Renal Artigo Tubuloglomerular feedback mechanisms in nephron segments

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Tubuloglomerular feedback mechanisms in nephron segments
beyo
Peter h
Introduction
One of the fascinating features of the kidney’s architec-
ture is that after emerging from Bowman’s capsule and
descending deep into the medulla, each tubule returns
to its parent glomerulus. This arrangement has always
fascinated scientists, and there was early speculation
that this particular association between tubule and vas-
cular elements might provide a framework for functional
coupling. On the basis of the vision of Guyton et al. [1],
experimental studies provided evidence that the salt
content in the distal nephron indeed regulates glomerular
filtration [2]. Although the molecular mechanisms of cell-
to-cell (tubuloglomerular) feedback signaling are still
debated, it is widely accepted that a paracrine effect of
a purinergic molecule, such as ATP or adenosine, is
responsible for the tubular signal-dependent regulation
of glomerular hemodynamics.
Anatomy of tubuloglomerular feedback
The macula densa plaque is a group of about 20 cells in
the tubular epithelium of the distal nephron at the site
where i
and affe
shiny a
a light microscope. It has been demonstrated that macula
densa cells exhibit markedly different morphologic and
physiologic properties than the rest of the tubular epi-
thelium. For instance, their smaller mitochondria are
more dispersed in the cytoplasm, and the basolateral
membrane is less invaginated than those of the thick
ascending limb cells. Macula densa cells are separated by
wide, lateral intercellular spaces that change in size with
alterations in luminal osmolality [3]. The apical mem-
brane of these cells is permeable to water and therefore
acts as a water-permeable window in the water-
impermeable thick ascending limb–distal tubule [4].
Also, these cells have lower sodium–potassium ATPase
activity than the adjacent tubular epithelial cells [5,6].
Barajas et al. [7] noted the presence of morphologically
distinct ‘perimacular cells’, which are macula densa-like
cells in the vicinity of the plaque but lack lateral inter-
cellular spaces. It is known that the region of anatomical
contact between distal nephron and glomerular vascu-
lature is not restricted to the macula densa plaque. It has
been reported that there is a frequent and often exten-
sive contact of the pre macula densa thick ascending limb
with the efferent arteriole. Also, in a large number of
aDivision o
Medical Un
South Caro
Laboratorie
Harbin Med
Pharmacy and Cardiology, 2nd Affiliated Hospital of
Harbin, Harbin, China
Correspond
Avenue, CR
Tel: +1 84
e-mail: pko
Current O
Hypertens
e r
the
Recent findings
on
cum
nd
din
Th
bu
le.
tom
g t
tio
na
–62
pinc
1062-482
t establishes contact with its parent glomerulus
rent arteriole. Its name derives from the dense,
ppearance of these cells when viewed under
nephrons, the connecting tubule establishes a contact
with the afferent arteriole, commonly with the one
supplying its parent glomerulus [7].
1 � 2009 Wolters Kluwer Health | Lippincott Williams & Wilkins DOI:10.1097/MNH.0b013e32831daf54
ence to Peter Komlosi, 173 Ashley
I 211, Charleston, SC 29425, USA
3 792 5350; fax: +1 843 792-5521;
mlosi@uab.edu
pinion in Nephrology and
ion 2009, 18:57–62
In addition to the classical c
afferent arteriole, there is ac
between the distal nephron a
terminal cortical thick ascen
connecting tubule segment.
and respond to changes in tu
the adjacent afferent arterio
Summary
There are multiple sites of ana
and the vasculature supplyin
regulation of glomerular filtra
Keywords
macula densa, renal hemody
Curr Opin Nephrol Hypertens 18:57
� 2009 Wolters Kluwer Health | Lip
1062-4821
nd the macula densa
Komlosia, Phillip D. Bella and Zhi-Ren Z
f Nephrology, Department of Medicine,
iversity of South Carolina, Charleston,
lina, USA, bState-Province Key
s of Biomedicine-Pharmaceutics of China,
ical University and cDepartments of
Purpose of review
To summarize recent evidenc
the macula densa in sensing
adjacent vasculature.
ht © Lippincott Williams & Wilkins. Unauthorized
anga,b,c
egarding the role of distal nephron segments other than
tubular environment and transmitting this signal to the
tact site between the macula densa plaque and the
ulating evidence suggesting a functional association
the vasculature at three distinct additional sites: at the
g limb, at the early distal tubule and also at the
e epithelial cells around the macula densa also sense
lar flow and salt content and may transmit this signal to
ical and functional contact between the distal nephron
he glomerulus, and these may contribute to the
n rate and renal hemodynamics.
mics, tubuloglomerular feedback
ott Williams & Wilkins
 reproduction of this article is prohibited.
