2 Mutations in Nephrogenic Diabetes Insipidus

Anne J. M. Loonen, MSc,* Nine V. A. M. Knoers,† Carel MD,H. vanPhD, Os, PhD,* and Peter M. T. Deen, PhD*

Summary: Water reabsorption in the renal collecting duct is regulated by the antidiuretic hormone vasopressin (AVP). When the vasopressin V2 receptor, present on the basolateral site of the renal principal cell, becomes activated by AVP, aquaporin-2 (AQP2) water channels will be inserted in the apical membrane, and in this fashion, water can be reabsorbed from the pro-urine into the interstitium. The essential role of the vasopressin V2 receptor and AQP2 in the maintenance of body water homeostasis became clear when it was shown that mutations in their cause nephrogenic diabetes insipidus, a disorder in which the kidney is unable to concentrate urine in response to AVP. This review describes the current knowledge on AQP2 mutations in nephrogenic diabetes insipidus. Semin Nephrol 28:252-265 © 2008 Elsevier Inc. All rights reserved. Keywords: Autosomal nephrogenic diabetes insipidus, vasopressin, aquaporin-2 water channel, disease, routing

he mammalian kidney has the abilitytransport to and mammalian osmoregulation. excrete or reabsorb free water indepen-Water balance is regulated by the combined T dent of changes in solute excretion.action of osmoreceptors, volume receptors, Physiologic studies have provided evidence thirstfor sensation, vasopressin, and water ex- the constitutive absorption of approximatelycretion or reabsorption by the kidney. To 90% of the glomerular filtration rate volumedate, in13 mammalian AQPs have been identi- the proximal tubules and descending limbsfied of (AQP0-12). Functional studies have iden- Henle’s loop, whereas facultative water reab-tified a subgroup of AQPs (AQPs 3, 7, and 9), sorption occurs in the collecting ducts termedunder aquaglyceroporins, that transport control of the antidiuretic hormone argininewater as well as glycerol and possibly urea vasopressin (AVP).Although all cell mem-and other small solutes.2– 4AQPs have 6 trans- branes have a surprisingly high diffusive membranewa- domains, connected by 5 loops ter permeability, there is now extensive (A-E),evi- and NH2 and COOH-termini that are dence that water transport in the nephronlocated is in the cytoplasmFig. ).(1 The AQP 1 facilitated by water channels.Because water family shows a highly conserved asparagine- movement across cell membranes is essentialproline-alanine (NPA) motif in both loops B for all living organisms, it is no surpriseand thatE, which fold back into the membrane in the initial cloning of aquaporinAQP) 1( has an hourglass fashion to form the water pore. reanimated research into the biology of Althoughwater AQPs form tetrameric complexes, each single subunit is able to form an aqueous *Department of Physiology, Nijmegen Centre for Molecular Life Sciences,pore and is able to transport water. Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands †Department of Human Genetics, Nijmegen Centre for Molecular Life Sci- ences, Radboud University Nijmegen Medical Centre, Nijmegen, The Neth- erlands AQP2 Address reprint requests to Peter M. T. Deen, PhD, 286, Department of Physiology, Radboud University Nijmegen Medical Centre Nijmegen/Ni- AQP2 is the AVP-dependent water channel of jmegen Centre for Molecular Life Sciences, PO Box 9101, 6500 HB Nijme- the collecting duct (for review see Knepper and gen, The Netherlands. E-mail: [email protected] 5 0270-9295/08/$ - see front matter Inoue ). It is well established that the collecting © 2008 Elsevier Inc. All rights reserved. doi:10.1016/j.semnephrol.2008.03.006 duct water permeability can be regulated in 2

252 Seminars in Nephrology, Vol 28, No 3, May 2008, pp 252-265 AQP2 mutations in NDI 253

