2. Chapter | 204 Renin–Angiotensin System
1500
of intrarenal proinflammatory cytokine expressions such as
interleukin-6, contributing to the increase in AGT expres-
sion via activation of a JAK-STAT pathway.29 Therefore,
Ang II increases intrarenal AGT levels via both direct and
indirect mechanisms mediated by activated NF-κB and the
JAK-STAT pathway. By contrast, tumor necrosis factor α,
which is also an Ang II-induced proinflammatory factor in
the kidney, suppresses AGT expression by increasing p50/
p50 complex in proximal tubular cells.30 This inhibitory
action on NF-κB provides a counterregulatory influence
limiting the magnitude of Ang II-induced AGT augmen-
tation in renal proximal tubular cells, which may explain
why higher doses of Ang II infusion in mice fail to augment
intrarenal AGT levels.20
Proximal tubuleAGT concentrations in anesthetized rats
are in the range of 300 nM, which greatly exceeds the free
Ang I and Ang II tubular fluid concentrations. Because of
its molecular size, it is unlikely that much plasma AGT fil-
ters across the glomerular membrane, further supporting the
concept that proximal tubule cells secrete AGT directly into
the tubule.12 In response to chronic Ang II infusions there is
an augmentation of AGT mRNA leading to increased syn-
thesis and secretion with some of the secreted AGT spilling
over to the distal nephron segments as reflected by increased
urinary AGT excretion.13 Under conditions of elevated salt
intake combined with chronic Ang II infusion, the urinary
AGT excretion response is elevated to much greater lev-
els than those seen in Ang II-infused rats fed a normal salt
diet.14 By contrast, normal rats fed a high salt diet exhibit
urinary AGT excretion rates similar to those observed in
rats fed a normal salt diet. Thus, during chronic Ang II infu-
sion, salt-sensitive hypertension develops and high salt par-
adoxically stimulates intrarenal RAS activity, as reflected
by exacerbation of the urinary AGT despite inhibition of
plasma renin activity.14 Formation of Ang I and II in the
tubular lumen subsequent to AGT secretion is probable
because some renin is filtered and/or secreted from juxta-
glomerular apparatus (JGA) cells.12 Once Ang I is formed,
conversion readily occurs because there is abundant ACE
associated with the proximal tubule brush border.32 Intact
AGT in urine reflects its presence throughout the nephron
and, to the extent that renin and ACE are available along
the nephron, substrate availability supports continued Ang
I generation and Ang II conversion in distal segments.19,25
Renin and (Pro)renin Receptor
Renin, synthesized by the JGA cells, is the primary source
of both circulating and intrarenal renin levels. Juxtaglo-
merular apparatus cells secrete renin into the renal inter-
stitium, thus providing a stimulus for the local generation
of Ang I, and this secreted active form contains 339–343
amino acid residues after proteolytic removal of the 43
amino acid residue at the N-terminus of prorenin. Circu-
lating active renin and prorenin are derived mainly from
the kidney; and circulating prorenin is taken up by some
tissues where it may contribute to the local synthesis of
angiotensin peptides. The only well-established role of
FIGURE 1 Intrarenal renin–angiotensin system cascade. Known and postulated enzymatic pathways responsible for formation and metabolism of
angiotensin peptides.