Copyrigh
Althoug
and late
most im
ment an
transfer
lines of
efferent
fusate N
or limite
arteriole
densa-d
muscle
reported
[10��], t
ical asso
and com
associat
that occ
densa (F
Intrace
epithe
Change
cell vol
in tubu
studies suggested that elevations in [NaCl]L lead to
increases in macula densa cell volume, and it was pro-
d th
AT
ced
ndi
ph
nal
strated
ase
c
la
ce
di
s b
n t
lar
ho
l st
cap
) to
G
gra
nic
re
ho
ired
se
red
58 Circulation and hemodynamics
Figure 1 Scheme demonstrating the sites of anatomical and
functional contact between the distal nephron and the vascu-
lature supplying the glomerulus
1, cTAL–
Orange d
CNT, con
tubule; EA
incre
these
macu
their
ascen
It ha
ing i
meru
was s
smal
ular
ance
full T
retro
isoto
TGF
ionop
requ
relea
dent
2
EA
cTAL
1
EA; 2, macula densa–AA; 3, early DT–AA; 4, CNT–AA.
ots mark the perimacular oscillating cells. AA, afferent arteriole;
necting tubule; cTAL, cortical thick ascending limb; DT, distal
, efferent arteriole.
pose
late
indu
tagla
using
lumi
AA
CNT
3
4
DT
t © Lippincott Williams & Wilkins. Unauthorized 
h never directly established, it has been assumed
r widely accepted that macula densa cells are the
portant if not the only sensors of tubular environ-
d mediator of tubule-to-glomerulus information
. This paradigm was challenged recently by two
studies. First, Ren et al. [8] reported that the
arterioles dilate upon elevations in tubular per-
aCl concentration ([NaCl]L). Because there is no
d direct anatomical contact between the efferent
and macula densa cells, it is unclear how macula
erived mediators could affect the vascular smooth
cells of the efferent arteriole. Second, as originally
by Morsing et al. [9] and recently by Ren et al.
here is a feedback loop that involves the anatom-
ciation of the connecting tubule, which returns to
es in contact with the afferent arteriole. These
ions are in addition to the tubulovascular contact
urs adjacent to the glomerulus at the macula
ig. 1).
llular signaling in the tubular
lium
s in [NaCl]L produce changes in macula densa
ume, which has been speculated to play a role
loglomerular feedback (TGF) signaling. Earlier
electrol
perfuse
luminal
iolar vas
in effer
clampin
[18�]. O
of tubu
TGF r
imenter
ing in m
in tubu
sensitiv
laborato
with a
([Ca2þ]i
was cau
voltage-
membra
failed t
densa [
evidenc
vasculat
macula
troversi
drum is
at this cell swelling could (among others) stimu-
P release [11–13]. Also, shrinkage of the cells,
by decreases in [NaCl]L, would stimulate pros-
n E2 synthesis and release [14]. Recent studies
ysiologically relevant alterations in [NaCl]L and
osmolality challenged this paradigm and demon-
that macula densa cells shrink upon concomitant
s in [NaCl]L and luminal osmolality, and also that
hanges in cell volume are sustained. Moreover,
densa cells have a limited capacityto regulate
ll volume as compared with adjacent cortical thick
ng limb cells [4].