Figure 1. AQP2 structure. An AQP monomer consists of 6 transmembrane domains connected by 5 loops (A through E) and its N- and C-terminus located intracellularly. Loops B and E meet each other with their characteristic NPA (Asparagine-Proline-Alanine) boxes (black rectangle) in the membrane and form the water selective pore. The N-glycosylation site (pink; *), the AQP2 mutations leading to recessive NDI (red) and dominant NDI (green; #) are indicated. ways: a short-term regulation, which occurs in (cAMP), cAMP levels in the cell subsequently in- minutes, and a long-term regulation, which crease, which leads to an increase in ki- takes hours. nase A activity and to phosphorylation of AQP2 In the short-term regulation, AVP is released water channels on its Ser256 residue,7,8 resulting upon states of hypovolemia or hypernatremia in its steady-state redistribution from intracellular from the posterior pituitary gland into the blood- vesicles to the apical membrane. After an osmotic stream and is transported to the kidneys, where it gradient of sodium and urea, water will enter the can bind to vasopressin V2 receptors located on cell via AQP2 and leave the cell on the basolateral the basolateral side of collecting duct principal side via AQP3 and AQP4.9–11 Fig. 2 shows an cells.6 This hormone binding results in the switch overview of this process. Phosphorylation of of a vasopressin type 2 receptor (V2R)-bound Ser256 is essential for the translocation of AQP2 guanosine diphosphate–coupled trimeric Gs pro- to the apical membrane, although it does not alter tein to its active guanosine triphosphate–bound the water permeability of AQP2.12 It has been form, which subsequently dissociates into its ␣- shown that the AQP2-S256A mutant, which mim- and ␤␥-subunits. The activated V2R triggers a sig- ics a constitutively nonphosphorylated AQP2 pro- naling cascade in which membrane-bound adeny- tein, is retained in intracellular vesicles, indepen- lyl cyclase is stimulated by the ␣-subunit of the dent of the presence of the adenylate cyclase trimeric Gs protein to convert adenosine triphos- activator, forskolin.7,8,13,14 Interesting in this re- phate to cyclic adenosine monophosphate spect is that in an unstimulated steady-state con- 254 A.J.M. Loonen et al

Figure 2. Regulation of AQP2-mediated water transport by vasopressin. AVP, V2R, stimulatory guanosine triphosphate binding protein (Gs␣ protein), adenylate cyclase (AC), adenosine triphosphate (ATP), cAMP, protein kinase A (PKA), phosphorylated AQP2 (P-AQP2), and phosphorylated cAMP response element–binding protein (glowing CREB) are indicated. For details see text. dition, phosphorylated AQP2 could be detected to be located in the promoter region of the AQP2 in intracellular vesicles in the kidney.15 AQP2 is and of these it was shown that they were expressed as a homotetramer13,16 and studies us- able to confer AVP-induced expression of a re- ing oocytes as a model system indicated that for a porter gene.25,26 Transcriptional regulation of the plasma membrane localization 3 out of 4 mono- AQP2 gene seems to be the main action of AVP mers in an AQP2 tetramer need to be phosphor- and is mediated by phosphorylation of a cAMP ylated.17 response element–binding protein and binding of Upon fluid intake, AVP release into the blood phosphorylated cAMP response element–binding decreases, AQP2 is redistributed into intracellu- protein to the cAMP response element in the lar vesicles, and water reabsorption is re- promoter region of the AQP2 gene.27 duced.18–21 Katsura et al22 have shown that the AVP-regulated recycling of AQP2 can occur at THE ROLE OF AQP2 IN DISEASES least 6 times with the same molecules. In the long-term regulation, circulating AVP Several pathophysiologic conditions exist that levels increase collecting duct water permeability can lead to a disturbed water homeostasis. Be- by increasing the expression level of AQP2.23,24 cause AVP is the hormone that controls serum Different cis-acting elements have been reported osmolality by decreasing free water clearance, AQP2 mutations in NDI 255 any condition that interferes with AVP produc- apical plasma membrane, which is otherwise tion, secretion, and binding to V2 receptors or extremely water impermeable. with AQP2 synthesis and trafficking will result Besides acquired NDI, a congenital form of in loss of the ability to concentrate urine. With NDI also exists, which is quite rare and has an central diabetes insipidus, the production of occurrence of 1 per 100,000 human beings. functional AVP is disturbed and therefore pa- Although congenital NDI is rare, it is important tients are not able to concentrate