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SECTION | XV Handbook of Biologically Active Peptides: Renal Peptides
renin is to cleave Ang I from AGT. However, the recently
cloned (pro)renin receptor ((P)RR) binds renin or pro-
renin, thus enhancing renin activity and fully activating the
biologically inactive prorenin peptide, which leads to an
increase in the catalytic efficiency of Ang I formation from
AGT. Activation of the (P)RR by renin or prorenin also
directly elicits intracellular signals that stimulate ERK1/
ERK2 and downstream pathways.22
There is growing awareness of the possible roles of renin
in other intrarenal structures where renin has been local-
ized. Renin producing cells have a unique origin that allows
their abundance along the afferent arteriole to be regulated
by various stimuli. ACE inhibition induces a recruitment of
cells in afferent arterioles beyond the JGA even though they
were not expressing the renin gene in the basal state.31 Posi-
tive renin immunoreactivity has also been observed in the
cells of glomeruli and in proximal and distal tubular seg-
ments. More recently, increased attention has been focused
on the presence of renin mRNA and protein expression in
distal nephron segments, specifically in the principal cells
of connecting tubules and collecting ducts, suggesting local
formation and secretion into the distal tubular fluid. Renin
synthesis in principal cells of collecting ducts is further
increased by chronic infusions of Ang II.25,26 Rats chroni-
cally infused with Ang II for 13 days show a suppression of
plasma renin activity but increases in urinary prorenin con-
tent and renin excretion.16 In addition, the urinary renin and
prorenin protein levels, examined by Western blot, are aug-
mented about 10-fold in Ang II-infused rats. Concomitant
AT1R blockade with candesartan prevents increases in both
urinary and tissue renin and in prorenin levels. Although
there is marked suppression of plasma renin activity,
increased renin synthesis by CD cells and secretion into the
luminal fluid lead to increased urinary levels of renin and
prorenin.16
The presence of renin in distal nephron segments pro-
vides the requisite pathway for Ang I generation from prox-
imally delivered AGT.25,26 Renin synthesis is augmented
in the principal cells of connecting tubules and cortical
and medullary collecting ducts of chronic Ang II-infused
rats and mice, Cyp1a1Ren2 transgenic rats, and in both
kidneys of two-kidney one clip Goldblatt hypertensive
rats.9,25,26 The AT1R via a PKC pathway directly mediates
the stimulation of renin synthesis in rat inner medullary col-
lecting duct because inhibition of PKC with calphostin C
prevents the Ang II-mediated increases in renin transcript
and prorenin protein levels in rat inner medullary collecting
duct (IMCD) cells while activation of PKC with phorbol
12-myristate 13-acetate increases renin expression to the
same extent as Ang II.7 Further, renin activity and renin and
prorenin protein levels are increased in the urine of these
rats6 indicating that both renin and prorenin are secreted by
the collecting duct cells into the lumen of distal nephron
segments and are also augmented in chronic Ang II-infused
hypertensive rats. The discovery of the (P)RR provides new
insights regarding its possible role in a setting of activated
intrarenal RAS. The (P)RR is expressed in the kidneys6
particularly in mesangial cells, podocytes, and intercalated
type A cells of distal nephron segments.2,6,11 Chronic infu-
sion of Ang II for 14 days in Sprague–Dawley rats increases
renal (P)RR transcript levels and augments the soluble form
of the (P)RR, s(P)RR.6 The augmentation of s(P)RR in the
urine of Ang II hypertensive rats suggests that s(P)RR can
bind renin and prorenin secreted by the principal collecting
duct cells and can catalyze additional formation of Ang I.
The existence of an inducible and functional form of s(P)
RR in the renal medulla and in the urine of chronic Ang
II-infused rats reflects increased s(P)RR in collecting duct
tubular fluid and further supports the potential role of this
soluble form to enhance intratubular renin activity. Thus,
the interaction between the (P)RR and renin in the lumen of
the collecting ducts may contribute substantially to facili-
tate intratubular formation of Ang I in hypertension.
Angiotensin-Converting Enzymes
As in other organs, ACE is located on endothelial cells
throughout the vasculature. ACE is also on membranes of
both proximal and distal nephron segments with the greatest
abundance found on the brush border of proximal tubules,
particularly in the S3 segment.21,32 Marked upregulation of
ACE in the brush border occurs in kidneys from Goldblatt
hypertensive rats and Ang II infused hypertensive rats.32
Humans predominantly express ACE in the brush border
