A Low Affinity Vasopressin V 2 -Receptor in Inherited Nephrogenic...

JOURNAL OF RECEPTOR RESEARCH, 12(3), 351-368 (1992)

A LOW AFFINITY VASOPRESSIN V2-RECEPTOR I N INHERITED

NEPHROGENIC DIABETES INSIPIDUS.

1 Heike Luzius, David A. Jans, Ernst-Gunther Grunbaum , Andreas M o r i t t ’ , Wolfgang Rascher‘ and Fa lk Fahrenholz*

Max-Planck-Inst i tut f u r Biophysik, Kennedyallee 70,

6000 F rank fu r t 70, FRG ’ Medizinische und Ger i ch t l i che V e t e r i n a r k l i n i k der

Justus-Liebig-Universitat, Frank fu r te rs t r . 126, D-6300 GieRen ‘ Unive rs i t a t sk l i n i kum Essen, Zentrum f u r Kinder und

Jugendmedizin, Hufelandstr . 55, D-4300 Essen, FRG

ABSTRACT

Congenital nephrogenic diabetes i n s i p i d u s (NDI) i s an X- l inked i n h e r i t e d d isorder character ized by rena l res is tance t o the a n t i d i u r e t i c hormonal ac t ion o f vasopressin. Thi s study describes the molecular bas is o f nephrogenic diabetes i ns ip idus i n a dog fami ly . Kidney membranes prepared from NDI-af fected male huskies were examined f o r vasopressin b ind ing and response. Compared t o membranes from unaffected canines, those from the kidney i nne r medulla o f NDI-dogs possessed normal VZ-receptor numbers, bu t w i t h 10 - fo ld lower a f f i n i t y f o r [ Argn] vasopressin (AVP). Adenylate cyclase s t imu la t i on by AVP i n con t ras t t o t h a t by f o r s k o l i n o r GTP-analogues was s i m i l a r l y reduced i n a dose responsive manner. The NDI-affected dogs showed a n t i d i u r e t i c responses t o very h igh doses o f V2-speci f ic agonists, cons is ten t w i t h t h e i r possessing V2-receptors o f lower a f f i n i t y . Prolonged treatment w i t h V2-agonists, 1-deamino [ D-Arg8] VP (dDAVP) and 1-deamino [ ValL,Sar7] AVP (dVSAVP), rendered the NDI-affected dogs near normal i n terms o f water i n take and u r i n e osmola l i t y .

Copyright 0 1992 by Marcel Dekker, Inc.

352 LUZIUS ET AL.

INTRODUCTION

The neurohypophyseal nonapept ide vasopress in e x e r t s i t s

i m p o r t a n t p h y s i o l o g i c a l e f f e c t s th rough two d i s t i n c t recep to rs , t h e V,- and V2-subtypes. The vascul a r / h e p a t i c V1 - recep to r , which

couples t o i n o s i t o l t r i s p h o s p h a t e metabolism, i s i n v o l v e d i n t h e

r e g u l a t i o n o f v a s o c o n s t r i c t o r and g l y c o g e n o l y t i c responses;

whereas t h e r e n a l V2-receptor mediates t h e a n t i d i u r e t i c response

t o vasopress in th rough c o u p l i n g t o adeny la te c y c l a s e a c t i v a t i o n

( 1 ) . Congeni ta l N D I i s an X - l i n k e d r e c e s s i v e d i s o r d e r brought

about by non-responsiveness o f t h e r e n a l t u b u l a r c e l l s t o

vasopress in (2-5) r e s u l t i n g i n t h e symptoms o f p o l y u r i a and

p o l y d i p s i a . The d i s o r d e r m a n i f e s t s i t s e l f as a severe d isease

e a r l y i n i n f a n c y and can r e s u l t i n mental r e t a r d a t i o n due t o b r a i n dehydra t i on .

