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Interaction of intrarenal adenosine and angiotensin II in kidney
vascular resistance
Marth la
Introduction
The regulation of renal blood flow, glomerular capillary
pressure and glomerular hemodynamics is under the
control of the tubuloglomerular feedback mechanism,
an intrinsic mechanism of the kidney [1,2]. This mech-
anism adjusts the tone of the afferent and efferent
arterioles according to the sodium load sensed by the
macula densa cells. The resistance of the arterioles is
affected by several vasoactive compounds that can
function as mediators or modulators of the vascular
tone, such as angiotensin II (AngII) and adenosine
(ADO) [3]. This review will focus in the intrinsic
mechanism involved in the ADO-AngII, interaction,
a recognized phenomenon described in 1979 [4], that
continu
cited in
on the
Regulation of vascular tone
The essential event that induces vasoconstriction
involves cytosolic Ca2þ; however there are many mech-
anisms that increase cytosolic calcium, which in turn
activate calmodulin andmyosin light chain kinase. These
mechanisms can be separated into those involving
increases in cellular entry of Ca2þ, via membrane chan-
nels, and those primarily involving release of Ca2þ from
intracellular stores. Of great importance is the role of
voltage-dependent Ca2þ channels in regulating vascular
smooth muscle tone primarily in preglomerular arterioles,
and intracellular release in efferent arterioles, as calcium
is the main effector of the autoregulatory response [5,6].
aDepartme
Cardiologı´a
Fedral and
Medicina U
Correspond
Departmen
Cardiologı´a
Mexico Cit
Tel: +5255
e-mail: mar
Current O
Hypertens
II (
tio
acti
m b
tha
in
vas
log
mp
pr
her
The ADO-metabolizing enzymes have become important regulators of the effects of
ADO on the tone of the afferent and efferent arterioles. As AngII is able to increase
de-novo renal ADO content through decrease of ADO-metabolizing enzymes,
accumulation of ADO induces downregulation of ADO A2 receptor population without
modifying ADO A1 receptor, thereby enhancing the constrictive effects of AngII in the
renal vasculature.
Keywords
adenosine, adenosine deaminase, adenosine receptors, angiotensin II, angiotensin II
AT1 receptors, ecto-50-nucleotidase
Curr Opin Nephrol Hypertens 18:63–67
� 2009 Wolters Kluwer Health | Lippincott Williams & Wilkins
1062-4821
1062-482
es under investigation. Some old papers are
order of provide an appropriate background
field.
A predominant effect of voltage Ca2þ channels has
been observed on preglomerular arterioles, thus calcium
channel blockers vasodilate the afferent arterioles, having
1 � 2009 Wolters Kluwer Health | Lippincott Williams & Wilkins DOI:10.1097/MNH.0b013e32831cf5d3
a Francoa, Oscar Pe´rez-Mende´za and F
nt of Nephrology, Instituto Nacional de
‘Ignacio Cha´vez’, Me´xico City, Distrito
bDepartment of Pharmacology, Facultad de
ASLP, San Luis Potosı´, Mexico
ence to Martha Franco, MD, PhD,
t of Nephrology, Instituto Nacional de
‘Ignacio Cha´vez’, Juan Badiano No.1,
y, 14080 D.F., Mexico
573 6902; fax: +5255 573 7716;
thafranco@lycos.com
pinion in Nephrology and
ion 2009, 18:63–67
Purpose of the review
The adenosine–angiotensin
regulation of glomerular filtra
feedback. Although the inter
mechanisms of the synergis
understood.
Recent findings
Current evidence suggests
50-nucleotidase or ADO deam
play an important role in the
afferent arterioles when tubu
concentration induced by te
ADO receptors, leading to a
ADO receptors balance furt
and AngII.
Summary
ht © Lippincott Williams & Wilkins. Unauthorized
vio Martı´nezb
ADO-AngII) interaction plays an important role in the
n rate, vascular resistance and tubuloglomerular
on was described more than 30 years ago, the intrinsic
etween both autacoids remains incompletely
t ADO-metabolizing enzymes such as ecto-
ase, as well as enzymes that degrade ATP to adenosine,
oconstrictor signals sent from the macula densa to the
lomerular feedback is activated; increased ADO
oral infusion of AngII results in downregulation of A2
edominant effect of A1 receptors; the alteration in the
contributes to the synergic interaction between ADO
 reproduction of this article is prohibited.