of proximal tubular segments with very little ACE expres-
sion on vascular endothelial cells or in the vasculature of
the glomerular tuft. The lower renal vascular endothelial
expression in humans helps explain the much lowerAng I to
Ang II conversion rates that have been reported for human
kidneys as compared with that of other species. In rats, ACE
activity is present in tubular fluid throughout the nephron
except in the distal tubule, with activity higher at the initial
portion of the proximal tubule, decreasing toward the distal
nephron, and increasing again in the collecting ducts and
urine. Therefore, intratubular Ang II formation may occur
not only in the proximal tubule but also beyond the distal
convoluted tubule. Renal tissue ACE activity is critical to
maintain the steady-state Ang II levels in the kidney. The
presence of ACE only in the kidney is sufficient to increase
kidneyAng II levels and promote the development of hyper-
tension in response to chronicAng I infusions.8 Tissue-ACE
knockout mice exhibit 80% lower intrarenal Ang II levels
compared with wild-type mice.3
ACE2, which acts on Ang II to form Ang 1–7 or on Ang
I to form Ang 1–9 (Fig. 1), is a membrane-associated and
secreted enzyme expressed predominantly on endothelium,
4. Chapter | 204 Renin–Angiotensin System
1502
but highly restricted in humans to heart, kidneys, and tes-
tes.21 Ang 1–7 may serve as an endogenous antagonist of
the Ang II induced actions mediated via AT1 receptors and
changes in ACE2 activity could affect the balance of Ang
peptides found in the kidney. This probably explains the ele-
vatedAng II levels in theACE2 knockout mice.28 Collectrin,
a novel homolog of ACE2 has been identified in mouse, rat,
and human. Both ACE2 and collectrin have tissue-restricted
expression in the kidney. Collectrin is localized on the lumi-
nal surface and in the cytoplasm of collecting duct cells,
and its mRNA is expressed in the renal collecting ducts
cells while ACE2 is present throughout the endothelium,
in proximal tubular epithelial cells and in medullary tis-
sue.21 In Ang-II-dependent hypertension, intrarenal ACE is
increased, but ACE2 levels are decreased leading to another
mechanism maintaining increased Ang II levels.26
Intrarenal Angiotensin II Receptors
Ang II receptors are widely distributed in various regions
and cell types of the kidney. Two major categories of Ang II
receptors, AT1 and AT2, have been described, pharmacologi-
cally characterized and cloned.18,21 As depicted in Figure 2,
most of the Ang-II-mediated hypertensinogenic actions are
generally attributed to the AT1 receptor.5,18 In rodents, there
are two AT1 receptor subtypes, with the AT1a being the pre-
dominant subtype in all nephron segments, while the AT1b
is more abundant in the glomerulus.18,21 In mature kidneys,
AT1a receptors have been localized to the renal microvascu-
lature in cortex and medulla, smooth muscle cells of afferent
and efferent arterioles, thick ascending limb of the loop of
Henle, proximal tubular apical and basolateral membranes,
mesangial cells, distal tubules, collecting ducts, and macula
densa cells. The afferent arteriole has both AT1a and AT1b
receptors, whereas the efferent arteriole primarily expresses
AT1a receptors.10 The essential role of the AT1a receptor in
mice is apparent from studies showing that 2-kidney, 1-clip
(2K1C) Goldblatt hypertension does not develop in AT1a
knockout mice.4
Vascular and tubular receptors respond differently dur-
ing high Ang II states.18 High Ang II levels associated with
a low salt diet decrease glomerular AT1 receptor expression
but increase proximal tubular AT1 receptor levels. Glomeru-
lar AT1 receptors and AT1a receptor protein are reduced in
both clipped and contralateral kidneys of 2K1C Goldblatt
and of 2 kidney-1-wrap hypertensive models and in kidneys
of Ang II infused rats.18 In the TGR(mRen2) harboring
the mouse renin2 gene, AT1 receptor binding is increased
in vascular smooth muscle of afferent and efferent arteri-
oles, JGA, glomerular mesangial cells, proximal tubular
cells, and renomedullary interstitial cells suggesting that
the upregulation of AT1 receptors contributes to the patho-
genesis of hypertension in these rats. In Ang II infused rats
studied with in vitro autoradiography, there are differential
responses with significant decreases in glomeruli and inner
stripe but not in proximal tubules.18
The AT2 receptor is highly expressed in human and
rodent kidney mesenchyme during fetal life and decreases
dramatically after birth.AT2 receptors have been localized to
the glomerular epithelial cells, proximal tubules, collecting
ducts, and parts of the renal vasculature of the adult rat. AT2
receptor activation is believed to counteract AT1 receptor
FIGURE 2 Major Ang II receptor subtypes and their renal actions.