The mo lecu la r b a s i s u n d e r l y i n g N D I has n o t y e t been

e luc ida ted . I n p a r t i c u l a r , t h e ques t i on as t o whether t h e

vasopress in r e c e p t o r - s i g n a l t r a n s d u c t i o n system i s a f f e c t e d i n

p a t i e n t s w i t h N D I remains unanswered. Recent s t u d i e s w i t h a

s p e c i f i c V2-agonist i m p l y t h e presence o f d e f e c t i v e e x t r a r e n a l

V2-receptors i n human p a t i e n t s w i t h N D I (6). Stud ies u s i n g a

mouse model system ( t h e D I +/+ mouse s t r a i n ) , suggest t h a t

congen i ta l ( b u t non-X- l inked) N D I can be caused by a l e s i o n i n r e n a l medul l a r y CAMP metabol i sm (7-9).

s t a t e water i n t a k e , u r i n e o u t p u t and u r i ne osmol a1 i t y ( l o ) ,

enab l i ng d i a g n o s i s o f f a m i l i a l N D I , which has p r e v i o u s l y been

desc r ibed i n t h e dog (11 ) . The female p a r e n t c o u l d be diagnosed

as a c a r r i e r o f t h e N D I gene, r e s p o n s i b l e f o r t h r e e NDI -a f fec ted

male pups and a f o u r t h u n a f f e c t e d male pup. The t h r e e N D I pups

(Akimo, A lex and Asco) were c h a r a c t e r i z e d i n more d e t a i l , and

found t o show t h e t y p i c a l N D I symptoms o f f a i l u r e t o reduce u r i n e o u t p u t o r c o n c e n t r a t e u r i n e i n response t o wa te r d e p r i v a t i o n o r

t rea tmen t w i t h t h e neurohypophyseal nonapept ide hormone AVP -

Recen t l y we c h a r a c t e r i z e d a dog f a m i l y w i t h r e s p e c t t o s teady

INHERITED NEPHROGENIC DIABETES INSIPIDUS 353

instead, an ( abnormal 1 increase i n p l asma osmol a1 i t y was

exh ib i t ed (10). The NDI-af fected dogs resembled normal canines i n

t h e i r r a p i d response t o AVP i n terms o f increased blood pressure

and reduced heart r a t e (E.G. Grunbaum, personal communication),

cons is ten t w i t h o ther s tud ies showing t h a t human N D I pa t i en ts

have normal vascular V , - receptor responses (12, 13). This novel

animal model thus shows a phenotypic resemblance t o human

hered i ta ry NDI .

V2-receptor o f kidney membranes prepared from NDI-huskies

and Alex) and normal canines. The V2-receptor o f NDI-dogs

possessed a 10 - fo ld lower b ind ing a f f i n i t y f o r l igand.

I n t h i s study we repo r t biochemical cha rac te r i za t i on o f the

Half-maximal s t imu la t i on o f adenylate cyclase a c t i v i t y i n kidney

membranes o f NDI-af fected huskies was induced a t about 10 - fo ld

higher concentrat ions o f vasopressin than i n membranes from

normal dogs. I n cont ras t , s t imu la t i on o f cyclase by f o r s k o l i n ,

NaF o r non-hydrolyzable GTP analogues was comparable f o r

membranes from normal and N D I canines, imp ly ing normal adenyl ate

cyclase and G-protein f u n c t i o n i n the NDI-huskies. This

in fo rmat ion was used f o r i n v i vo experiments, where treatment o f

the NDI-huskies w i t h high concentrat ions o f V2-receptor-speci f ic

agonists e f fec ted an almost complete reversa l o f the N D I

phenotype w i t h respect t o water i n take and u r i n e osmola l i t y . This

study represents a d i r e c t demonstration o f an a l te red V2-receptor

i n a new animal model f o r nephrogenic diabetes i ns ip idus .

MATERIAL AND METHODS

The l i t t e r o f t h e female husky dog which was diagnosed as N D I

c a r r i e r consisted o f t h ree male dogs w i t h N D I (Asco, Akimo and

Alex), one unaf fec ted male, one unaffected female dog and one

c a r r i e r female dog. The pedigree and the desc r ip t i on o f the

phenotype has been presented (10). I n v i vo treatments were

354 LUZIUS ET AL.

c a r r i e d out on two male N D I huskies (Alex and ASCO, bo th 2 years o ld ) and two normal canines (Beagle 323 and 327, both 2 years

o ld ) . I n v i t r o experiments were c a r r i e d ou t using rena l plasma membranes from two male NDI-huskies (Akimo, 7 months o l d and Alex, 2 years o l d ) and two normal canines (German sheepdog, 2 and 1/2 months o l d male and Bernese mountain "Sennen" dog, 7 months o l d male).