Copyrigh
minimal effect on efferent arterioles. The observations
mentioned earlier suggest that Ca2þ influx through vol-
tage-gat
of affere
are mor
intracel
investig
channel
T-type
ent and
efferent
which a
Regula
Adenos
A1 ADO
tors (A2
the blo
aration,
respond
adenosi
trations
to contr
tors [10
dilation
significa
tor ant
A2a AD
vations
A1-indu
postglom
In this
mouse
10�11 to
fused a
the dia
tration r
an initia
of A2 re
agonist)
ADO r
more, t
constric
vasosod
ADO re
control
effect o
Recent
that AD
[13�]. T
Western
demons
recepto
of ADO receptors [14] has been reported in the
efferent arteriole.
he
it
on
os
n o
on
l.
ase
an
re
tio
d
3-m
A
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].
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ts
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. F
lin
er
ati
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64 Circulation and hemodynamics
ceptor, as well A2a and A2b ADO receptors in the
of afferent arteriolar tone shows a predominant
f A1 receptor [11].
studies in isolated efferent arterioles point out
O only induces vasodilation in these vessels
he expression of ADO receptors shown by
blotting, Northern blotting and RT-PCR have
trated abundant expression of A1 and A2b
rs in the afferent arteriole but no expression
tidic
resul
A2 in
olites
traen
[17�]
signa
block
indic
in th
ed channels is fairly important in the regulation
nt arteriolar tone. In contrast, efferent arterioles
e dependent on other mechanisms that induce
lular Ca2þ mobilization [5]. In this regard, the
ation of Ca2þ subtypes has revealed that L-type
s are only distributed in the afferent arteriole, and
and N-type channels are distributed in the affer-
efferent arterioles [5,7�]. Thus, afferent and
arterioles have distinct activation mechanisms,
llow different responses to several stimuli.
tion of vascular tone by adenosine
ine receptors mediate renal vasoconstriction via
receptors and vasodilation via A2 ADO recep-
a and A2b) [8,9]. It has been demonstrated in
od-perfused rat juxtamedullary nephron prep-
that both afferent and efferent arterioles
to adenosine with vasoconstriction at a low
ne concentration; however, at high concen-
the arteriolar diameters return to values similar
ol, indicating the activation of A2 ADO recep-
,11]. A1 ADO receptor blockade induces vaso-
in afferent and efferent arterioles, which is
ntly attenuated by the addition of an A2a recep-
agonist, suggesting the presence of A1 and
O receptors in both arterioles [10]; these obser-
suggest that A2a receptors may buffer the
ced vasoconstriction in the preglomerular and
erular arterioles [12�].
regard, recent studies in isolated and perfused
afferent arterioles have demonstrated that ADO
10�9mol/l reduces the diameter of microper-
fferent arterioles attached to the glomeruli, and
meter returns to control values at the concen-
ange between 10�8 to 10�4mol/l [11], suggesting
l activation of A1 receptors followed by activation
ceptors; in addition, in this study CPA (A1 ADO
induces vasoconstriction and CGS21680 (A2a
eceptor agonist) induces vasodilation. Further-
he use of a specific A1 antagonist prevents the
tion response and an A2a antagonist inhibits the
ilatory effect, thus the physiological role of the A1
On t
ioles
vasoc
of ph
bitio
the c
et a
incre
lated
was
deple
vente
an IP
as an
aboli
ADO
that
influ
nels
patch
the a
activ
medi
Reg
Most
recep
ance
impo
nami
[16��
Gaq
recep
pholi
pholi
inosi
C, wi
throuCalci
and
smoo
resul
t © Lippincott Williams & Wilkins. Unauthorized 
nt role in the control of glomerular hemody-
glomerular filtration rate and TG feedback
The AT1 receptor is coupled to Gaq/11,
13 and Gbg complexes. The stimulation of this
r results in activation of phospholipase C, phos-
se A2 and phospholipase D; activation of phos-
se C induces formation of diacylglycerol and
trisphosphate, which activates protein kinase
a consequent increase of free intracellular calcium
calcium efflux from the sarcoplasmic reticulum.
