Relationship of Juxtaglomerular Apparatus
to Renin and Angiotensin
By
Louis
TOBIAN, M.D.
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IN A SYMPOSIUM devoted to angiotensin, it is appropriate to consider briefly
the juxtaglomerular apparatus. Angiotensin
makes its appearance in the body as a direct
result of the proteolytic action of renin, and
there is considerable evidence to support the
hypothesis that all the renin in a kidney
comes from the juxtaalomerular apparatus.
Before reviewing this evidence, the anatomy
of the juxtaglomerular apparatus should be
considered. It consists of 2 separate cell
types, the granular cells and the macula
densa cells. The granular juxtaglomerular
cells actually lie within the medial layer of
the afferent glomerular arteriole. They have
small, uniform-sized granules in the cytoplasm, which can be clearly stained with
Bowie 's stain1 or with osmic acid.2 When
examined with the electron nmicroseope, these
cells are seen to have a rich endoplasmic
reticulum with an abundanee of RNA granules, a Golgi apparatus, and their specific
cytoplasmic secretory granules.2 When there
are abundant granules in the cytoplasm, these
cells have all the appearances of actively
secreting cells. One side of the granular cell
abuts the intimal layer of the afferent arteriole. On the other side, the border of the
cell may interdiaitate with the border of
the macula densa cells. The macula densa
consists of specialized cells which are part
of the wall of the distal convoluted tubule.
Their stainling characteristics are different
from tlle usual epithelial cells lining the
distal tubule. The macula densa cells are
always at the very first part of the distal
tubtule and are always in close proximity to
the vascular pole of the glomerulus of their
particular nephron. As mentioned above,
there are certain areas where the membranes
of the granular juxtaglomerular cells and the
macula densa cells are inseparable and actually interdigitate with one another. The 2
cell types are probably also closely related
physiologically. When the granular cells
change their rate of secretion, certain enzymes in the macula densa cells also change
their activity.3
There are 3 separate lines of evidence
indicating that all renin comes from the
juxtaglomerular apparatus. The first line of
evidence relates to the striking correlation
in the rat between the abundance of granules
in the juxtaglomerular cells and the content
of extractable rellin in the kidney. For instance, if 1 renal artery is narrowed in the
rat, the juxtaglomerular granules practically
disappear in the contralateral kidniey. At the
same time, the amount of extractable renin
in this contralateral kidney also becomes
vanishingly small.4 If the "ischemic" kidney
is subsequently excised and the lhypertension
is "cured," both the juxtaglomerular granules and the extractable renin reappear in
normal abundance in the contralateral kidney.5 Similarly, if desoxycorticosterone and
salt are given to rats, the juxtaglomerular
(JG) granules practically disappear, and
there is a virtual disappearance of extractable reniin.4 When rats are placed on a low
intake of sodium, both the renin content
and the JG granularity increase in their
kidneys." Conversely, rats on a high intake
of sodium have a concomitant reduction of
both renin and JG granules.7 In all the
studies just referred to, the amount of renin
and JG granules have been determined in
the same kidney.
Gross and coworkers have investigated the
amount of extractable renin in many physiologic states in the rat.8 These results can be
Froom the Department of Medicine, University of
Minnesota Schlool of Mledicine and the University of
Minlesota Hospital, Minneapolis, Minnesota.
Circulation, Volume XXV, January
1962
189
19()
T1OTBIIAN
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eorrelated with other studies of JG graiiularitv. For instanlce, rats receiving desoxvcorticosterone and practically no dietarv
sodium have a fairly inormal graniularity of
the JG cells' 9 and a niorm::al am:louint of
extractable renin.10 In. ntietacorticoid hypertension in rats, the kidneys have a subnormal
amount of both renin11 and juxtaglonterular
granules.9 In rats with adretnal insufficienec.
there is an inereased granularity of the JG
ecells1 8 1 2 and an increased contenit of renin.13
In all the rat experimenits, the amnount of
renin and abundanee of JG graniules have
shown a very strong correlation. These observations would fit iii with the hypothesis that
the juxtagloinerular graniules contaiin reinn.