Mater i a1 s

p rev ious ly (14). 1-Deamino [D-Arg ] VP (dDAVP) was obtained from D r . G. Toth, Medical Un ivers i ty , Szeged. For i n v i vo studies, dDAVP was purchased as MinirenR from Fer r ing-Arzne imi t te l GmbH, K ie l , FRG. [ H IAVP (15 Ci/mrnol, 0.56 TBqImmol) was from Amersham. AVP was obtained from Bachem, (Bubendorf, Switzer land). 1-Isobutyl-2-methylxanthine (IBMX) was from Sigma. Creat ine kinase, phosphocreatine and the GTP-analogue Gpp(NH)p were from Boehringer Mannheim. Fo rsko l i n was obtained from Calbiochem.

4 7 1-Deamino [Val ,Sar 1 AVP (dVSAVP) was prepared as described 8

P1 asma membrane preparat ions Renal plasma membranes were prepared from two kidneys o f

NDI-huskies o r normal canines. Dogs were s a c r i f i c e d by intravenous i n j e c t i o n o f an overdose th iopen ta l sodium (100 mglkg). Kidneys were removed by an abdominal access and f rozen i n l i q u i d ni t rogen. Membranes were prepared using a mod i f i ca t i on o f the procedure o f Iyengar e t a1 ., (15). A l l steps were c a r r i e d ou t a t 4°C. The inne r medulla was dissected from t h e kidneys, dropped i n t o 0.9 % NaC1, 1mM EDTA (pH 7,4), 10 p g h l t r y p s i n i n h i b i t o r and washed 4 times. The t i s s u e was then washed once i n 0.25 M saccharose, 5 mM Hepps (pH 7.71, 1 mM EDTA, 10 pg/ml t r y p s i n i n h i b i t o r (homogenization b u f f e r ) and homogenized using fou r 5-s burs ts a t f u l l speed o f a Waring blender and f o u r strokes w i t h a Dounce homogenizer d r i ven a t 1500 rpm by a Potter-Elvejhem- homogenizer. The homogenate was then f i l t e r e d through a

fine-meshed sieve. The f i n a l homogenate was spun down a t 600 xg f o r 10 min t o remove c e l l debr is and nuc le i . The 600 xg supernatant was cent r i fuged a t 48.000 xg f o r 30 min t o y i e l d a 48.000 xg membrane f rac t i on , resuspended i n the above homogenization b u f f e r (w i thout t r y p s i n i n h i b i t o r ) . 80-90 % o f t he t o t a l i 3 H ] AVP b ind ing was r o u t i n e l y recovered i n the 48.000 xg p e l l e t . Membranes were stored as f rozen a l i quo ts a t -70°C. No change i n [ 3H1 AVP b ind ing proper t ies o f membranes between

binding t e s t s performed a f t e r d i f f e r e n t times o f storage was found.

Receptor b ind ing assays Binding tes ts and compet i t ion b ind ing experiments were

performed w i t h 100 pg membranes per t e s t as described previously (16). Membranes were incubated w i t h var ious concentrat ions o f [ 3 H 1 AVP i n t h e absence o r presence (non-spec i f i c b inding) o f a 100-fold higher concentrat ion o f AVP f o r 20 min a t 30°C. I n compet i t ion experiments, membranes were equ i l i b ra ted w i t h a f i x e d concentrat ion o f [ 3H1 AVP (10-8M) and vary ing concentrat ions o f the non- label led l igand. Unbound l i gand was then removed by r a p i d

f i l t r a t i o n over ce l l u lose acetate f i l t e r s (0.22 pm) a t 4"C, and washing. F i l t e r s were t rea ted w i t h methylcel losolve and counted by l i q u i d s c i n t i l l a t i o n (16). Binding parameters were determined using a weighted non- l inear least-squares f i t t o l o g i s t i c curves as described (16).

