A crosstransplantation study between genetically matched angiotensin AT1 receptor knockout and wild-type mice revealed that renal AT1 receptors are required for the development of angiotensin II-induced hypertension (Crowley et al., 2006). However, in this experimental setting, hypertension-related left ventricular hypertrophy seemed to depend on blood pressure elevation rather than on the expression of AT1 receptors in the heart

Rettig, Rainer

Steckelings, Ulrike Muscha

Unger, Thomas

Elsevier - Publisher Connector 

Angiotensin in the Kidney: A Key to Understanding Hypertension? 

Cell Metabolism
PreviewsAngiotensin in the Kidney:
A Key to Understanding Hypertension?
Ulrike Muscha Steckelings,1 Rainer Rettig,2 and Thomas Unger1,*
1Center for Cardiovascular Research, Institute of Pharmacology, Charite´-Universita¨tsmedizin Berlin, 10115 Berlin, Germany
2 Institute of Physiology, University of Greifswald, 17495 Karlsburg, Germany
*Correspondence: thomas.unger@charite.de
DOI 10.1016/j.cmet.2006.12.007
A crosstransplantation study between genetically matched angiotensin AT1 receptor knockout
andwild-typemice revealed that renal AT1 receptors are required for the development of angiotensin
II-induced hypertension (Crowley et al., 2006). However, in this experimental setting, hypertension-
related left ventricular hypertrophy seemed to depend on blood pressure elevation rather than on
the expression of AT1 receptors in the heart.Hypertension and resulting end-organ
damage such as stroke, heart failure,
myocardial infarction, and renal dis-
ease rank among the leading causes
of death in industrialized nations.
Although the selection of antihyperten-
sive medication is broad and stringent
therapy in most cases effectively
lowers elevated blood pressure (BP),
the cause of so-called primary hyper-
tension, which accounts for more than
90% of cases, is still not understood.
In the search for the genesis of pri-
mary hypertension, the kidney has
long been suspected to play a key
role. Studies based on the transplanta-
tion of kidneys from hypertensive into
normotensive rats or mice and vice
versa have provided profound evi-
dence for this assumption because in
most of these experiments, hyperten-
sion or normotension was transferred
with the transplanted kidney (Rettig
and Grisk, 2005).
The renin-angiotensin system (RAS),
in particular its effector hormone an-
giotensin II (Ang II), is a key regulator
of BP. Several actions leading to an in-
crease in BP are elicited by Ang II via
the angiotensin AT1 receptor (AT1R),
including vasoconstriction, renal so-
dium reabsorption (directly or through
the release of aldosterone), vasopres-
sin release, and facilitation of sympa-
thetic nerve activity. Ang II via the
AT1R also significantly contributes to
end-organ damage. Interference with
the RAS, by AT1R blockade or ACE
inhibition, is a potent way of pharma-
ceutically reducing BP and prevent-
ing end-organ damage. However, thequestion remained of whether all of
the listed actions of Ang II, targeting
different organs and tissues, contrib-
ute equally to hypertension in vivo.
Crowley et al. (2006) recently ad-
dressed this question, specifically
aiming at the impact of renal AT1R on
the pathogenesis of hypertension and
left ventricular hypertrophy. In a cross-
transplantation model, they used
genetically matched F1(C57BL/6 3
129) wild-type mice (WT mice) and
F1(C57BL/6 3 129) mice homozygous
for a targeted disruption of the Agtr1a
gene locus encoding the AT1aR
(AT1aR-KO mice). Four groups of
mice were generated in this study (Fig-
ure 1): (A) WT mice transplanted with
a kidney from a WT donor (WT group),
(B) a ‘‘kidney KO’’ group with WT re-
cipients of a kidney from AT1aR-KO
donors, (C) a ‘‘system KO’’ group
consisting of AT1aR/KO mice trans-
planted with a WT kidney, and (D)
AT1aR-KO mice transplanted with
AT1aR-KO kidneys (total KO group).
In all transplanted animals, kidney
function was provided solely by the
transplanted kidney.
BaselineBP inmiceof all groupswas
normotensive. Hypertension was in-
duced by continuous infusion of Ang
II (1000 ng/kg/min) by osmotic mini-
pumps over a period of 4 weeks. In
the second half of the observation pe-
riod, from week 2 to week 4, BP levels
in all groups came to an equilibrium,
revealing that only those animals carry-
ing a WT kidney developed hyperten-
sion. Remarkably, those animals ex-
pressing AT1aR in the periphery butCell Metabolismnot in the kidney (kidney KO group)
stayed normotensive (although on a
slightly higher level than the total KO
mice), while those mice expressing
AT1aR only in the kidney (systemic
KO group) became hypertensive to an
extent comparable to WT mice. The
authors interpret a slower increase in
BP in systemic KO compared to WT
mice and an early but short-lasting
increase in BP in the kidney KO mice
as resulting from early peripheral
vasoconstriction (which is lacking in
systemic KO mice).
Looking for the BP-elevating renal
mechanisms, the authors found that