binds to calmodulin, activatesmyosin light chain
ances actin and myosin interaction, leading to
muscle contraction. Phospholipase D activation
in hydrolysis of phosphatidilcholine to phospha-
d, diacylglycerol, protein kinase C activation that
nmuscle contraction. Activation of phospholipase
ces liberation of arachidonic acid and its metab-
romboxan A2, leukotrienes and hydroxyeicosate-
acid, all of them with vasoconstrictor properties
or a complete review of other AngII effects on
g see reference [17�]. Furthermore, Ca2þ channel
s prevent the constriction induced by AngII,
ng that L-type Ca2þ channels are only present
ferent vessels and T-type Ca2þ channels regulate
contrary, in isolated and perfused afferent arter-
has been demonstrated that adenosine-induced
striction is mediated by Gi/Go-coupled activation
pholipase C. In this context, Gi-dependent inhi-
f adenylate cyclase seems to play a minor role in
strictive response [15]. In further studies, Hansen
[16��] demonstrated that ADO significantly
s the intracellular calcium concentration in iso-
d perfused mouse afferent arterioles; the calcium
leased from the sarcoplasmic reticulum, as
n of intracellular Ca2þ stores completely pre-
the constrictor response to ADO. In addition,
ediated pathway mediated the calcium release,
DO dose–response relationship is completely
d by a specific IP3 antagonist. Inhibition of the
duced vasoconstriction by nifedipine indicates
addition to the mechanisms mentioned earlier,
f calcium through voltage-dependent Ca2þ chan-
ntributes to maintain cytosolic calcium levels;
lamp experiments in this study demonstrated
vation of a depolarizing chloride current. The
n of protein kinase C was not involved in the
on of contraction induced by ADO [16��].
tion of vascular tone by angiotensin II
f the actions of AngII are mediated by type 1
rs (AT1), and regulate afferent and efferent resist-
a dose dependent manner; thus AngII plays an
reproduction of this article is prohibited.
Copyrig
afferent and efferent resistances. The role of T-type Ca2þ
channels on efferent arterioles may contribute to the
vasocon
Synerg
angiot
Conside
betwee
studies
the vas
extent
thus, A
effects
conditio
Of parti
in whic
to AngI
effects
carried
perform
follow t
strictor
the mo
recepto
zation
microva
isolated
applied
sitizatio
observe
arteriola
the con
have co
the AD
desensi
ent arte
10�4mo
was sig
without
30min
when N
in the A
with AD
AngII.
changes
ioles, b
transpo
fact, th
myosin
enhance
suggest
tation in
and ML
that the
not med ��
In addition, important evidence has been obtained from
gene-manipulated mice; in A1 ADO receptor deficient
, th
ns
res
An
sen
gs
ef
an
of
art
ga
atio
pin
ng
rth
ase
re
pha
ed
e afferent arterioles; this enzyme has the ability to
osp
rat
osp
ac
. T
��,
ns
iole
ot
be
co
.
ula
m
iot
ter
the
ion
ell
te
] t
te
s c
ng
nt
in
mi
r
rat
s
er
Angiotensin II–adenosine interaction in the kidney Franco et al. 65
iated by ADO receptors [20 ]. block
striction elicited by AngII [18].
ic interaction between adenosine and
ensin II
rable evidence suggests a synergic interaction
n AngII and ADO in the renal vessels. Elegant
have demonstrated in in-vivo experiments that
oconstriction caused by ADO depends on the
of activation of the renin–angiotensin system;
ngII depleted states decrease the constrictor
of ADO; in contrast, under AngII high activity
ns, the constrictor effects of ADO are larger [3].
cular importance are the cross-blockade studies,
h specific ADO blockers decrease the response
I as well as AngII blockers interference with the
of ADO or ADO A1 agonists [3]. Most studies
out in isolated afferent arterioles, as well as those
ed in the isolated juxtaglomerular preparation,
he same pattern. In afferent arterioles, vasocon-
effects are observed and the effect is higher in
st distal part of the vessel [1]. In addition, a
r-independent effect of ADO on the desensiti-
of AngII–induced contractions in the renal
sculature has been proposed. Lai et al. [19], in
and perfused afferent arterioles, successively
AngII for 2min on the bath side; a clear desen-
n of the AngII-induced contraction was
d. Addition of adenosine did not change the
r diameter; however, ADO treatment restored
tractile response to AngII. Patzak et al. [20��]
ntinued studying the mechanisms involved in
O restoration of AngII vasoconstriction after
tization; in this work isolated and perfused affer-
rioles were treated with ADO from 10�11 to
l/l, followed by AngII; the effect of this peptide
nificantly larger after ADO pretreatment than
pretreatment, and the effect remained after
of ADO pretreatment; this was not observed
6-cyclopentyladenosine was used; furthermore,
1 ADO receptor-deficient mice, pretreatment
O also increases the vasoconstrictor effect of
Additional studies have demonstrated no
in cytosolic calcium in ADO-pretreated arter-
ut the effect is inhibited by blocking the ADO
rt into the cells with nitrobenzyl thioinosine; in
e phosphorylation of MAP kinase as well as of
regulatory ligh-chain protein (MLC20) were
d with the ADO pretreatment. This study
s that the ADO effect depends on its transpor-
to the cells and phosphorylation of p38 MAPK
C20 in vascular smooth muscle cells, as well as
effect of ADO independent of calcium and it is
mice
respo
able
AT1
is ab
analo
In an
subst
tion
renal
in ele
form
clam
findi
In fu
ATP
back
phos
locat
in th
deph
gene
deph
the m
[25�]
29,30
respo
arter
the n
may
For a
[27�]
Reg
enzy
ang
II in
On
infus
as w
eleva
[34��
eleva
it wa
of A
conte
tion
ische
eithe
resto
value
ht © Lippincott Williams & Wilkins. Unauthorized
horylate ATP and ADP and may catalyze the
ion of AMP. In the NTPDase1-deficient mice
horylation of ATP by the enzyme is required for
ula densa-dependent regulation of vascular tone
he studies mentioned earlier [25�,26,27�,28,
31] point to ADO as the vasoactive compound
ible for the contraction present in the afferent
, during the activation of TGF and support
ion that changes in ADO-metabolizing enzymes
involved in the ADO-AngII interaction [27�].