een established that intracellular calcium signal-
he tubular epithelium is required for tubuloglo-
signaling to occur. In support of this proposal, it
wn with in-vivo micropuncture, that the relatively
op-flow pressure responses (an index of glomer-
illary pressure and therefore of vascular resist-
a hypotonic NaCl solution were restored to the
F response by adding a Ca2þ ionophore to the
de perfusate, whereas adding the ionophore to an
NaCl solution only marginally affected maximal
sponses [15] (to demonstrate the effect of Ca2þ
re, the presence of Ca2þ in the perfusate was
). Luminal administration of a blocker of Ca2þ
from intracellular stores induced a dose-depen-
uction in TGF responses produced by an isotonic
yte solution [16]. Also, in the in-vitro double-
d juxtaglomerular nephron preparation, reducing
Ca2þ concentration to zero caused afferent arter-
odilatation [17]. [NaCl]L-dependent adjustments
ent arteriolar diameter were also blocked by
g calcium signaling in the tubular epithelium
n the basis of these data suggesting a vital role
lar epithelial intracellular calcium signaling in
esponses, it had been anticipated that exper-
s would confirm that intracellular calcium signal-
acula densa cells is highly responsive to changes
lar environment. With the advent of calcium-
e fluorescent dyes, previous studies from our
ry concluded that elevated [NaCl]L is associated
modest rise in intracellular Ca2þ concentration
) in macula densa cells [19]. The rise in [Ca2þ]i
sed by cellular depolarization and opening of
dependent Ca2þ channels in the basolateral
ne of macula densa cells. However, others have
o find [NaCl]L-dependent increases in macula
Ca2þ]i [20–22]. In other words, we have strong
e for the role of intracellular Ca2þ in tubule-to-
ure signaling, although the involvement of
densa intracellular Ca2þ in this process is con-
al. One possible explanation for this conun-
that at least one component of juxtaglomerular
reproduction of this article is prohibited.
Copyrig
signaling depends on Ca2þ signaling in cells other than
macula densa.
Paramacular signaling
In an attempt to further characterize intracellular calcium
signaling in macula densa cells, we developed a highly
sensitive charged–coupled device camera-based ratio-
metric calcium imaging system. To our surprise, we
noted that [Ca2þ]i in macula densa cells was much lower
than in the adjacent cells, and there were only small
changes in [Ca2þ]i with increases in [NaCl]L or tubular
fluid flow. The cause and significance of low [Ca2þ]i in
macula densa cells is unclear, but it has been speculated
that the unusual distribution and possibly altered func-
tional state of macula densa mitochondria may act as a
Ca2þ sink and buffer changes in [Ca2þ]i. In support of this
notion, our preliminary experiments show that elevations
in [NaCl]L induce increases in intramitochondrial [Ca
2þ]
in macula densa cells. More importantly, we observed
that [Ca2þ]i in epithelial cells in the vicinity of the plaque
demonstrated spontaneous oscillations and was very
responsive to changes in [NaCl]L and tubular flow.
Elevations in [NaCl]L and luminal osmolality led to
increases in [Ca2þ]i in the oscillating cells in the early
distal tubule. Strong oscillatory behavior was most con-
Paramacular signaling Komlosi et al. 59
Figure 2 Four-dimensional imaging of tubule-dependent activation of the afferent arteriole in situ with multiphoton fluorescence
microcopy using Ca2R-sensing dye fluo-4
(a and b) G lim
endothelia ons
glomerula MC
luminal N w o
diameter ( L, c
cells; VSM
lomerulus perfused through the AA with attached cortical thick ascending
l cells. (c–e) Snapshots at time points indicated from four-dimensional rec
r DT (arrows) and concomitant increases in fluorescence in the adjacent VS
aCl concentration from 0 to 80mmol/l. (f–h) Snapshots from the axial vie
seeMovie 1 demonstrating reversible changes). AA, afferent arteriole; cTA
Cs, vascular smooth muscle cells.
ht © Lippincott Williams & Wilkins. Unauthorized
b and distal tubule. Note the vascular smooth muscle cells and
truction demonstrating increased fluorescence in the early ad-
s of the AA (arrowheads) in response to an elevation in tubular
f the afferent arteriole showing decreases in vascular luminal
ortical thick ascending limb; DT, distal tubule; ECs, endothelial
 reproduction of this article is prohibited.