their urine. to identify it very early in life to prevent dehy- Numerous mutations in AVP have been re- dration and its consequences. Congenital NDI ported and can be the cause of central diabetes can be divided into X-linked (V2R) and autoso- insipidus.28–32 However, administration of the mal-recessive and -dominant NDI (AQP2). The synthetic AVP homolog 1-desamino-8-D-argi- role of the V2R gene in NDI is covered by Dr. nine vasopressin (DDAVP) usually is able to Daniel Bichet on page 245 in this issue. In this decrease urine output in these patients. review, we discuss congenital NDI, which re- Besides central diabetes insipidus, a dis- sults from mutations found in AQP2. The dis- turbed water balance also can be of renal ori- covery of different genetic causes of NDI has gin, which consequently is called nephrogenic important implications for genetic counseling, diabetes insipidus (NDI). Acquired NDI is the especially in those families in which only one most common form. Lithium, which is the drug member is affected. of choice for treating bipolar disorders, is able to reduce depressive symptoms in 70% to 80% THE AQP2 GENE of patients and reduces the mortality rate ob- 12q13 harbors the human AQP2 served in this illness.33 Development of NDI is gene (GenBank accession number z29491)37,38 an unpleasant side effect of this therapy and as part of an aquaporin gene cluster to which because 0.1% of the world population is on AQP0, AQP5, and AQP6 also belong. The AQP2 lithium therapy and severe forms of this side gene comprises 4 exons distributed over ap- effect are present in about 10% to 20% of pa- proximately 5 kb of genomic DNA. The 1.5-kb tients, lithium-induced NDI is the most com- mRNA encodes a protein of 271 amino acids, mon acquired form of NDI.34 Conditions of hy- which has a predicted molecular weight of 29 pokalemia (as is common in hypertensive kd. patients treated with thiazide diuretics), hyper- calcemia, and bilateral ureteral obstruction of- ten also lead to acquired forms of NDI, a disease IDENTIFICATION OF THE AQP2 GENE AS in which the kidney does not respond to AVP. THE GENE CAUSING AUTOSOMAL- Paradoxically, diseased states such as conges- RECESSIVE NDI tive heart failure, cirrhosis, pre-eclampsia, and An apparently sporadic Dutch male NDI patient the syndrome of inappropriate release of the provided evidence for the existence of a non– antidiuretic hormone (SIADH) induce excessive X-linked type of NDI. Careful clinical studies renal water reabsorption, which can lead to unraveled a clue leading to the elucidation of a life-threatening hyponatremia and edema for- new gene defect for NDI. The patient involved mation. From numerous rat model studies it has could be differentiated from patients with X- become clear that all these forms of acquired linked NDI on the basis of a DDAVP infusion NDI coincide with a strong reduction in expres- test. DDAVP is a selective agonist for the V2R. sion of AQP2, whereas the states of excessive In addition to the renal V2R, which mediates renal water uptake coincide with increased the antidiuretic effect of AVP and DDAVP, there AQP2 expression (for reviews see Nielsen et is evidence for an extrarenal V2R, which medi- al,21 Schrier et al,35 and Marples et al36). So far, ates extrarenal effects of these ligands. An in- all data collected on AQP2 confirm its unique crease in factor VIII, von Willebrand factor, and role, which is AVP-regulated control of the os- tissue-type plasminogen activator, and a de- motic water permeability of the principal cell crease in diastolic blood pressure39,40 are the by insertion of AQP2 water channels in the result of stimulation of this extrarenal V2R. In 256 A.J.M. Loonen et al contrast to the blunted coagulation, fibrino- cases. In a minority of patients with X-linked lytic, and vasodilatory responses seen in most NDI, namely in those patients who are carry- NDI patients after DDAVP infusion and reflect- ing V2R mutations resulting in partial insen- ing a general V2R defect,41–43 the Dutch male sitivity to AVP, the disease onset was re- NDI patient showed a normal response to ported to be not directly after birth, but later DDAVP.44 This finding indicated that