mprehensive review on this topic see reference
tion of adenosine-metabolizing
es and adenosine receptors by
ensin II in the adenosine–angiotensin
action
basis of the evidence that AngII temporal
induces marked renal vasoconstriction [32],
as the fact that interstitial AngII is strikingly
d [33] under these conditions, Franco et al.
ested the hypothesis that AngII was able to
the concentrations of intrarenal ADO. Indeed,
learly demonstrated that the temporal infusion
II was able to elevate interstitial and tissue
of ADO [34��]. In this regard, the vasoconstric-
duced by AngII suggests that AngII-induced
a leads to de-novo formation of ADO, causing
additive or modulated vasoconstriction. The
ion of glomerular hemodynamics to near-normal
by an acute infusion of a specific ADO A1
(8-cyclopentyl-1,3-dipropylxanthine, DPCPX)
e TGF is completely inhibited, and the renal
e to AngII is significantly reduced [21]. Compar-
ults have been obtained in mice with deletions of
gII receptors or ADO-converting enzyme: TGF
t in these animals and the response to ADO
is markedly diminished [22,23].
fort to identify the mediatorof the TGF signal,
tial evidence has been obtained of the participa-
ADO-metabolizing enzymes in the regulation of
eriole vascular tone; initially, Thomson et al. [24],
nt micropuncture studies in rats, prevented ADO
n by blockade of 50-nucleotidase (50ND) or by
g ADO activity at the single nephron level, this
strongly suggesting ADO as themediator of TGF.
er experiments in the ecto-50ND [23] and ecto-
deficient mice [25�], the tubuloglomerular fee-
sponse is significantly reduced. Nucleoside tri-
te diphosphohydrolase (NTPDase1) has been
in the glomeruli, in the renal vasculature and
 reproduction of this article is prohibited.
Copyrigh
suggests that the increased local renal ADO concen-
tration interacts with AngII. In addition, AngII induced
a signifi
activity
mRNA
tration
recepto
strictor
Regula
enzym
oxide
Some st
associat
ecto-50ND activity [36,37] This is something unexpected
as high
decreas
acute ex
elevatio
effect o
compen
increasi
Further
inhibits
nitric ox
howeve
model
of nitra
nitric o
free rad
and thr
is possi
occur [3
not infl
previou
needed
synergi
action u
effects
metabo
Conclu
Recent
enzyme
centrati
the alte
important role in the ADO-AngII interaction. The renal
vasocon
formati
of ADO
Change
kidney
that me
effects; the alteration in ADO receptors further contrib-
utes to the synergic interaction between ADO and
I.
I A
e
r m
no
ork
al C
re
of p
ighl
spe
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nal
Lite
var
icroc
ll PD
03;
einh
giot
:F2
ielm
an
ysio
var
e re
var
mod
yas
col
udy
ts t
Ca
les.
llon
v 2
scho
ysio
shiy
cept
14.
i EY
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06;
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terio
ns 2
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tion
ract
t art
n Y, Garvin JL, Liu R, Carretero OA. Possible mechanism of efferent
teriole (ef-Ar) tubuloglomerular feedback. Kidney Int 2007; 71:861–
6.
udy
release, wh
efferent art
epto
ckso
eglo
nse
nstr
rfus
65.