The second line of evidenee emerges fromi
microdissection studies oni kidneys. These
studies were done in 2 differenit laboratories,
that of Bing in Copenhagen and of Cook at
Oxford. Originally 'eart, Gordon. Cook, and
Pickering founid that the parts of a kidnev
cortex which were purely tubular contained
very little extractable renin. Renin could be
found only in those areas of kidney with
glomeruli.'4 Cook antd Pickering then caused
glomeruli to become clogged with mnagnetic
iron particles. When the gloineruli were subsequently isolated maianeti(eallv. thev eoi tained most of the ienin in a kidney.'o5 Cook
then devised all ingenious procedure with a
iniieroouillotiine for splitting the isolated
glomeruli into a half which oontained the
vascular pole and another half which waas
opposite to the vascular pole. He extracted
these halves for renini anid fouind that all of
the renin was in the half with the vaseular
pole. This fin-lding inidicated that renin was
niot in the glomerular tuft itself, since there
was an equal amyiouLnt of tiff in either half.
The prineipal specialized structures present
at the vascular root of the gYlomerulus are the
gcyranular cells and the macula densa. One or
both of these structures probably containi the
reninl.
Bing and coworkers also discovered inde-
pendently that all of the renin in a kidnev
was in the nieighborhood of the glomeruli.16
Tliev
then isolated glomerular
tufts by mi-
crodisseetion and found no renini in themi."'
Also, on inierodissection, they n-oted that
there was very little renin in the areas be
tween the loomeruli.17 They conecluded that
renin was located very near the glomeruli
but not in the glomerular tufts alnd not in
the areas bet-ween glomeruli.'7 Again, the
struetures of the vascular pole of tl-e glomierulis were inlplieated. Biug founid that afferent
arterioles did nlot contain renin.17 They dissected the arterioles free, but there is a
question as to how much of the wall, or
material in the wall, was removed by the
dissection. Bing favors the illaeula densa as
the locus of reniin. Their work does niot inidicate coiielusivelv that reniin is in I part of
the juxtaglomnerular apparatus or the other,
but it eertainily narrows it down to ain area
somewhere in the juxtagJlomierular apparatus.
Thus, both Cook anid Bing found the main
locus for renin in a kidney to be the striuetures at the vascular pole of the kidniey, the
samne area oceupied by ilbe juxtaglomerular
apparatus.
The third line of evideniee eomes fron
Ilartroft and Edelman, who prepared antibodies to renin and tagged them with fluoreseeini. Frozen sections of the kidney of a
rabbit that had bee:n on a low-salt diet were
exposed to a layer of solution containing
the fluLoreseenit antibody. Exaimiinationi of these
sections showed that the fluoreseent antibodyloealized in the cytoplasm of the granular
juxtaglomerular cells. This particular experiiuenit would emphatically point to the granular cells tlhemselves as the locus of renin.18
All 3 of these litnes of evidenice lead to
the same conclusion: that renin is located
mainly in the juxtaglomerular apparatus.
Anly 1 of these approaches would be quite
suggestive, but the combination of all 3 con-titutes very strong evidence for this hypothesis. Henee, wheni one thiink;ks of reniin, he
should also be thinlking of the juxtaglomerular apparatus. Renin is pi-robably seereted bv
some element in the JG apparatus.
In workinig either with extractable reninl
or with stains of the jnxtaglomerular granules, one is struck by the fact that opposite
Circulation, V'olu-ne XX V Janura19tryI
JUXTAGLOMERULAR APPARATUS, RENIN, AND ANGIOTENSIN
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physiologic maneuvers produce opposite effects on the content of granules or of renin.
Hence, it is probable that the presence of
abundant JG granules represents one extreme of secretion, and the complete absence
of granules represents the opposite extreme.
In certain situations, hypergranularity is
associated with hyperplasia of the JG cells.