Copyrigh
sistently observed in epithelial cells in approximately
100-mm vicinity of the macula densa plaque (perimacular
cells). I
the cal
spontan
of the c
macula
this rece
from th
unclear
whethe
paracrin
lar ATP
observa
feedbac
[NaCl]L
lations
thiazide
Naþ2Cl
porter m
We hav
immedi
exhibits
lations,
the affe
determi
sensing
glomeru
To dete
naling i
afferent
the cort
and the
afferent
fluo-4. T
signalin
oped a
ton micr
Fig. 2 a
elevatio
[Ca2þ]i
arteriole
associat
of the af
struction
We do n
distal tu
the acti
[Ca2þ]I;
tive and
standing
glomeru
As gene
in indiv
a complicated oscillatory pattern [28,29]. Interestingly,
the pattern of oscillations is altered in spontaneously
rte
he
cte
the
si
is
cy
ide
ef
ron
pr
ase
ly i
ug
ye
re
ns
es
s s
ffe
ow
re
nc
to
glo
atio
fr
cte
suc
iole
T
al
de
tion
rm
on
pr
e j
tio
ent
as
a, t
iola
ect
ten
ron
igh
l i
tal
ate
ns
60 Circulation and hemodynamics
t has been shown in other cells, that activation of
cium-sensing receptor may be responsible for
eous oscillations in [Ca2þ]i [23,24]. Expression
alcium-sensing receptor is particularly high in the
densa and neighboring cells [25], and activation of
ptor facilitated the oscillations. Omission of Ca2þ
e bath abolished the oscillations. At present, it is
whether these cells oscillate asynchronously or
r there is direct communication or through a
e mediator. Interestingly, scavenging extracellu-
did not affect the oscillations (unpublished
tions). Similar to its action on tubuloglomerular
k responses [26], furosemide blocked the
-dependent changes in intracellular Ca2þ oscil-
in the early distal tubule, whereas hydrochloro-
had no effect [27��]. This suggests that the
�:Kþ cotransporter and not the Naþ:Cl� cotrans-
ediates the sensing of the tubular environment.
e also demonstrated that the early distal tubule
ately downstream from the macula densa, which
spontaneous and [NaCl]L-dependent oscil-
establishes an anatomical region of contact with
rent arteriole [27��]. It is therefore intriguing to
ne whether these cells play a role in tubular
and may transmit information to the adjacent
lus and arterioles.
rmine the possible role of intracellular Ca2þ sig-
n perimacular cells in the [NaCl]L-dependent
arteriole activation, we cannulated and perfused
ical thick ascending limb–distal tubule segment
afferent arteriole simultaneously and assessed
arteriole [Ca2þ]i with the Ca
2þ-sensitive dye
o facilitate the assessment of intracellular Ca2þ
g in this complicated preparation, we have devel-
four-dimensional imaging model using multipho-
oscopy. As shown in the representative pictures in
nd also in Movie 1 (http://links.lww.com/A567),
ns in [NaCl]L resulted in marked increases in
in the early DT and also in the adjacent afferent
. Increases in [Ca2þ]i in the afferent arteriole were
ed with reversible reductions in luminal diameter
ferent arteriole, best visualized in the axial recon-
view of the experiment (Fig. 2f–h and Movie 1).
ot yet have direct evidence that the increases in
bule [Ca2þ]i contributed to or were associated with
vation of afferent arteriole smooth muscle cell
however, these new findings are at least sugges-
should stimulate future research efforts in under-
communicationprocesses between tubule and
lar structures.
rally appreciated, filtration and salt reabsorption
idual nephrons are dynamic processes and exhibit
hype
that t
chara
that
latory
In th
quen
coinc
The
neph
than
incre
nent
Altho
is as
cells
respo
studi
is thi
the a
34]. H
or A2
evide
recep
extra
Elev
oxide
expe
[40],
arter
cells.
theli
provi
filtra
In te
the c
been
at th
eleva
affer
decre
dens
arter
conn
is of
neph
in ne
latera
imen
regul
respo
t © Lippincott Williams & Wilkins. Unauthorized 
nsive animals. Although it has been suggested
se oscillations can be accounted for by some of the
ristics of feedback signaling, it is also possible
re are pacemaker cells, which can generate oscil-
gnals that are then transmitted to the vasculature.
respect, it is interesting that the dominant fre-
of oscillations in [Ca2þ]i in the perimacular cells
s with that of the nephron function.
fect of changes in salt delivery to the distal
on glomerular hemodynamics is more complex
eviously thought. Elevations in [NaCl]L lead to
d [Ca2þ]i in the tubular epithelium, most promi-
n the oscillatory cells of the early distal tubule.
h its relationship with intracellular Ca2þ signaling
t unclear, it has been shown that macula densa
lease ATP at the basolateral membrane in
e to elevated tubular salt content [13,30]. Earlier
suggest that ATP is degraded to adenosine, and it
ubstance that elicits constriction and dilation of
rent and efferent arterioles, respectively [18�,31–
ever, it is unclear how adenosine would reach A1
ceptors on the efferent arteriole. Others found
e that ATP exerts its effect directly through P2X
rs on the arteriole or the electronically coupled
merular mesangial cells [35–38].