Adenyl ate cyc l ase assay

hormone and other agonists was determined w i t h 50 pg membrane per t e s t i n a f i n a l volume o f 100 p l . Adenylate cyclase a c t i v i t y was measured a t 37°C f o r 15 min i n a medium conta in ing 25 rnM bis-Tr is/HCl pH 8.3, 3 mM MgC12, 1.4 mM EDTA, 0.2 mM IBMX, 1 mM

ATP, 30 U/m l c rea t i ne kinase and 20 mM phosphocreatin (16). The reac t i on was stopped by adding 25 p l 1 N H C l . A f t e r

Adenylate cyclase basal a c t i v i t y and a c t i v i t y induced by

LUZIUS ET AL. 3 56

neu t ra l i za t i on , CAMP l e v e l s were determined using the compet i t ive

b ind ing assay k i t f rom Amersham, according t o Tovey e t a l . (17).

I n v i vo experiments

(Alex and Asco) o f t he husky fam i l y were used, w i t h two normal

beagles (8323 and B327) as cont ro ls . For short- term treatments,

V2-agoni s t (dDAVP and dVSAVP) admin is t ra t ion was performed by

intravenous i n f u s i o n o f 1 U/kg body weight w i t h i n 30 minutes. 1 U

dDAVP i s equ iva len t t o 0.96 pg and 1 U dVSAVP t o 1.81 pg (14) .

Ur ine was co l l ec ted a f t e r 1 and 2 hours. Ur ine osmo la l i t y was

determined by standard procedures (13, 18, 19). For long-term

treatments, V2-agonist (dDAVP and dVSAVP) admini s t r a t i o n was

performed by intramuscular i n j e c t i o n o f 0.33 U/kg body weight 3

times per day. Water i n take and u r i n e osmola la i ty a f t e r the dDAVP

and dVSAVP app l i ca t i ons were determined a f t e r 9 and 6 days

respec t ive ly .

For the var ious treatment p ro toco ls two NDI-affected male dogs

RESULTS

I n order t o t e s t the p o s s i b i l i t y t h a t impaired V2-receptor

f unc t i on could be responsible f o r the N D I phenotype, membranes

were prepared from the kidney inner medulla o f NDI-affected

huskies and compared t o those o f normal canines. Scatchard

analysis and curve f i t t i n g ana lys is o f b ind ing experiments w i t h

13H1 AVP (F ig . 1, Table 1) revealed t h a t the huskies w i t h N D I

symptoms and normal canines possessed comparable dens i t i es (about

0.2 pmol/mg) o f one homogeneous popu la t ion o f rena l V2-receptors,

but t h a t t he V2-receptors from the NDI-affected huskies were o f

10 - fo ld lower a f f i n i t y f o r t he a n t i d i u r e t i c hormone. An apparent d i ssoc ia t i on constant KD o f about 1 x lO-’M was

determined by Scatchard ana lys is f o r b ind ing o f 1 3 H l AVP t o membranes prepared from kidney i nne r medulla o f two normal

canines, which i s i n the range described f o r t he rena l

INHERITED NEPHROGENIC DIABETES I N S I P I D U S 357

- 0.24

F z 5 0.20

- Q 0.1 6

5 0.08 6

0.04 L

-1 2 -10 - 8 -6 log concentration free PH]AVP (M)

Fig . 1. from an N D I husky (Akimo) (0-0) o r a normal German sheepdog

(0 - 0 ) . Membranes were prepared from kidney medulla

f o l l o w i n g the method o f Iyengar e t a l . (15) . Incubat ions were

performed w i t h 100 vg of membranes, and increas ing concentrat ions

o f [ 3Hf AVP i n t h e absence o r presence (non-spec i f i c b ind ing) o f

a 100 f o l d excess o f AVP f o r 20 min a t 30°C. Unbound l i gand was

then removed by f i l t r a t i o n and washing, f i l t e r s counted by l i q u i d

s c i n t i l l a t i o n and b ind ing curves f i t t e d as descr ibed prev ious ly

(16). Data are the mean o f an experiment performed i n t r i p l i c a t e .

The i n s e t i s a Scatchard p l o t o f the da ta (see Table 1 ) .

Spec i f i c b ind ing o f [ 3H1AVP t o kidney membranes der ived

or 13H

-’ 1 .