66 Circulation and hemodynamics
striction induced by AngII leads to de-novo
on of ADO through a decrease in the activity
deaminase or, possibly, by increasing 50ND.
s in the ADO milieu induced by AngII in the
results in an unbalance between ADO receptors
diate vasodilation (A2) and vasoconstrictor (A1)
A1 rec
14 Ja
pr
15 Ha
co
pe
24
NaCl diet induces volume expansion, as well as a
e in renin release and AngII production, at least in
periments. In this regard, it is possible that AngII
n for a long term could have a direct regulatory
n the enzyme or maybe 50ND may increase as a
satory mechanism in chronic high NaCl states,
ng ADO production to regulate TGF.
more, it has been suggested that nitric oxide
50ND in the kidney [37,38]. In acute studies,
ide increases to counteract the effect of AngII,
r, in chronic states as in the Ang II-infused
we have demonstrated that urinary excretion
tes falls to near zero at day 14, indicating that
xide is consumed by the production of oxygen
ical species generated by the AngII infusion
ough the NADPH pathway [32]; in addition, it
ble that nitrosylation rather than nitration may
7], thus the consumption of nitric oxide would
uence 50ND in the AngII-infused model as
sly demonstrated [32]. Further studies will be
to clarify the mechanisms involved in the
c interaction between ADO and AngII inter-
nder chronic elevation of AngII, as well as the
of NaCl and nitric oxide upon the ADO
lizing enzymes.
sion
studies show that the ADO-metabolizing
s participate in the regulation of adenosine con-
on in the kidney and tubuloglomerular feedback;
ration of ADO-metabolizing enzymes plays an
Additio
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This st
cant decrease in membrane ADO deaminase
, as well as downregulation of protein and
of the enzyme. The elevated ADO concen-
induced a downregulation of the A2a ADO
rs [34��], which allows a predominant vasocon-
effect mediated by A1 ADO receptors.
tion of adenosine-metabolizing
es and adenosine by NaCl and nitric
in adenosine–angiotensin II interaction
udies have demonstrated that high NaCl diet is
ed with higher renal ADO content [35] or higher
AngI
AngI
as th
othe
Ack
This w
Nation
Refe
Papers
been h
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t © Lippincott Williams & Wilkins. Unauthorized 
suggests that increasing cell Ca2þ in the macula densa stimulates ATP
ich is hydrolyzed to adenosine, activating A2 ADO receptors in the
eriole and inducing vasodilation. In the afferent arteriole ADO activates
rs and induces vasoconstriction.
n EK, Zhu C, Tofovic SP. Expression of adenosine receptors in the
merular microcirculation. Am J Physiol 2002; 283:F41–51.
n PB, Castrop H, Briggs J, Schnermann J. Adenosine induces vaso-
iction through Gi-dependent activation of phospholipase C in isolated
ed afferent arterioles of mice. J Am Soc Nephrol 2003; 14:2457–
In addition, independent pathways of ADO or
T1 receptors begin to be investigated, as well
regulation of ADO-metabolizing enzymes by
ediators.
wledgements
was supported by Grant 79661 (to M. Franco) from the
ouncil of Science and Technology (CONACYT), Mexico.
nces and recommended reading
articular interest, published within the annual period of review, have
ighted as:
cial interest
standing interest
references related to this topic can also be found in the Current
rature section in this issue (p. 95).
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reproduction of this article is prohibited.
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16
��
Hansen PB, Friis UG, Uhrenholt TR, et al. Intracellular signaling pathways in
the vasoconstrictor responses of mouse afferent arterioles to adenosine. Acta
Physiol 2007; 191:89–97.
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ADO causes renal arteriolar constriction.
17
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20
��
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receptors and activate p38 MAP kinase.
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24 Thoms
tidase
298.
25
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 reproduction of this article is prohibited.
	Interaction of intrarenal adenosine and angiotensin II in kidney vascular™resistance
	Introduction
	Regulation of vascular tone
	Regulation of vascular tone by adenosine
	Regulation of vascular tone by angiotensin II
	Synergic interaction between adenosine and angiotensin II
	Regulation of adenosine-metabolizing enzymes and adenosine receptors by angiotensin II in the adenosine-angiotensin II interaction
	Regulation of adenosine-metabolizing enzymes and adenosine by NaCl and nitric oxide in adenosine-angiotensin II interaction
	Conclusion
	Acknowledgements
	References and recommended reading