ns in [NaCl]L also induce elaboration of nitric
om macula densa cells [39]. This substance is
d to exert its effects only in its immediate vicinity
h as to dilate the terminal segment of the afferent
and affect the release of renin from granular
he concerted action of the juxtaglomerular epi-
sensors on the afferent and efferent arterioles
s an effective way of regulating glomerular
pressure.
s of the role of tubulovascular association between
necting tubule and the afferent arteriole, it has
oposed to counteract the effects of TGF signaling
uxtaglomerular apparatus [10��]. In other words,
ns in [NaCl]L lead to dilation of the adjacent
arteriole. Because of reabsorption of Naþ and
ing luminal salt concentration beyond the macula
he luminal signal is likely different at the afferent
r contact sites at the glomerulus and at the
ing tubule. It is of note that the connecting tubule
associated with afferent arterioles of other
s, so it may be a mechanism to suppress filtration
boring nephrons (similar to the phenomenon of
nhibition in the retina). There is, in fact, exper-
evidence that nephrons communicate and are
d as groups [41,42]. In contrast to the feedback
es at the juxtaglomerular apparatus and epithelial
reproduction of this article is prohibited.
Copyrig
Ca2þ signaling at the early distal tubule, furosemide had
no effect on the responses at the connecting tubule.
Howeve
with am
at the c
Conclu
Recent
feedbac
possible
and glo
neating
is need
nature o
Ackno
This work
from the
Komlosi,
Digestive
Services,
Veterans
Bell. Th
secretaria
Refere
Papers of p
been highl
� of spe
�� of out
Additional
World Lite
1 Guyto
back a
2 Schnermann J, Wright FS, Davis JM, et al. Regulation of superficial nephron
filtratio
175.
3 Kirk K
isolate
894.
4 Komlo
densa
2006;
5 Schne
kidney
6 Peti-P
in mac
Renal
7 Baraja
morph
pathop
Press
8 Ren Y
in the
9 Morsin
feedba
68.
10
��
Ren Y
tubule
2007; 71:1116–1121.
This article
transductio
experiment
study to di
11 Liu R, Pittner J, Persson AE. Changes of cell volume and nitric oxide
concentration in macula densa cells caused by changes in luminal NaCl
concentration. J Am Soc Nephrol 2002; 13:2688–2696.
ti-Peterdi J, Morishima S, Bell PD, Okada Y. Two-photon excitation fluor-
cen
ysio
ll P
P re
0:4
rris
cal i
ll P
bulo
ll P
ome
rus
bulo
:S26
n Y
terio
6.
eno
en d
ticle
rs.
ti-P
lls.
lom
lic f
lls a
rose
lom
ent
cen
ysio
R,
lciu
Cl
eitw
cell
142
ung
Ca2
ysio
25 Riccar
a2þ
Pt
righ
ratio
:16
mlo
lls a
46.
ticle
mac
spo
n to
ng.
lste
al in
e r
9.
yssa
erat
7:4
mlo
leas
nal
astro
feedba
Clin In
hne
edba
Pt
Paramacular signaling Komlosi et al. 61
outlines the functional connection and possible mechanisms of signal
n between the connecting tubule and afferent arteriole. Earlier in-vivo
s suggested that such a site of communication exists, but this is the first
rectly demonstrate it.
32 Sc
fe
(3
n rate by tubulo-glomerular feedback. Pflugers Arch 1970; 318:147–
L, Bell PD, Barfuss DW, Ribadeneira M. Direct visualization of the
d and perfused macula densa. Am J Physiol 1985; 248 (6 Pt 2):890–
si P, Fintha A, Bell PD. Unraveling the relationship between macula
cell volume and luminal solute concentration/osmolality. Kidney Int
70:865–871.
rmann J, Marver D. ATPase activity in macula densa cells of the rabbit
. Pflugers Arch 1986; 407:82–86.
eterdi J, Bebok Z, Lapointe JY, Bell PD. Novel regulation of cell [Na(þ)]
ula densa cells: apical Na(þ) recycling by H-K-ATPase. Am J Physiol
Physiol 2002; 282:F324–F329.
s L, Salido EC, Liu L, Powers KV. The juxtaglomerular apparatus: a
ologic perspective. In: Laragh JH, Brenner BM, editors. Hypertension:
hysiology, diagnosis, and management, 2nd ed. New York: Raven
Ltd; 1995. pp. 1335–1348.