-’ (1

or I 3

pi i ca

TABLE 2

Competit ion b ind ing ana lys is o f V 2 - r C p t o r i n m

from a normal and a NDI-affected dog w i t h AVP and two V2-agonists.

mbr n S

Parameter Bernese mountain dog

K~ f o r AVP (MI* (1.4 - t 0 . 2 ) ~ 1 0 - ~ (2.7 - + 1 . 5 ) ~ 1 0 - ~

KD f o r dDAVP(M)* (1.7 2 0 . 3 ) ~ 1 0 - ~ (5 .5 - t 3 . 1 ) ~ 1 0 - ~ KD f o r dVSAVP(M)* (8.6 2 0 . 3 ) ~ 1 0 - ’ ~ (1.2 - + 0 . 6 ) ~ 1 0 - ~

* The KD-values f o r AVP, dDAVP and dVSAVP were determined by compet i t ive

b ind ing experiments w i t h [ H ] AVP. The KD-values were determined using

a weighted non- l inear l e a s t squares f i t t o l o g i s t i c curves, as described

(6 ) . Resul ts represent the means 2 SD f o r a s ing le experiment performed i n t r i p l i c a t e .

V2-receptor o f o ther mammalian species (1, 16). I n contrast , a KD-value o f about 1 x 10-8M was determined f o r two NDI-affected

huskies (Table 1 ) .

agonists 1-deamino [ D-Arg 1 VP (dDAVP), and 1-deamino 1Val ,Sar ] AVP (dVSAVP) (14) confirmed the lower a f f i n i t y o f the rena l

V2-receptor i n membranes der ived from NDI-af fected canines f o r

l igands (Table 2).

The a f f i n i t y f o r dDAVP was reduced by a f a c t o r o f about 30,

the a f f i n i t y of dVSAVP by a f a c t o r of about 10. The l a t t e r V2-agonist r e t a i n s the highest a f f i n i t y o f t he l igands tes ted f o r t he V2 rena l receptor of bo th normal and NDI-affected canines.

Competit ion b ind ing s tud ies w i t h I 3 H 1 AVP and the V2-speci f ic 8 4 7

360 LUZIUS ET AL.

-12 -11 -10 -9 -8 -7 -6 -5 log [AVP] (MI

Fig . 2. Concentrat ion dependence o f adenylate cyclase a c t i v a t i o n

by AVP i n kidney membranes from an N D I husky (Akimo) (0- 0 ) o r a normal German sheepdog (0- 0 ) . Membranes were

incubated w i t h inc reas ing concentrat ions o f l igand, and adenylate

cyclase a c t i v i t y was measured as described prev ious ly (16, 17) .

Results are expressed as a f r a c t i o n o f the maximal a c t i v i t y (amax). Curves were f i t t e d as described prev ious ly (16). Results

are shown f o r an experiment, performed i n t r i p l i c a t e , f o r which the SD was between 3 and 20 % o f the mean.

The d i f f e rence i n the V2-receptor a f f i n i t y f o r hormone between N D I and normal canines was r e f l e c t e d i n t h e concentrat ion

dependence o f AVP-medi ated adenyl ate cyc l ase s t imu la t i on (Fig. 2) . The concentrat ion o f AVP requ i red t o g i ve a h a l f -

maximal response (KA) was 10- fo ld higher f o r membranes from

NDI-huskies (KA = 3.5 x 10-8M) than f o r membranes from normal

canines (KA = 3.5 x although both membranes gave r i s e t o a s imi 1 a r maximal response. Responses t o the adenyl ate cyc l ase

ac t i va to r f o r s k o l i n and the non-hydrolyzable GTP-analogue

c E \ ul E n x a

al 0 c

0 b a s a l FSK NaF GPPNHP ( 1 0 - ~ M I ( I O - ~ M I ( I O - ~ M I

F i g . 3. Adenylate c y c l a s e a c t i v a t i o n by non- recep to r mediated

agon is t s i n k idney membranes f r o m an N D I husky (Akimo) (

a normal German sheepdog ( 0 1. Membranes (50 pg) prepared as on legend t o F i g . 1, were i ncuba ted w i t h no a d d i t i o n (basa l

a c t i v i t y ) o r 10-5M f o r s k o l i n (FSK), 10-2M NaF o r 10-4M Gpp(NH)p.

Resu l t s a r e shown f o r an exper iment performed i n t r i p l i c a t e w i t h

t h e SD i n d i c a t e d .

Gpp(NH)p i n membranes f rom NDI -a f fec ted canines were s i m i l a r t o

o r somewhat h i g h e r t h a n those f r o m normal canines ( F i g . 31 , c o n s i s t e n t w i t h p r e v i o u s conc lus ions t h a t G-p ro te ins and

adeny la te c y c l a s e a r e f u n c t i o n a l i n s u b j e c t s w i t h N D I (4, 6).