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SECTION | XV Handbook of Biologically Active Peptides: Renal Peptides
effects by stimulating the formation of bradykinin and nitric
oxide leading to increases in interstitial fluid concentration
of cyclic guanosine monophosphate (cGMP). AT2 receptor
activation influences proximal tubule sodium reabsorption
either by a cell-membrane-receptor-mediated mechanism or
via an interstitial nitric-oxide-cGMP pathway.17,18
INTRARENAL LEVELS OF ANGIOTENSIN II
Interstitial Angiotensin II
Intrarenal Ang II is not distributed in a homogeneous
fashion but is compartmentalized in both a regional and
segmental manner.19 Medullary Ang II levels are higher
than cortical levels in normal rats and increase further in
Ang II infused hypertensive rats.18 Within the cortex, there
is distribution of Ang II in the interstitial fluid, tubular
fluid, and intracellular compartments. The interstitial and
intratubular compartments contribute to the disproportion-
ately high intrarenal Ang II levels. Ang II concentrations
in interstitial fluid are much higher than the plasma con-
centrations with values in the range of 3–5 pmoles/mL.19
Renal interstitial fluid Ang II levels increase further in
hypertensive rats infused with Ang II for 2 weeks. The
high renal interstitial values indicate local regulation of
Ang II formation in the renal interstitial compartment and
an enhancement of interstitial Ang II production in Ang II
dependent hypertension.12
Tubular Ang II
As shown in Figure 3, proximal tubule fluid concentrations
of Ang I and Ang II are also much greater than the plasma
concentrations and have been found to be in the range of
5–10 pmoles/ml.19 In perfused tubules, where the contri-
bution resulting from glomerular filtration is prevented,
Ang II concentrations are similar to those in nonperfused
tubules indicating that the proximal tubule secretes Ang II
or a precursor into the proximal tubule fluid. In addition to
AGT, proximal tubule cells have renin that can act on AGT
to generate Ang I. Evidence that renin is augmented in the
urine of chronic Ang II-infused rats also indicates secretion
of renin by the collecting duct cell into the tubular lumen16
and provides a pathway for Ang I generation from proxi-
mally delivered AGT, leading to concentrations of Ang II in
distal tubular fluid in the picomolar range.34
Intracellular Angiotensin II
Ang II is internalized via AT1–receptor-mediated endo-
cytosis and endosomal accumulation of Ang II in inter-
microvillar clefts and endosomes is increased further in
Ang II infused hypertensive rats.35 AT1 receptor block-
ade prevents the endosomal accumulation even though
plasma Ang II increases. The presence of Ang II in renal
endosomes indicates that some of the internalized Ang II
remains intact and contributes to the total Ang II content
measured in tissue homogenates.35 Endocytosis of the Ang
II-AT1 receptor complex is required for the full expression
of functional responses coupled to the activation of signal
transduction pathways, but the full extent of the functions
exerted by intracellular Ang II has not been determined.15
In Ang-II-dependent hypertension, a higher fraction of
the total kidney Ang II is internalized into intracellular
endosomes consisting of both light endosomes and inter-
microvillar clefts via an AT1-receptor-mediated process.
AT1 receptor blockade prevents the augmentation of intra-
cellular Ang II.35
FIGURE 3 Intratubular processing of the renin–angiotensin system. All components of the renin–angiotensin system are present in the kidney provid-
ing multiple pathways for enhanced intrarenal Ang II formation. PT—proximal tubule; DT—distal tubule; CD—collecting duct; AGT—angiotensinogen;
JGA—juxtaglomerular apparatus; AA—afferent arteriole; EA—efferent arteriole; ACE—angiotensin converting enzyme; PRR—(pro)renin receptor (modi-
fied from Ref. 19).
6. Chapter | 204 Renin–Angiotensin System
1504
Our understanding of the functions of internalized Ang
II remains incomplete. Ang II may be recycled and secreted
to exert further actions by binding to Ang II receptors on
the cell membranes. Ang II may also act on cytosolic recep-
tors to activate intracellular signaling mechanisms.15 Ang II
may also migrate to the nucleus to exert genomic effects.21
Nuclear binding sites of the AT1 subtype in renal cells have
been reported. Because Ang II exerts a positive stimulation
on AGT mRNA and protein production, intracellular Ang II
may have genomic actions to regulate AGT or renin mRNA
expression in proximal tubule cells either directly or via
NF-κB.1,21,30
BIOLOGICAL ACTIONS
OF INTRARENAL ANG II
In view of the near ubiquitous distribution of Ang II recep-
tors in the various structures of the kidney, it is not surpris-
ing that Ang II exerts pleiotropic effects at multiple levels
within the kidney. As shown in Figure 2, the actions of Ang
II span both cortical and medullary, vascular and tubular
and can be stimulatory or inhibitory.18 At the level of the
vasculature, Ang II exerts important direct and indirect
effects to regulate vascular tone of the afferent and efferent
arterioles and of the mesangial cells.17 Ang II also regulates
afferent arteriolar tone through its influence on the tubulo-
glomerular feedback mechanism with elevated Ang II levels
increasing the sensitivity of the feedback mechanism, thus
regulating the amount of filtrate that escapes the proximal