, Garvin JL, Carretero OA. Efferent arteriole tubuloglomerular feedback
renal nephron. Kidney Int 2001; 59:222–229.
g P, Velazquez H, Ellison D, Wright FS. Resetting of tubuloglomerular
ck by interrupting early distal flow. Acta Physiol Scand 1993; 148:63–
, Garvin JL, Liu R, Carretero OA. Crosstalk between the connecting
and the afferent arteriole regulates renal microcirculation. Kidney Int
C
(3
26 W
filt
53
27
��
Ko
ce
19
This ar
of the
very re
positio
signali
28 Ho
im
siv
33
29 Le
alt
11
30 Ko
re
Re
31 C
r, inhibition of the epithelial sodium channels
iloride abolished the [NaCl]L-induced responses
onnecting tubule.
sion
studies on the mechanism of tubuloglomerular
k responses provide a new paradigm in terms of
sites of interaction between the distal nephron
merular hemodynamics. Further research deli-
the functional importance of these contact points
ed and may help us understand the dynamic
f renal function.
wledgements
was supported by Scientist Development Grant 0630096N
American Heart Association, Dallas, Texas, USA to Peter
grant 32032 from the National Institute of Diabetes and
and Kidney Diseases, Department of Health and Human
Bethesda, Maryland, USA and a grant from the Department of
Affairs, Washington, District of Columbia to Phillip Darwin
e authors wish to thank B.J. Randall Harris for
l assistance.
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. 94).
n AC, Langston JB, Navar G. Theory for renal autoregulation by feed-
t the juxtaglomerular apparatus. Circ Res 1964; 15 (Suppl):187–197.
12 Pe
es
Ph
13 Be
AT
10
14 Ha
gi
15 Be
tu
16 Be
gl
17 Na
tu
2)
18
�
Re
ar
86
The ph
has be
This ar
recepto
19 Pe
ce
20 Sa
so
ce
fu
21 Sa
m
as
Ph
22 Liu
ca
Na
23 Br
tra
C
24 Yo
of
Ph
ht © Lippincott Williams & Wilkins. Unauthorized
ce imaging of the living juxtaglomerular apparatus. Am J Physiol Renal
l 2002; 283:F197–F201.
D, Lapointe JY,Sabirov R, et al. Macula densa cell signaling involves
lease through a maxi anion channel. Proc Natl Acad Sci U S A 2003;
322–4327.
RC. Cyclooxygenase-2 and the kidney: functional and pathophysiolo-
mplications. J Hypertens Suppl 2002; 20:S3–S9.
D, Navar LG. Cytoplasmic calcium in the mediation of macula densa
-glomerular feedback responses. Science 1982; 215:670–673.
D, Reddington M. Intracellular calcium in the transmission of tubulo-
rular feedback signals. Am J Physiol 1983; 245:F295–F302.
e M, Inoue T, Nakayama M, et al. Effect of luminal Cl- and Ca2þ on
glomerular feedback mechanism. Jpn J Physiol 1994; 44 (Suppl
9–S272.
, Garvin JL, Liu R, Carretero OA. Possible mechanism of efferent
le (Ef-Art) tubuloglomerular feedback. Kidney Int 2007; 71:861–
menon of signaling between distal nephron and the efferent arteriole
escribed earlier by this group, but the mechanisms were yet unknown.
describes a possible mechanism by adenosine binding to its A2
eterdi J, Bell PD. Cytosolic [Ca2þ] signaling pathway in macula densa
Am J Physiol 1999; 277 (3 Pt 2):F472–F476.
onsson M, Gonzalez E, Westerlund P, Persson AE. Intracellular cyto-
ree calcium concentration in the macula densa and in ascending limb
t different luminal concentrations of sodium chloride and with added
mide. Acta Physiol Scand 1991; 142:283–290.
onsson M, Gonzalez E, Sjolin L, Persson AE. Simultaneous measure-
of cytosolic free Ca2þ in macula densa cells and in cortical thick
ding limb cells using fluorescence digital imaging microscopy. Acta
l Scand 1990; 138:425–426.
Persson AE. Simultaneous changes of cell volume and cytosolic
m concentration in macula densa cells caused by alterations of luminal
concentration. J Physiol 2005; 563 (Pt 3):895–901.
ieser GE, Gama L. Calcium-sensing receptor activation induces in-
ular calcium oscillations. Am J Physiol Cell Physiol 2001; 280:C1412–
1.
