protein called aquaporin-2 (AQP2) that is responsible for increased apical membrane Pf in the principal cells of the CD. AVP binds with the vasopressin-2 receptor (V2R) located in the basolateral membrane of the CD principal cells. The V2R is coupled to a Gs protein, and when AVP and V2R bind, the Gs protein activates the adenylyl cyclase (AdC) enzyme complex. This, in turn, elevates levels of cyclic adenosine monophosphate (cAMP). cAMP then activates protein kinase A (PKA). The next portion of the molecular sequence is not yet perfectly clear, but it seems to involve the phosphorylation of various proteins that help AQP2s travel to and insert themselves into the apical membrane of the CD cells.
The AQP2s act as channels through which water can cross the membrane, allowing much more water than normal to flow through the cells. This is how the membrane Pf is increased. When AVP absents itself from the cell, the AQP2s are removed from the apical membrane and taken back inside the cell. This returns the apical membrane to a state of low Pf.
The structure responsible for increasing apical membrane Purea is called the UT-2 urea transporter. The molecular pathway that instigates UT-2 function is independent of the pathway that delivers AQP2 to the apical membrane, though both are regulated by AVP. AVP appears to increase the number of UT-2s present in the terminal IMCD rather than altering their affinity for urea.
AVP also stimulates transient mobilization of intracellular calcium in CD cells. AVP binds with three receptors: the V1a receptor, the V1b receptor and the V2 receptor. Each receptor is linked to a different molecular pathway, and when AVP binds with each respective receptor, it results in a different molecular sequence being initiated, which results in a different physiologic effect. The authors conclude the AVP/V2R bond is what mobilizes intracellular calcium in the terminal IMCD.
Phosphoinositides are inositol-containing compounds that have been phosphorylated (i.e. have formed links with phosphate groups). They help mobilize calcium when stimulated by select hormones. When AVP activates the phosphoinositide pathway it inhibits the osmotic Pf in both the IMCD and CCD. There is data to suggest it does this by reducing levels of cAMP in the cells. And there is also some evidence that AVP activating the phosphosinositide pathway can inhibit Pf in the absence of changes in cAMP levels, though it has not been established how it does this.
AVP also stimulates production of prostaglandin E2 (PGE2) in CD cells. It does this whether introduced to the cell through the apical or basolateral membrane. This suggest that the AVP receptors for this process are on both sides of the cell. Several studies have shown that PGE1 or PGE2 inhibit AVP stimulated Pf in rabbit CCD.
The number of AQP2s and UT-2s present in CD cells is regulated by both short-term and long-term mechanisms. Evidence suggests that AVP regulates AQP2 and UT-2 in the short-term as introduction of AVP rapidly increases both water and urea permeability, and removal of AVP rapidly decreases both types of permeability. Abundant evidence supports the theory that AVP induces AQP2 to travel to and insert itself into the apical membranes to increase their Pf. And when AVP is removed, AQP2 is removed from the apical membrane. It is less clear how AVP regulates UT-2s in the short-term.
Intrinsic Pf is altered by long-term changes in water intake. This long-term regulation is associated with large changes in the amount of AQP2s present in CD cell membranes. For example, depriving rats from water for 24 hours leads to an increase in the number of AQP2s in CD cells. Researchers suggest that this long-term regulation is mediated by AVP. One researcher reports that urea transport in CD cells is regulated by long-term changes in dietary protein intake.