In most secretory tissues, hyperplasia usually
represenlts a state of hypersecretion. Therefore, hypergranuilarity of the JG cells probably represents a state of hypersecretion, and
the absence of JG granules probably indicates a very low rate of secretion.
Certain experimental maneuvers cause a
hypergranularity of the JG cells, and others
cause a diminution in granularity. All the
observations seem to fit in with the hypothesis that the JG cells act as stretch receptors.
First, the JG cells are in the media of the
afferent glonierular arteriole and, therefore,
would undergo the saine changes in stretch
that affect the wall of the afferent arteriole.
It is quite reasonable to postulate that stretch
reeeptors, acting as volume receptors, exist in
the walls of arteries.19 The JG cells are in an
excellent anatomie location to perform such a
job. Various observations would indicate that
whenever the wall of the afferent arteriole
with its JG cells becomes less distended, the
JG cells become hypergranulated, indicating
an increased rate of secretion. Conversely,
when the wall of the afferent arteriole is
slightly overdistended, the JG cells are increasingly stretched and, as a result,
become less granulated and slow their rate
of secretion.
The JG cells increase their granulation in
the following situations:
1. Adrenal insufficiency.9' 12
2. Shock.S
3. Experimental constriction of the thoracic
iniferior vena eava in the dog with resulting
aseites.20
4. Low sodium intake." 9
3. Cure of renal hypertension by relmoving
an "ischemic" kidney.9 JG grainules reappear
abundantly in the remaining kidney.
6. Narrowing the renal artery of the kidCirculation, Volume XXV, January 1962
191
ney which is contralateral to an "ischemnic"
kidney.9 This contralateral kidneyr often has
an increase in JG granularity.
7. Narrowing the renal artery in 1 of the
2 kidneys.9 The "isehemic" kidney shows the
inerease in JG granularity.
8. Experimelntal amninonucleoside nephrosis in the rat with resulting edema an-d
ascites.21
9. Chronic chlorothiazide administration
in the rat.22
In all of these situations, either the pressure in the renal arterial bed is reduced, or
the voluine of blood in the arteries is decreased. Either type of change would be
expected to diminish the stretch of the JG
cells.
On the other hand, juxtaglomerular granules are considerably reduced in the following situations:
1. Administration of desoxycorticosteroine
and salt." 9
2. High intake of salt." 7
3. The "untouched " contralateral kidnev
which is opposite to a kidney in which the
renal artery is narrowed.9' 25
4. Kidneys in rats with metacorticoid
hypertension.9
5. Kidneys in rats with adrenal regeneration hypertension.9
6. The lone kidney in rats with "nephrosclerotic " hypertension.9
7. Isolated kidneys which have been perfused for 2 hours at a high perfusiol
pressure.24
8. Rats receiving
the sympathoinimetic
drug, naphazoline hydrochloride.25
In all of these situations, either the blood
pressure in the renal arterial bed is increased,
or the volume of blood in the arteries is
increased. With either type of stinmulus
there would be an increased stretch of the
JG cells. Therefore, when the stretch is increased, there is a reduction of JG granules;
when the stretch is decreased, there is an
increase in the granularity. A diminished
stretch would thus be a stimulus for hypersecretion, while an increase in stretch would
slow the rate of secretion. One is left witl-
TOBIAN
192
a strong suspicion that the JG cells act as
stretch receptors that are continuously monitorincr the volume of blood in the affereiit
glomerular arteriole. If this is so, they would
seem to qualify as one of the mysterious
" volume receptors" for which many of us
are searching.
Effect of desoxycorticosterone acetate and of
sodium on juxtaglomerular apparatus. Tindocriiiology 61: 293, 1957.
13. GRoss, F., AND SULSER, F.: Der Einfluss der
14.
References
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Circulation, Volume XXV. January
1962
Relationship of Juxtaglomerular Apparatus to Renin and Angiotensin
LOUIS TOBIAN
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Circulation. 1962;25:189-192
doi: 10.1161/01.CIR.25.1.189
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