SH, Rozengurt E. Amino acids and Ca2þ stimulate different patterns
þ oscillations through the Ca2þ-sensing receptor. Am J Physiol Cell
l 2002; 282:C1414–C1422.
di D, Hall AE, Chattopadhyay N, et al. Localization of the extracellular
/polyvalent cation-sensing protein in rat kidney. Am J Physiol 1998; 274
2):F611–F622.
t FS, Schnermann J. Interference with feedback control of glomerular
n rate by furosemide, triflocin, and cyanide. J Clin Invest 1974;
95–1708.
si P, Banizs B, Fintha A, et al. Oscillating cortical thick ascending limb
t the juxtaglomerular apparatus. J Am Soc Nephrol 2008; 19:1940–
provides the first description of special epithelial cells in the vicinity
ula densa plaque. These spontaneously Ca2þ oscillating cells are
nsive to changes in luminal environment and, because of their juxta-
the afferent arteriole, may participate in the tubule-to-vasculature
in-Rathlou NH, Leyssac PP. TGF-mediated oscillations in the prox-
tratubular pressure: differences between spontaneously hyperten-
ats and Wistar-Kyoto rats. Acta Physiol Scand 1986; 126:333–
c PP, Baumbach L. An oscillating intratubular pressure response to
ions in Henle loop flow in the rat kidney. Acta Physiol Scand 1983;
15–419.
si P, Peti-Peterdi J, Fuson AL, et al. Macula densa basolateral ATP
e is regulated by luminal [NaCl] and dietary salt intake. Am J Physiol
Physiol 2004; 286:F1054–F1058.
p H, Huang Y, Hashimoto S, et al. Impairment of tubuloglomerular
ck regulation of GFR in ecto-50-nucleotidase/CD73-deficient mice. J
vest 2004; 114:634–642.
rmann J, Weihprecht H, Briggs JP. Inhibition of tubuloglomerular
ck during adenosine1 receptor blockade. Am J Physiol 1990; 258
2):F553–F561.
 reproduction of this article is prohibited.
Copyrigh
33 Schnermann JB, Traynor T, Yang T, et al. Absence of tubuloglomerular
feedback responses in AT1A receptor- deficient mice. Am J Physiol 1997;
273 (2 Pt 2):315–320.
34 Brown R, Ollerstam A, Johansson B, et al. Abolished tubuloglomerular
feedback and increased plasma renin in adenosine A1 receptor-deficient
mice. Am J Physiol Regul Integr Comp Physiol 2001; 281:R1362–R1367.
35 Nishiyama A, Majid DS, Walker M III, et al. Renal interstitial atp responses to
changes in arterial pressure during alterations in tubuloglomerular feedback
activity. Hypertension 2001; 37 (2 Pt 2):753–759.
36 Inscho EW, Cook AK, Mui V, Miller J. Direct assessment of renal microvascular
responses to P2-purinoceptor agonists. Am J Physiol 1998; 274 (4 Pt 2):718–
727.
37 Inscho EW. P2 receptors in regulation of renal microvascular function. Am J
Physiol Renal Physiol 2001; 280:F927–F944.
38 Inscho EW, Cook AK, Imig JD, et al. Renal autoregulation in P2X knockout
mice. Acta Physiol Scand 2004; 181:445–453.
39 Kovacs G, Komlosi P, Fuson A, et al. Neuronal nitric oxide synthase: its role
and regulation in macula densa cells. J Am Soc Nephrol 2003; 14:2475–
2483.
40 Tojo A, Onozato ML, Fukuda S, et al. Nitric oxide generated by nNOS in the
macula densa regulates the afferent arteriolar diameter in rat kidney. Med
Electron Microsc 2004; 37:236–241.
41 Holstein-Rathlou NH. Synchronization of proximal intratubular pressure
oscillations: evidence for interaction between nephrons. Pflugers Arch
1987; 408:438–443.
42 Peti-Peterdi J. Calcium wave of tubuloglomerular feedback. Am J Physiol
Renal Physiol 2006; 291:F473–F480.
62 Circulation and hemodynamics
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	Tubuloglomerular feedback mechanisms in nephron segments beyond the macula™densa
	Introduction
	Anatomy of tubuloglomerular feedback
	Intracellular signaling in the tubular epithelium
	Paramacular signaling
	Conclusion
	Acknowledgements
	References and recommended reading