That NDI-af fected husk ies possessed approx ima te l y normal

numbers of l o w - a f f i n i t y b u t f u n c t i o n a l V - r e c e p t o r s i m p l i e d t h a t 2

362 LUZIUS ET AL.

TABLE 3

Urine osmola l i t y responses t o in fus ion of V2-speci f ic analogues.

* Par m e t e r Untreated dDAVP

l h 2h

470 560

390 460

240 1080

980 960

dVSAVP

385 480

360 390

B 323 91 0 1100 980

B 327 560 1200 1100

* Un i t s are i n mosmol/kg H20. V2-agonist admin is t ra t ion was performed by intravenous i n f u s i o n o f lU/kg body weight w i t h i n 30

minutes.

canines w i t h N D I would respond t o the admin is t ra t ion o f very high hormone concentrat ions, i n p a r t i c u l a r o f V2-spec i f i c agonists which do n o t pe r tu rb the vascular system v i a t h e V,-receptor. Short-term p a r t i a l responses t o both dDAVP and dVSAVP cou ld be demonstrated i n normal and NDI-affected canines, whereby the NDI huskies showed increas ing u r ine osmola l i t y 1 and 2 hours a f t e r

TABLE 4

The e f f e c t o f longterm treatment o f NDI-affected dogs w i t h V2-spec i f i c analogues.

Water Intake (m1/24h/kg body weight 1

Untreated dDAVP* dVSAVP* (9d) (6d)

A1 ex 212.5 61.1 52.2

Asco 152.1 54.2 50.4

Urine o s m l a1 i ty (mosmol/kg H20)

A1 ex 75 100 770

Asco 110 1180 830

V2-agonist admin is t ra t ion was performed by intramuscular

i n j e c t i o n o f 0.33 U/kg body weight 3 t imes per day.

admin is t ra t ion o f e i t h e r one o f t he V2-agonists (Table 3 ) and reduced u r i n e output 1 hour a f t e r admin i s t ra t i on o f t he dVSAVP ( r e s u l t no t shown), approximating the phenotype o f the untreated normal dogs t o some ex ten t .

This response t o treatment w i t h V2-agonists was f u r t h e r

i nves t i ga ted by long-term admin is t ra t ion o f very high doses f o r 9 and 6 days, respec t i ve l y ( 1 U/kg body weight/day) of dDAVP and

364 LUZIUS ET AL.

dVSAVP. Treated huskies, p a r t i c u l a r l y those t rea ted w i t h dVSAVP, were almost i d e n t i c a l t o untreated normal canines w i t h respect t o

water intake, and u r i n e osmo la l i t y (Table 4 ) . The grea ter

e f fec t i veness o f dVSAVP, compared t o dDAVP, i n revers ing the N D I

phenotype could be a t t r i b u t e d t o i t s somewhat higher V2-receptor

a f f i n i t y (Table 2 ) .

DISCUSSION

This study represents a demonstration o f an a l te red

V2-receptor i n a new animal model t h a t phenotyp ica l l y resembles

human h e r i d i t a r y nephrogenic diabetes i ns ip idus . The N O 1 phenotype i n the dog family studied appears t o be the d i r e c t

r e s u l t o f reduced V2-receptor a f f i n i t y f o r l igand. Approximately

normal numbers o f receptors were present, which coup1 ed

f u n c t i o n a l l y t o adenylate cyclase upon vasopressin treatment. A t en - fo ld higher hormone concentrat ion, however, was requ i red i n

the case o f kidney membranes from NDI-affected dogs t o e f f e c t a

l eve l o f s t imu la t i on comparable t o t h a t i n con t ro l membranes,

consistent w i t h t h e reduced V2-receptor a f f i n i t y . I n cont ras t ,

adenylate cyclase s t imu la t i on i n response t o fo rsko l i n , NaF and

non-hydrolyzable GTP-analogues was comparable between membranes

from normal o r NDI-canines i n d i c a t i n g t h a t the NDI phenotype

could not be a t t r i b u t e d t o a l t e r e d adenylate cyclase o r G-protein

func t ion . Rather, the l e s i o n i n the NDI-huskies seemed t o res ide

i n t h e V2-receptor i t s e l f . A r o l e f o r V2-receptors i n clearance

o f vasopressin and analogues w i t h high V2-receptor a f f i n i t y has

been suggested by e a r l i e r studies (20, 21) and a recent study

( 2 2 ) w i t h dogs. Our r e s u l t s were cons is ten t w i t h t h i s i n t h a t t he

NDI-affected dogs showed higher AVP concentrat ions fo l l ow ing

intravenous AVP admin is t ra t ion concomitant w i t h t h e i r low

a f f i n i t y rena l V2-receptors (10).