the unre- in childhood. In general, the initial symptoms sponsiveness to vasopressin in this boy was in most autosomal-dominant cases also ap- restricted to the kidney. The results of the pear later in childhood. After the observation DDAVP test, together with the finding that no of normal extrarenal responses to DDAVP in deleterious mutations were found in the coding the first patient shown to have AQP2 muta- region of the V2R gene, suggested a defect in a tions, it was suggested that intravenous kidney-specific protein in the cellular vasopres- DDAVP administration with measurement of sin-signaling cascade beyond the V2R. When von Willebrand factor, factor VIII, and tissue- Fushimi et al45 cloned a water channel of the rat type plasminogen activator levels, could be of renal collecting duct (CD), which later was re- use in the differentiation between the named AQP2, a candidate gene became avail- X-linked and autosomal-recessive forms of able. Expression of its mRNA in Xenopus oo- NDI. Indeed, it was shown that male patients cytes increased osmotic swelling in response to with autosomal-recessive NDI show normal transfer to a hypotonic buffer, suggesting that it extrarenal responses to DDAVP, whereas in encoded the vasopressin-regulated water chan- all studied patients with X-linked NDI these nel. Cloning and localization studies of the hu- extrarenal responses are absent as a result of man equivalent AQP2 gene favored its potential an extrarenal mutant vasopressin type 2 re- involvement in autosomal NDI because it local- ceptor.49 In female patients, the interpreta- ized on chromosome 12q13.37,46 Subsequently, tion of this intravenous DDAVP test is more the AQP2 gene of the Dutch variant NDI patient complicated. Although absence of the extra- was sequenced and he appeared to carry 2 renal responses to intravenous administration point mutations in the AQP2 gene, one result- of DDAVP in females clearly points to the ing in substitution of a cysteine for arginine 187 presence of a V2 receptor defect, a normal (R187C) in the third extracellular loop of the response cannot be interpreted as indicative water channel and the other resulting in substi- of a defect beyond the V2 receptor and, thus, tution of a proline for serine 216 (S216P) in the of an AQP2 defect.50 For instance, a symptom- sixth transmembrane domain.47 The parents of atic female patient described by Moses et al,51 the boy each carried 1 of these 2 missense who was shown to be heterozygous for a V2R mutations but showed no signs of concentrat- mutation, showed a 2-fold increase in factor ing disabilities. Further studies revealed that VIII activity after administration of DDAVP. each mutation resulted in nonfunctional water This discrepancy between the extrarenal and channels.47 All together, the findings indicated renal response to DDAVP in these female V2 that aberrant AQP2 water channels underlie receptor mutation carriers may be owing to autosomal-recessive NDI, an assumption that variability of the pattern of X-chromosome was strengthened further by the subsequent inactivation between different tissues.52 detection of mutations in other families, in which patients were from consanguineous cou- AUTOSOMAL-RECESSIVE NDI ples.48 About 10% of patients diagnosed with NDI have mutations in the AQP2 gene. Of these, greater DIFFERENCES BETWEEN NDI CAUSED BY than 90% are diagnosed with recessive NDI. To AQP2 OR V2R MUTATIONS date, 39 mutations in AQP2 have been reported No differences in clinical symptoms between (Table 1), of which 32 are involved in recessive X-linked and autosomal-recessive forms of NDI. Interestingly, nearly all the mutations in NDI can be observed, nor in the time of onset autosomal-recessive NDI are found in the re- of the disease, with the exception of a few gion encoding the AQP2 segment between the AQP2 mutations in NDI 257

Table 1. AQP2 Mutations That Cause NDI

Abbreviations: he, heterozygous; ho, homozygous; all, allele; r, recessive; d, dominant; NF, nonfunctional; P, partial functional (level in %); conserved yes (Y) or no (N) between AQP ; dD, infusion with dDAVP; ndD, nasal dDAVP; deh, dehydration; NR, nonresponsive; >300, urine more than 300 m0sm/kg water.