Ang II induced sodium reabsorption,
which was followed by expanded
body fluid volume in those mice carry-
ing a WT kidney, but not in kidney KO
and total KO mice.
Interestingly, the authors also
looked at hypertension-induced left
ventricular hypertrophy (LVH) in their
model as an indicator of end-organ
damage. They found that LVH primar-
ily depended on BP elevation—more
than on the stimulation of cardiac
AT1R. This conclusion was based on
the observation that systemic KO
mice (which are hypertensive but do
not express AT1R in the heart) develop
LVH, whereas kidney KO mice (which
are normotensive and possess cardiac
AT1R) do not.
The study by Crowley et al. (2006)
continues the more than 30-year-old
tradition of crosstransplantation ex-
periments aiming at examining the
role of the kidney in hypertension (Re-
ttig and Grisk, 2005). In most of these5, January 2007 ª2007 Elsevier Inc. 7
Cell Metabolism
PreviewsFigure 1. Design of the Kidney Crosstransplantation Study
(A) Wild-type mice transplanted with a kidney from a WT donor, thus exhibiting a normal
expression of AT1aR in all organs, including the kidney.
(B) ‘‘Kidney KO’’ mice: WT recipients of a kidney from AT1aR-KO donors, thus lacking AT1aR only
in the kidney.
(C) ‘‘System KO’’ mice: AT1aR/KO mice transplanted with a WT kidney, resulting in AT1aR
function only in the kidney.
(D) AT1aR-KO mice transplanted with AT1aR-KO kidneys (total KO group), thus completely
lacking AT1aR.
In all transplanted animals, kidney function was solely provided by the transplanted kidney.
(Figure adapted from Crowley et al., 2005.)studies, including studies in humans,
hypertension (or normotension) has
been transplanted with the kidney. At
first glance, these data seem to doubt-
lessly support the hypothesis that the
determinants of hypertension are lo-
cated within the kidney. However,
a common experience of scientists
also applies to these studies: Things
are not that easy!
For example, interpreting the cross-
transplantation studies, one has to
keep in mind that none of themany an-
imalmodels used in these experiments
(e.g., Dahl salt-sensitive hypertensive
rats, Milan rats, stroke-prone sponta-
neously hypertensive rats [SHR-SP],
and Prague hypertensive rats) really
resembles primary hypertension in hu-
mans (Dahl and Heine, 1975; Bianchi
et al., 1973; Rettig et al., 1989; Heller
et al., 1996). This also holds true for
the model of Ang II-induced hyperten-
sion used in the study by Crowley et al.
(2006). In most patients suffering from
primary hypertension, Ang II plasma
levels are apparently normal. Raised
Ang II plasma levels are mainly found
in secondary hypertension—e.g., due
to renal artery stenosis. Therefore, ob-
servations and conclusions made in8 Cell Metabolism 5, January 2007 ª200this study refer to Ang II-induced hy-
pertension—and not necessarily to
primary hypertension. For the same
reason, the authors should perhaps
bemore cautious with their statements
regarding the effectiveness of AT1R
blockers (ARB) and ACE inhibitors in
hypertension and prevention of LVH.
So far, no experimental evidence sup-
ports their hypothesis that ‘‘the bene-
fits of these agents in LVH are not
a consequence of blocking cellular
actions of Ang II in the heart, but may
be due to differences in the degree or
pattern of blood pressure control that
was achieved.’’ The authors also do
not discuss that the ARB losartan
proved to be more effective than
a b blocker for the prevention and
regression of LVH despite equal BP
reduction in the large clinical LIFE
study (Dahlo¨f et al., 2002). More data
on the effectiveness of RAS inhibition
in LVH reduction when compared to
other antihypertensives will be avail-
able soon from the JIKEI HEART
Study, which is expected to be pub-
lished in 2007 (Mochizuki et al., 2004).
The authors provide good evidence
that reduced renal sodium excretion
may be a key pathogenic mechanism7 Elsevier Inc.in Ang II-induced hypertension. How-
ever, again, this does not necessarily
apply to hypertension in general or hu-
man primary hypertension in particular
because in crosstransplantation stud-
ies using another animal model (genet-
ically spontaneous hypertensive rats),
sodium retention was excluded as
the causal factor (Grisk et al., 2004).
In summary, the study by Crowley
et al. (2006) provides novel insight
into the mechanisms of Ang II-induced
hypertension and related end-organ
damage by means of an inventive ex-
perimental design using kidney cross-
transplantations between AT1aR-KO
mice and their WT counterparts. Their
data point to the kidney as the key
organ in the pathogenesis of Ang II-
induced hypertension and increased
sodium retention as the underlying
pathomechanism. However, the ques-
tion as to the pathomechanism under-
lying human primary hypertension
remains unanswered.
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Angiotensin in the Kidney: A Key to Understanding Hypertension?

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