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News Physiol Sci 14: 221, 1999;
1548-9213/99 $5.00
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News in Physiological Sciences, Vol. 14, No. 5, 221, October 1999
© 1999 Int. Union Physiol. Sci./Am. Physiol. Soc.

Trendsetters

Escape from Vasopressin-Induced Antidiuresis: Insights at the Molecular Level

Joseph G. Verbalis

Division of Endocrinology and Metabolism, Georgetown University Medical Center, Washington, DC 20007
In this section we feature some of the latest and most striking new findings in physiology, interpreting the term "physiology" in its broadest sense. In each instance, an effort will be made to place the new findings in perspective.

Heinz Valtin

Editor, TRENDSETTERS

In 1878, Claude Bernard defined maintenance of the "milieu interieur" as an essential requirement for life, a concept that was formalized by Walter Cannon, in 1932, into the term "homeostasis." Body fluid homeostasis, which is critical to a constant internal environment, is regulated largely through the secretion of mineralocorticoids and vasopressin (VP), which promote the conservation of sodium and water, respectively, when body fluid volume is decreased. Ordinarily, the secretion of these hormones is diminished or shut off when the body fluid volumes have been reexpanded. In some disease states, however, inappropriate and continued hypersecretion can lead to life-threatening high levels of sodium and water. Luckily, physiological mechanisms allow animals to escape from the effects of mineralocorticoids and VP when the body fluid volumes are increased (3), a phenomenon called, appropriately, "escape." This article deals with recent developments in understanding some of the molecular events that explain escape from VP.

Plasma hyperosmolality and hypovolemia are major stimulants for the secretion of VP (also called antidiuretic hormone or ADH); conversely, plasma hyposmolality and hypervolemia inhibit this secretion. During some clinical circumstances [e.g., the syndrome of inappropriate antidiuretic hormone secretion (SIADH), severe congestive heart failure, and hepatic cirrhosis], the secretion of VP continues despite plasma hyposmolality, and it can lead to continued water retention and further dilutional hyposmolality. This dangerous, potentially fatal, vicious cycle is usually curbed by the phenomenon of escape. When escape occurs, the kidneys are again able to lower the urine osmolality and excrete water, even in the face of high plasma levels of VP. This observation suggests a decreased sensitivity of the kidneys to VP, and recent work (1, 2) has provided support for this suggestion.

VP leads to renal resorption of water by increasing the osmotic water permeability of principal cells, which are located in late distal tubules and collecting ducts. This action of VP is mediated through a cascade of intracellular events that includes many steps and culminates in the insertion of water channels (called aquaporins) into the apical membrane of principal cells. Studies in recent years have provided substantial evidence that escape from VP-induced antidiuresis is associated with, and likely caused by, altered regulation of renal aquaporins.

Of the four types of aquaporins expressed in renal tubules, aquaporin-2 (AQP2) is the one located in the apical membrane of principal cells and the only one that is regulated by VP. Several groups have shown that long-term infusion of VP or of its synthetic analog, DDAVP (1-desamino-8-D-arginine vasopressin), into rats leads to a marked increase in the expression of AQP2 mRNA and protein. However, when the rats were subsequently loaded with water while the infusion of DDAVP was continued, their levels of AQP2 protein (as determined by Western blot) and mRNA (by Northern blot) were significantly lower than those of control rats on continuous treatment with DDAVP but not given water loads (2). These differences were specific to AQP2, for they were not observed on Western blots utilizing antibodies to other renal aquaporins. Furthermore, the time course and magnitude of the AQP2 downregulation correlated closely with the onset and magnitude of "escape," as reflected in a decrease of urine osmolality ( Fig. 1).



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  		FIGURE 1. Correlation between relative changes in renal expression of aquaporin-2 (AQP2) and urine osmolality during escape from vasopressin-induced antidiuresis in rats. The experimental protocol is explained in the text. Mean values are expressed as percentages of the values in rats not undergoing escape (control rats). *Significant changes (P < 0.05) from controls.

 
Thus the results shown in Fig. 1 are compatible with the view that escape involves decreased water permeability of collecting ducts—an explanation, by the way, that was postulated 40 years ago (3). That view has been supported further by the finding that isolated, perfused collecting ducts from rats showing escape generate less of the intracellular mediator cyclic 3',5'-adenosine monophosphate (cAMP) than do collecting ducts from control rats (1); generation of cAMP is one of the early events in the intracellular cascade referred to above, which leads to the insertion of AQP2 into the apical membrane of principal cells and increased synthesis of AQP2. Consequently, changes in VP/V2 receptor-Gs-adenylate cyclase function likely underlie the escape phenomenon. Even these results, however, raise further questions. What, exactly, causes the decreased formation of cAMP? How does volume expansion in the face of high VP lead to decreased generation of cAMP? What other cellular processes may be involved? Although it may take many more years to find all of the answers, by understanding the cellular events underlying antidiuresis we are now much closer to understanding the phenomenon of escape than we were just a short while ago.

References

  1. Ecelbarger, C. A., C.-L. Chou, A. J. Lee, S. R. DiGiovanni, J. G. Verbalis, and M. A. Knepper. Escape from vasopressin-induced antidiuresis: role of vasopressin resistance of the collecting duct. Am. J. Physiol. 274 (Renal Physiol. 43): F1161–F1166, 1998.[Abstract/Free Full Text]
  2. Ecelbarger, C. A., S. Nielsen, B. R. Olson, T. Murase, E. A. Baker, M. A. Knerpper, and J. G. Verbalis. Role of renal aquaporins in escape from vasopressin-induced antidiuresis in rat. J. Clin. Invest. 99: 1852–1863, 1997.[Medline]
  3. Levinsky, N. G., D. G. Davidson, and R. W. Berliner. Changes in urine concentration during prolonged administration of vasopressin and water. Am. J. Physiol. 196: 451–456, 1959.

Occasionally, the Editor of the Trendsetters section invites contributions from the authors of published scientific articles that have been identified as being of special interest. All précis to Trendsetters are by invitation only.




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