first and the last transmembrane domain. Be- this part of the protein illustrates the sensitivity cause this segment forms the AQP2 water pore, of the pore structural changes. To establish the the misfolding resulting from the mutations in involvement of an identified AQP2 gene muta- 258 A.J.M. Loonen et al tion in NDI and to study the underlying mech- NDI in the 2 families we encountered (patients anism by which the mutation would lead to were heterozygous for an R187C or A190T muta- recessive NDI, the Xenopus oocyte expression tion in one allele, combined with a P262L muta- system was mostly used. Expression of the en- tion in the other allele) can be explained as fol- coded mutants in cell systems showed that al- lows: in the 2 patients, AQP2-R187C and AQP2- most all mutants were misfolded and, therefore, A190T mutants are retained in the ER, and do not retained in the endoplasmic reticulum (ER), fol- interact with AQP2-P262L. AQP2-P262L folds lowed by rapid proteasomal degradation.47,53–57 properly and assembles into homotetramers, but Because of this rapid degradation, AQP2 pro- will be retained mainly in intracellular vesicles. teins could not be detected in the urine of The consequent lack of sufficient AQP2 proteins patients suffering from recessive NDI as a result in the apical membrane of the patient’s collecting of AQP2 gene mutations, in contrast to healthy duct cells then explains their NDI phenotype. In controls.58 The inability of these AQP2 mutants the parents coding for wt-AQP2 and AQP2-R187C to form heterotetramers with wt-AQP2, leaving or A190T, wt-AQP2 will not interact with either only the formation of WT-AQP2 homotetram- mutant but will form homotetrameric complexes, ers, provides an explanation for the healthy of which the insertion into the apical membrane phenotype of the patients’ parents.13 An in- in collecting duct cells will be regulated properly creased wt-AQP2 expression from the normal by vasopressin and will give a healthy phenotype. allele does not seem to be necessary because In the proband’s healthy relatives encoding wt- heterozygote AQP2 knock-out mice have a AQP2 and AQP2-P262L, both proteins likely as- healthy phenotype and express approximately semble into heterotetramers. However, the domi- half of the AQP2 amount found in normal nancy of wt-AQP2 sorting on the localization of mice.59 Although retained in the ER, at high AQP2-P262L will then result in a proper AVP- expression levels that allow some of the AQP2 regulated trafficking of the heterotetrameric com- mutant proteins to escape from the ER and to plexes to the apical membrane of their collecting be routed to the plasma membrane,60 7 mutants duct cells. (L22V, A47V, G64R, T125M, T126M, A147T, and V168M) appeared to be able to confer wa- AUTOSOMAL-DOMINANT NDI ter permeability.54–56,61,62 Recently, the AQP2- At present, 7 families have been described with P262L mutation was found to be involved in autosomal-dominant NDI, making it the least recessive NDI and this was rather surprising prominent form of NDI. The identified muta- because P262 is located in the AQP2 C-terminal tions in these families comprise deletions, inser- tail, a region that until then was believed to tions, and missense mutations (Table 1). result in dominant NDI instead of recessive Clinical analyses of patients with recessive NDI. The answer to this intriguing situation and dominant NDI caused by AQP2 mutations came from our cell biological studies.63 AQP2- revealed 3 interesting differences.64–67 First, in P262L appeared to be a functional water chan- recessive NDI, symptoms (polyuria, polydipsia) nel that was retained in intracellular compart- are already present at birth, whereas in domi- ments different from the ER and that formed nant NDI they often become apparent in the hetero-oligomers with wt-AQP2. These were all second half of the first year or later. Second, similar to AQP2 mutants in dominant NDI. Im- urine osmolalities of patients with recessive munocytochemical analysis of cells co-expressing NDI never exceed 200 mOsm/kg H2O, whereas AQP2-P262L with wt-AQP2, however, revealed in dominant NDI this can be higher. Third, that these wt-mutant complexes were located in some patients diagnosed with dominant NDI the apical membrane and, thus, that here, the respond to DDAVP administration or dehydra- apical sorting of wt-AQP2 was dominant over the tion by showing a transient increase in urine missorting signals of AQP2-P262L. This was differ- concentration. This seems to more general, be- ent from dominant NDI, because in this form the