The r e s u l t s o f t h i s study are cons is ten t w i t h repo r t s

concerning human NDI-patients (6) where a pre-CAMP V2-receptor

INHERITED NEPHROGENIC DIABETES I r I S I P I D U S 365

d e f e c t i v e mechanism has been proposed. Recent genomic mapping

(23) and b iochemica l d a t a u s i n g somatic c e l l h y b r i d d e r i v a t i v e s

c a r r y i n g smal l human X-chromosome f ragments (24) i n d i c a t e t h a t

t h e human NDI l o c u s comaps w i t h , and v e r y l i k e l y encodes t h e

s t r u c t u r a l gene f o r t h e V2-receptor . Most forms o f human N D I

would appear t o be more severe t h a n t h a t i n t h e can ine model

desc r ibed here. W h i l s t t h e dogs wi th NDI respond a f t e r

d e h y d r a t i o n t o h i g h doses o f vasopress in t o a smal l e x t e n t i n terms o f u r i n e c o n c e n t r a t i o n responses ( l o ) , most human p a t i e n t s

w i t h N D I f a i l t o do so. We show he re t h a t t h e NDI-phenotype i n t h e dog f a m i l y c o u l d be

reve rsed by p ro longed t rea tmen t (6-9d) w i t h h i g h doses o f

V 2 - s p e c i f i c agon is t s . The dDAVP analogue, commonly used i n t h e

t rea tmen t o f human c e n t r a l D I p a t i e n t s and used w i t h o n l y p a r t i a l

success i n some N D I p a t i e n t s (12, 251, was e f f e c t i v e i n t r e a t i n g

t h e NDI husk ies as desc r ibed here.

Treatment o f t h e NDI -a f fec ted dogs w i t h t h e dVSAVP analogue was

p a r t i c u l a r y e f f i c a c i o u s , r e s u l t i n g a f t e r 6d t rea tmen t i n va lues

f o r wa te r i n t a k e and u r i n e o s m o l a l i t y which were comp le te l y

comparable t o those o f u n t r e a t e d normal canines ( T a b l e 4). T h i s

e f f e c t c o u l d be r e l a t e d t o i t s somewhat h i g h e r a f f i n i t y f o r t h e

V2-receptor .

demonstrate t h a t h e r e d i t a r y N D I can be t h e d i r e c t r e s u l t o f a

m u t a t i o n a f f e c t i n g t h e a f f i n i t y o f t h e V2-receptor f o r l i g a n d . I t w i l l c l e a r l y be o f g r e a t i n t e r e s t t o determine t h e amino a c i d

s u b s t i t u t i o n r e s p o n s i b l e f o r t h e V2-receptor m u t a t i o n desc r ibed

h e r e i n a dog f a m i l y , s i n c e t h i s may a s s i s t i n d e f i n i n g t h e

r e c e p t o r l i g a n d b i n d i n g s i t e .

The i n v i v o and i n v i t r o s t u d i e s i n t h i s new animal model

ACKNOWLEDGEMENTS

P r o f . Z. Grzonka ( U n i v e r s i t y Gdansk, Poland) i s thanked f o r t h e

V2-agonist, dVSAVP, as i s D r . G. To th ( U n i v e r s i t y Szeged,

3 66 LUZIUS ET AL.

Hungary) f o r dDAVP. P a t r i c i a Jans i s acknowledged f o r inva luab le

techn ica l assistance and H i l t r u n Mu l le r f o r t y p i n g the manuscript. An essent ia l p a r t o f t h i s work belongs t o the Ph.D. thes i s of H.L. ( U n i v e r s i t a t F rank fu r t ) . This work was supported by a grant o f t he Deutsche Forschungsgemeinschaft t o F.F.

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