nephron and enters the distal nephron segments. In the post-
glomerular circulation, Ang II regulates both the cortical
and medullary capillary blood flow and helps to regulate
the relative blood flowing to the medullary tissues through
its control of the tone of the pericytes.17
Interestingly, although Ang II constricts both afferent
and efferent arterioles, the mechanisms are different. The
afferent arteriolar constrictor responses to Ang II involve
activation of L-type Ca++ channels to provide sustained
Ca++ entry and vasoconstriction.17 By contrast, efferent
arterioles of normal rats do not vasodilate or vasodilate
much less in response to L-type Ca++ channel blockers
and the vasoconstrictor effects of Ang II are not blocked
by L-type Ca++ channel blockers. Rather, T-type channels
have greater functional significance in regulating the effer-
ent arteriolar constrictor responses to Ang II.17 T-type Ca++
channel blockers markedly attenuate the efferent vasocon-
strictor responses to Ang II. Storage operated Ca++ chan-
nels in efferent and afferent arterioles are also activated by
Ang II. Thus, although both afferent and efferent arterioles
respond to Ang II, the mechanisms for Ca++ entry and the
activation pathways are different. These differences may be
attributable to the differential abundance of AT1A and AT1B
receptors on the afferent and efferent arterioles.10
Virtually, all aspects of the filtration and tubular reab-
sorptive processes are influenced by Ang II. Ang II directly
regulates the glomerular filtration coefficient with high Ang
II concentrations reducing and low levels or blockade of
AT1 receptors increasing the filtration coefficient.17,18 At
the level of the proximal tubule, Ang II binds to receptors at
both the apical and basolateral membranes, stimulating the
activity of the sodium/hydrogen exchanger and the sodium
bicarbonate co-transporter, thereby exerting an important
influence on net proximal reabsorption rate.18 Transport
mechanisms in the proximal tubule, loop of Henle, and dis-
tal nephron segments are also influenced by Ang II.18,27,34
Under conditions in which the activity of the RAS is
stimulated and greater amounts of AGT are secreted from
the proximal tubule, the locus of influence shifts to include
the distal nephron segments where the interaction between
the (P)RR and renin/prorenin may contribute substantially
to increase intrarenal and intratubular formation of Ang II
(Fig. 4).7,20 The in vivo demonstration that increased urinary
Ang II concentrations in mice infused chronically with Ang
II enhance distal sodium reabsorption34 emphasizes further
the importance that renin and the (P)RR may have in the
distal nephron segments contributing to the increases in
intratubular Ang II formation. Ang II stimulates the sodium/
hydrogen exchanger and the sodium chloride cotransporter
in distal tubules, and the amiloride sensitive sodium channel
in principal cells of connecting tubules and collecting duct
segments.20,23 This enhanced stimulatory effect allows the
kidney to have maximum capability to conserve sodium by
markedly decreasing fractional sodium reabsorption.34 At
the whole kidney level, this is manifested as a marked sup-
pression of the pressure natriuresis relationship. Ang II also
regulates acid base balance through its effects on the Na+/
H+ exchanger as well as by influencing the activity of the
H+ ATPase in intercalated cells.2 Collectively, the actions of
Ang II allow the kidney to maximize sodium conservation
without compromising its ability to regulate its many other
functions.
CONCLUDING COMMENTS
AND PERSPECTIVE
Recent findings have stimulated interest in the molecular
mechanisms regulating the various components of the intra-
renal RAS and particularly the interstitial, intracellular, and
intratubular concentrations of Ang II and related peptides.
Intratubular and interstitial Ang II levels are regulated inde-
pendently of the circulatingAng II and exert powerful actions
via the stimulation of AT1 receptors on the vascular, glomer-
ular, and tubular structures to provide a synchronous cascade
of effects contributing to the ability of the kidney to retain
>99% of the filtered sodium. From a functional perspective,
the effects of Ang II on proximal nephron reabsorption as
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SECTION | XV Handbook of Biologically Active Peptides: Renal Peptides
well as on distal nephron transport function, coupled with
the associated actions of elevated aldosterone levels, mark-
edly increase the sodium retaining capability of the kidney.
When activated in a physiologically appropriate setting under
conditions of volume contraction or salt deficient states,
these actions can be life saving. When inappropriately main-
tained or augmented, however, these effects contribute to the
development and maintenance of hypertension. Further, the
sustained increases in intrarenal Ang II in a setting of hyper-
tension can lead to progressive renal injury, cell proliferation,
and fibrosis associated with activation of several major cyto-
kines and growth factors.12,33
ACKNOWLEDGMENTS
The authors thank Debbie Olavarrieta for the preparation of the man-
uscript and figures. The authors’ research related to this review has
been supported by research grants from NHLBI, NIDDK, NCRR, and
AHA.
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