cause for long-QT syndrome, con- mutants retain wt-AQP2 in intracellular locations. genita, osteochondrodysplasia, and Rainbow Based on these data, the recessive inheritance of syndrome/brachydactyly, it also has been ob- AQP2 mutations in NDI 259 served that the dominant form of the disease mutants with the 721delG, 727delG, del763- can be subclinically milder than the recessive 772, or del812-818 mutations have similar ex- form.68–71 tended C-terminal tails. In polarized MDCK Interestingly, all mutations in dominant cells, AQP2-727delG appeared to accumulate in NDI are found in the coding region of the late endosomes/lysosomes and, to some extent, C-terminal tail of AQP2, which is not a part of in the basolateral plasma membrane,66 whereas the water pore–forming segment, but, as the other mutants were localized in the baso- shown by the role of phosphorylation of S256 lateral membrane.75 Because the extended tail in in AQP2, has an important role in AQP2 traf- AQP2-del812-818 starts only at the stop codon of ficking. Indeed, all AQP2 proteins in domi- wt-AQP2 and the extended tails contain the nant NDI appeared to be functional water known basolateral membrane targeting di-leucine channels, whereas expression in oocytes and motif,76 the missorting of these mutants was sug- Madin-Darby canine kidney (MDCK) cells re- gested to be owing to this introduced basolateral vealed that all these AQP2 mutants in domi- sorting signal. nant NDI were indeed sorted to other subcel- Early studies in oocytes suggested that the lular locations in the cell than wt-AQP2. In exchange of E258 for a lysine (E258K) also polarized MDCK cells, wt-AQP2 is translo- introduced a missorting signal because deletion cated from intracellular vesicles to the apical of the segment surrounding E258 greatly re- membrane by forskolin.72 In contrast, the stored the plasma membrane expression of the AQP2 mutant AQP2-R254L was sorted to for- AQP2-E258K mutant.67 This was corroborated skolin-insensitive vesicles, AQP2-E258K was by the study of Procino et al,73 who found that routed to the Golgi complex (oocytes) or late the mutation precluded phosphorylation of endosomes/lysosomes (mammalian cells), AQP2-E258K at S256 by Golgi casein kinase, AQP2-727delG trafficked to the basolateral and suggested that this resulted in its missorting membrane and late endosomes/lysosomes, to multivesicular bodies. By analysis of several and AQP2-721delG, 812-818del, 763-772del, mutants in polarized MDCK cells, however, we and AQP2-insA were reported to target the recently discovered that AQP2-E258K is well basolateral membrane.63–67,73,74 Importantly, phosphorylated at S256 and that mimicking because none of these mutants were mis- phosphorylation at S256 in AQP2-E258K by folded, they were able to interact with and changing S256 into an aspartate did not change form heterotetramers with wt-AQP2, which is its localization to multivesicular bodies.77 More- in contrast to AQP2 mutants in recessive over, because AQP2-E258R and AQP2-E258A NDI.13 In addition, in cells co-expressing wt also were sorted to multivesicular bodies, we and mutant AQP2 proteins, it appeared that concluded that it was the loss of E258 in AQP2 the wt/mutant complexes also were mis- instead of introduced signal that caused the sorted, which was owing to the wt-mutant missorting of AQP2-E258K. Because wt-AQP2 interaction and dominancy of the missorting also is sorted to multivesicular bodies when signals in the mutant proteins. Extrapolated constitutively coupled to a ubiquitin moiety,78 to principal cells of the patients, this would it will be interesting to investigate whether lead to severely decreased amounts of AQP2 AQP2-E258K in some way structurally mimics in the apical membrane, explaining the dom- ubiquitinated wt-AQP2. Besides AQP2-E258K, inant mode of inheritance of NDI in these AQP2-R254L also is missorted because of a lost families.13 signal because this mutation destroyed the pro- Interestingly, the AQP2 gene mutation lead- tein kinase A consensus site, resulting in the ing to dominant NDI can introduce a missorting lack of forskolin-induced phosphorylation of signal or remove a sorting signal of wt-AQP2. AQP2-R254L at S256.63 Correction of its S256 With AQP2-insA, the changed C-terminal tail phosphorylation by substituting S256 for an as- targeted it to the basolateral membrane, which partate, however, resulted in the expression of harbored 2 basolateral sorting signals.64 Al- the corresponding protein (AQP2-R254L- though starting at different positions, the AQP2 S256D) in the apical and