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Escape from antidiuresis: A good story

Escape from antidiuresis: A good story
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  Kidney International, Vol. 60 (2001), pp. 1608–1610 EDITORIAL Escape from antidiuresis: A good story Good stories often share common characteristics. lecting tubule lumen into the medullary interstitium [7],They address topics of interest and/or significance, they a regulatory mechanism that impacts at this stage of theare played out over extended periods of time, and they urinary concentrating mechanism would be maximally ef-have elements of controversy, if not drama. But perhaps fectiveatlimitingAVP-inducedantidiuresis.Usingsimilarmostimportant,theygenerallyincludeadefinablebegin- animal models of dilutional hyponatremia [8], the resultsning, a middle, and an end. The story of escape from ofthetwostudiesdifferquantitatively,butnotqualitatively.vasopressin [arginine vasopressin (AVP)]-induced anti- Ecelbarger et al found 70 to 80% decreases in l-deamino-diuresis certainly fulfills most of these criteria. The phe- 8- d -arginine vasopressin (dDAVP)-stimulated AQP-2nomenon of AVP escape has arguably been one of the protein and mRNA expression in the kidney that corre-mostinterestingunresolvedaspectsofrenalfunctionthat lated temporally with the decrease in urine osmolalityhas been studied over the last half century. How the and increase in urine volume characteristic of escape.kidney is able to escape AVP-induced antidiuresis is also Similarly,Saitoetalfound35to55%decreasesinAQP-2of considerable significance because this process allows protein and mRNA expression after 7 days of dDAVP-survivaloftheorganismbyallowingfreewaterexcretion, induced hyponatremia. In both cases, this marked down-despite inappropriate secretion of AVP, thus effectively regulation of AQP-2 expression occurred despite phar-antagonizing the effects of one of the most powerfulmacological dDAVP infusion. Therefore, both studieshormones involved in body fluid homeostasis. The storyclearlyindicateanAVP-independentregulationofAQP-2of escape has continued to evolve over the last half cen-expression. Although a causal rather than correlationaltury since this phenomenon was first recognized in 1959associationbetweentheAQP-2down-regulation andAVPwith the landmark report of Levinsky, Davidson, andescape has not yet been definitely established, given theBerliner [1]. And, as for controversy, each decade hasstrong association between AQP-2 membrane insertionwitnessed a new potential explanation for this phenome-and collecting tubule water permeability, this amount of non,includingdecreasedwaterpermeabilityofcollectingchange in AQP-2 expression is clearly sufficient to alterduct principal cells [1], dissipation of the cortico-medul-the degree of antidiuresis produced [9]. Thus, it seemslary osmotic gradient [2], increased generation of renallikely that this is, in fact, a very plausible ending to ourprostaglandin E 2  [3], and renal hemodynamic changesstory.mediated by increased renal artery perfusion pressureHowever,abeginningandanenddonotbythemselvesleading to a pressure diuresis [4]. Although the variousmake a satisfying story. There needs to be a middle thatmechanisms proposed to underlie escape have differed,ties these ends together and fleshes out the relationshipall studies to date are in agreement that expansion of thebetween them. What are the events that occur betweenextracellular fluid (ECF) space by AVP-induced waterAVP-inducedvolumeexpansionandAQP-2down-regu-retention is crucial for the onset and maintenance of lation, and how are they related? The results of Saito etAVP and previous studies differ substantially and furtherThus, we have the makings of an interesting, and con-fuel the controversy that has surrounded this area fortroversial, story with a clear beginning: ECF volume ex-the last half century. Ecelbarger et al found a 40 to 45%pansion. But now we also know the ending of this story.down-regulation of dDAVP-stimulated cyclic adenosineIn thisissue of  Kidney International  ,Saitoet al [5] confirmmonophosphate (cAMP) generation in inner medullarytherecent findings of Ecelbargeretal [6] thatAVP escapecollecting duct cell suspensions prepared from escapedisassociatedwithamarkeddown-regulationofexpressionrats compared to controls [10]. Because cAMP mediatesoftheAVP-sensitivewaterchannel,aquaporin-2(AQP-2),signal transduction between the AVP V 2  receptor and itsin the kidney. Because AQP-2 insertion into the apicaleffects on both AQP-2 membrane insertion and AQP-2membrane of collecting tubule principal cells representstranscription [9], resistance to AVP-stimulated adenyl-the final step of facilitated water transport from the col-atecyclaseactivitywouldrepresentaprimecandidateformodulation of AVP effects at a cellular level. Consistentwiththisidea,Tianetalfoundamarkeddown-regulation Key words:  vasopressin, extracellular fluid, aquaporin-2, hypo-osmo-lality.  of the AVP V 2  receptor number (B max ) in escaped ratsthat was 70% below control levels and 35% below the ©  2001 by the International Society of Nephrology 1608  Editorial   1609 levels of nonescaped dDAVP-treated rats [11], which the level of AQP-2 transcription, an inevitable questionremains: What mediates these effects? Somehow, ECFare known toundergo ligand-inducedreceptor desensiti-zation. In contrast, Saito et al found no differences in volume expansion must be sensed by the collecting ductcells. Although changes in osmolality appear to be ancAMP generation between the escaped and control ratsand observed a 40% reduction in V 2  B max  secondary to attractive candidate for such a mediator, down-regula-tionofAQP-2 withescapeoccursthroughout thekidney,dDAVP treatment but not any further decreases in theincluding in the cortex where osmotic perturbations areescaped rats [5]. Such discrepancies between studies aremuch less marked [12]. Furthermore, escape can be re-usually attributable to differences in the animal model,versed even in the presence of continued hypo-osmolal-orin themethodologiesused tomake themeasurements.ity [12], consistent with previous studies in AVP-infusedThe former explanation seems unlikely in this situationdogs in which maintenance of constant renal perfusiongiven the similarities of the animal models. Instead, it ispressure via servo-control prevented the occurrence of much more likely that the significant differences in theescapedespiteseverehypo-osmolality[4].Takentogether,methodologies employed explain these discrepancies.these combined studies indicate that hypo-osmolality byAlthoughbothstudiesmeasuredAVPordDAVP-stimu-itself is not a prerequisite for escape. Future studies willlated cAMP generation from medullary suspensions, theneedtoconsideradditionalpotentialmediatorsofescapecAMP generation in the presence of 3-isobutyl-l-methyl-andparticularlythoseendocrine,paracrineandmechani-xanthine (IBMX) was 3-fold (basally) to 8-fold (stimu-calfactorsinvolvedwithbothsensingandcontrollingintra-lated) higher in the studies of Ecelbarger et al comparedrenal hemodynamics and inner medullary blood flow [13].to Saito et al. This difference in cAMP generation mayConsequently, while we understand much more aboutreflect the differences in tissue used to prepare the sus-escape today as a result of the studies of Ecelbarger etpensions, as Saito et al used outer and inner medullaryal, Murase et al, Tian et al, and Saito et al, escape fromtissue, with a resulting greater admixture of thick ascend-AVP-induced antidiuresis very much remains a work ining limb cells with collecting duct cells, whereas Ecel-progress. There are still more characters to be implicated,barger et al used only inner medullary tissue, illustratingthelikelihoodofintricatesubplots,andeventhepossibil-the difficulty with interpretation of adenylate cyclaseity of promiscuous hormonal-receptor relationships leftactivity measurements when using mixed cell tissue ex-to be written. Readers can therefore look forward totracts. Even greater differences exist with regard