basolateral membrane, 260 A.J.M. Loonen et al indicating that even if phosphorylation of this servation that the age of onset of dominant NDI mutant could be overcome, the leucine at po- in human beings often is later and subclinically sition 256 would induce a partial missorting to milder compared with recessive NDI. Although the basolateral membrane. the urine concentrating ability was reduced se- verely compared with wild-type mice, adminis- MOUSE MODELS TO STUDY tration of DDAVP did significantly increase CONGENITAL NDI urine concentration in the heterozygous mice. Although an increased urine osmolality with Recently, 5 congenital NDI mouse models were DDAVP also was observed in some human pa- created,79–83 providing novel and important in tients suffering from dominant NDI, this is not vivo information on the role of AQP2 in water found commonly. Treatment of these mice with conservation in health and disease. Rojek et al80 generated mice lacking functional AQP2 either rolipram (a phosphodiesterase [PDE]-4 inhibi- completely (AQP2-total-knock-out [KO]) or only tor), but not PDE3 or PDE5 inhibitors, resulted in the collecting ducts (AQP2-CD-KO) by exploit- in an increased urine concentration. If repro- ing the Cre/loxP technology. LoxP sites were in- ducible in human beings, this suggests that serted into AQP2 introns 2 and 3, and transgenic PDE4 inhibitors might be an interesting therapy mice were bred with strains expressing Cre re- to treat dominant NDI. combinase under the control of CD-specific Although the molecular mechanism causing Hoxb7- or global EIIa promoter. Consistent with autosomal-recessive and -dominant NDI in vivo 85 the complete lack of functional AQP2 in the ho- appeared similar to the in vitro studies, the mozygous knock-in of an AQP2 mutant in reces- relation between the location of the AQP2 mu- sive NDI, AQP2-T126M,59 AQP2-total-KO mice tation and the trait of inheritance in mice came looked healthy at birth but failed to thrive and with some surprises. Although AQP2-S256L in- died within 2 weeks as a result of severe urine teracted with wt-AQP2 and was impaired in its concentrating defects and massive contraction of phosphorylation at S256, similar to AQP2- extracellular fluid volume. Moreover, hydrone- R254L, it caused recessive instead of dominant 82 phrosis also was observed. A nearly 100% absence NDI in mice. The considerable apical mem- of AQP2 in the CDs was observed in the AQP2- brane expression of AQP2 in the heterozygous CD-KO mice, but clear expression of AQP2 in the mice explained this difference. Assuming that connecting tubules (CNTs) was visible. Although the expression of wt-AQP2 and AQP2-S256L in these mice survived to adulthood, growth retar- these mice is similar, the differences in inheri- dation and progressive hydronephrosis was ob- tance suggest that AQP2-R254L and AQP2- served, which was caused by a 10-fold increased S256L differ in their ability to cause missorting urine volume compared with controls. Consis- of wt-AQP2 (ie, AQP2-R254L stronger than tently, their urine osmolality was 10-fold de- AQP2-S256L). This is in line with our in vitro creased. The other 4 congenital NDI mice79–83 data that AQP2-P262L, which also interacts showed similar phenotypes, and increased serum with wt-AQP2, causes recessive instead of dom- blood urea nitrogen levels were observed in the inant NDI, because its missorting is overruled AQP2-S256L mice and in mice with the distal by wt-AQP2 when co-expressed.63 C-tail deleted,82 indicating renal failure. Although A greater surprise was found by Lloyd et al,81 growth retardation often is observed in uncon- who investigated mice suffering from NDI as a trolled NDI in human beings, hydronephrosis and result of an F204V AQP2 mutation. Similar to renal failure rarely have been noted84 and this mutants in recessive NDI, this mutation is local- indicates that NDI is more severe in mice. ized between the first and sixth transmembrane The first mouse model used to study domi- domain of AQP2 and also resulted in an ER- nant NDI was generated by Sohara et al82 and retained protein. However, although AQP2 null this was performed by homologous recombina- mutants and a mouse model homozygous for a tion of part of the last exon of the human AQP2 human AQP2 mutant causing recessive NDI mutant (763-772del). The AQP2-763-772del het- (AQP2 -T126M) die soon after birth because of erozygous mice survived, in line with the ob- dehydration, mice homozygous for AQP2- AQP2 mutations in NDI 261