to themore interesting chapters before this story is completed.radioligand binding assays. Saito et al employed a stan-dard [ 3 H]AVP binding assay, whereas Tian et al devel- Joseph G. Verbalis opeda newbindingassay employinganAVP V 2 receptor Washington, DC, USA antagonist with an iodinatable tyrosine residue that does Correspondence to Joseph G. Verbalis, M.D., Professor of Medicine not interfere with receptor binding, thus allowing higher and Physiology, Georgetown University, 4000 Reservoir Rd., NW, 232 specific activity [11]. A review of previously reported Building D, Washington, DC 20007, USA. values for B max  of the AVP V 2  receptor measured under  E-mail: basal conditions from inner medullary membrane prepa- REFERENCES rations of Sprague-Dawley rats via saturation bindinganalyses shows means of 272    109 fmol/mg protein  1.  Levinsky NG, Davidson DG, Berliner RW : Changes in urineconcentration during prolonged administration of vasopressin and when iodinated radioligands were employed (four stud- water.  Am J Physiol   196:451–456, 1959 ies, including the results of Tian et al) and 200    69 2.  ChanWY :Astudyofthemechanismofvasopressinescape:Effects fmol/mg protein when tritiated radioligands were used  ofchronicvasopressinandoverhydrationonrenaltissueosmolalityand electrolytes in dogs.  J Pharmacol Exp Ther   184:244–252, 1973 (four studies). In contrast, the B max  found by Saito et al 3.  Gross PA, Kim JK, Anderson RJ : Mechanisms of escape from using a competition binding analysis was much higher desmopressin in the rat.  Circ Res  53:794–804, 1983 (11,800 fmol/mg protein [5]), raising the possibility that  4.  Hall JE, Montani JP, Woods LL, Mizelle HL : Renal escapefrom vasopressin: Role of pressure diuresis.  Am J Physiol   250: differences in assay sensitivity could account for the dis- F907–F916, 1986 cordant results regarding changes in B max  with escape. 5.  Saito T, Higashiyama M, Nagasaka S,  et al  : Role of aquaporin-2 Additional studies will therefore be required to resolve  gene expression in hyponatremic rats with chronic vasopressin-induced antidiuresis.  Kidney Int   60:1266–1276, 2001 the apparent discrepancies between the present study 6.  Ecelbarger CA, Nielsen S, Murase T,  et al  : Role of renal aqua- and those done previously and, specifically, to address porins in escape from vasopressin-induced antidiuresis.  J Clin In- the most accurate methods for measuring receptor num-  vest   99:1852–1863, 19977.  Knepper MA : Molecular physiology of urinary concentrating ber and adenylate cyclase activity in this system. How- mechanism: Regulation of aquaporin water channels by vasopres- ever, even after these issues are resolved, there are still sin.  Am J Physiol   272:F3–F12, 1997 more basic questions that demand answers. Whether the  8.  VerbalisJG,DrutaroskyMD : Adaptation to chronic hypoosmo-lality in rats.  Kidney Int   34:351–360, 1988 AQP-2 down-regulation with escape occurs via changes 9. Nielsen S, Marples D, Frokiaer J,  et al  : The aquaporin family of  in AVP-V 2  receptor expression and signal transduction, waterchannelsinkidney:Anupdateonphysiologyandpathophysi-ology of aquaporin-2.  Kidney Int   49:1718–1723, 1996 or whether it is regulated at other sites such as directly at  Editorial  1610 10.  EcelbargerCA,ChouCL,LeeAJ, etal  :Escapefromvasopressin- 12.  MuraseT,Ecelbarger CA,BakerEA, et al  : Kidney aquaporin-2expression during escape from antidiuresis is not related to plasmainduced antidiuresis: Role of vasopressin resistance of the collect-ing duct.  Am J Physiol   274:F1161–F1166, 1998 or tissue osmolality.  J Am Soc Nephrol   10:2067–2075, 199913.  Cowley AW Jr : Control of the renal medullary circulation by11.  Tian Y, Sandberg K, Murase T,  et al  : Vasopressin V 2  receptorbinding is down-regulated during renal escape from vasopressin- vasopressin V 1  and V 2  receptors in the rat.  Exp Physiol   86:223S–231S, 2000induced antidiuresis.  Endocrinology  141:307–314, 2000
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