F204V were viable because sufficient amounts proaches to develop alternative therapies for of this mutant appeared at the apical membrane NDI have been tested in vitro. One of the most of principal cells to guarantee survival. More- promising approaches at the moment is the use over, in vitro and in heterozygote mice, AQP2- of cell-permeable V2R or V1R inverse agonists F204V clearly interacted with wt-AQP2, reveal- in the rescue of ER-retained, but functional, ing that an AQP2 mutant with a mutation V2R mutants in NDI (described by Dr. Daniel between the first and sixth transmembrane do- Bichet on page 245 in this issue).92–94 In the main may interact with wt-AQP2. Interestingly, coming years it will be exciting to see how well a similar situation might be the case for AQP2- these compounds work out in vivo. Because V168M because this mutant was less ER-re- most AQP2 mutants in NDI are ER-retained, and tained when expressed in cells, and the pheno- many of them are functional, the rescue ap- type of human beings homozygous for this proach as described for V2R mutants earlier mutation varied from severe NDI to no NDI at also would be very useful for AQP2 mutants. all. Whether this or some other AQP2 mutants For AQP water channels, however, no specific in human recessive NDI may indeed interact interacting compounds are known. Although with wt-AQP2, however, remains to be estab- the number of patients with recessive NDI as a lished. result of AQP2 mutations is low and the con- ventional therapy relieves NDI to a great extent, THERAPIES IN CONGENITAL NDI identification of compounds that can rescue AQP2 mutants in NDI often is considered not The most important component of treatment of worth the effort. However, because of its role NDI, whether acquired or congenital, is re- in excessive water reabsorption in congestive placement of urinary water losses by an ade- heart failure, cirrhosis, SIADH and pre-eclamp- quate supply of fluid, in combination with a sia, which are encountered quite frequently, decreased solute diet to decrease obligatory wa- efforts are on their way to identify AQP2-spe- ter excretion. Most infants with NDI, however, cific inhibitors. Possibly, cell permeable forms cannot drink the required amounts of fluid. of these compounds might become the drugs Initially, a diet low in sodium (1 mmol/kg/d) as with which to rescue AQP2 mutants in NDI and well as protein (2 g/kg/d) was recommended, to provide an additional therapy for many of the but severe limitations of dietary protein may NDI patients with AQP2 gene mutations.96 introduce serious nutritional deficiencies and therefore a dietary restriction of sodium only is REFERENCES preferable. Nowadays, the treatment usually 1. King LS, Agre P. Pathophysiology of the aquaporin consists of diuretics such as hydrochlorothia- water channels. Annu Rev Physiol. 1996;58:619-48. zide and amiloride, which have been shown to 2. Koyama N, Ishibashi K, Kuwahara M, et al. Cloning be effective in lowering urine volume in and functional expression of human aquaporin8 NDI.86,87 Administration of hydrochlorothiazide cDNA and analysis of its gene. Genomics. 1998;54: 169-72. combined with either a COX inhibitor such as 3. Borgnia M, Nielsen S, Engel A, et al. Cellular and indomethacin or the potassium-sparing diuretic molecular biology of the aquaporin water channels. amiloride was shown to be more effective in Annu Rev Biochem. 1999;68:425-58. reducing urine volume than the thiazide di- 4. Hara-chikuma M, Verkman AS. Physiological roles of uretic alone.43,88–91 However, long-term use of glycerol-transporting : the aquaglycero- prostaglandin-synthesis inhibitors often is com- porins. Cell Mol Life Sci. 2006;63:1386-92. 5. Knepper MA, Inoue T. Regulation of aquaporin-2 plicated by hematopoietic and gastrointestinal water channel trafficking by vasopressin. Curr Opin side effects. Renal dysfunction also can occur Cell Biol. 1997;9:560-4. during indomethacin treatment, mostly consist- 6. Nonoguchi H, Owada A, Kobayashi N, et al. Immu- ing of a reduction in the glomerular filtration nohistochemical localization of V2 vasopressin re- rate. Although these treatments decrease exces- ceptor along the nephron and functional role of luminal V2 receptor in terminal inner medullary col- sive water excretion to a great extent, patients lecting ducts. J Clin Invest. 1995;96:1768-78. with this therapy still can void 8 to 10 L/d. 7. Fushimi K, Sasaki S, Marumo F. Phosphorylation of During the past 10 years, different ap- serine 256 is required for cAMP- dependent regula- 262 A.J.M. Loonen et al

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