Nephrol Dial Transplant (2007) 22: 1281–1288
doi:10.1093/ndt/gfm077
Advance Access publication 8 March 2007
Editorial Comments
Novel sources of reactive oxygen species in the human body
Anna Orient1, Ágnes Donkó1, Attila Szabó2, Thomas L. Leto3 and Miklós Geiszt1
1
Department of Physiology, 2First Department of Pediatrics, Semmelweis University, Faculty of Medicine, Budapest,
Hungary and 3Laboratory of Host Defenses, National Institue of Allergy and Infectious diseases, NIH, Bethesda, USA
Keywords: hydrogen peroxide; NADPH oxidase; Nox;
reactive oxygen species; ROS; superoxide
Introduction
There are several sources of reactive oxygen in the
human body. Production of superoxide in mitochondria is a by-product of the function of the respiratory
chain [1]. The first known example of regulated
generation of reactive oxygen species (ROS) in
mammalian cells was through the respiratory burst of
phagocytic cells by nicotinamide adenine dinucleotide
phosphate (NADPH) oxidase. This enzyme complex
uses electrons derived from intracellular NADPH to
generate superoxide anion, which is further processed
to form hydrogen peroxide and other ROS-providing
host defense against bacterial and fungal pathogens [2].
The essential role of the phagocytic oxidase in host
defense is well illustrated by the serious phenotype of
chronic granulomatous disease (CGD), in which
susceptibility to infections develops in the absence of
a functional phagocytic oxidase [3].
Non-mitochondrial production of ROS was detected
in various cell types, showing that intentional generation of ROS is a general feature of many tissues, rather
than a unique function of phagocytes. Homology
searches in human genome databases resulted in the
discovery of six novel NADPH oxidase enzymes:
Nox1, Nox3, Nox4, Nox5, Duox1 and Duox2 [4–6].
They all have at least partially similar structure and
generate ROS in response to various stimuli. The
physiological function of these proteins and their
potential role in the pathogenesis of human diseases
is currently under intensive investigation.
Correspondence and offprint requests to: Miklós Geiszt, Department
of Physiology, Semmelweis University, Faculty of Medicine,
PO Box 259, H-1444 Budapest, Hungary.
Email: [email protected]
Structural aspects
The phagocytic oxidase is a multi-protein enzyme
complex, consisting of a membrane-bound flavocytochrome and several cytosolic regulators [2]. The
flavocytochrome b558 has two parts: the Nox family
member and ‘prototype’ gp91phox (now designated
Nox2) and the smaller subunit p22phox. The N-terminal
part of Nox2 is composed of six transmembrane
segments. This region contains four conserved histidine
residues, which are responsible for haem binding. The
two haems, embedded within the channel of the six ahelices, enable the transfer of electrons through the
membrane. The carboxyl terminus of Nox2 has motifs
for binding the coenzymes NADPH and flavin adenine
dinucleotide (FAD).
Nox1, 3 and 4 are similar in size and domain
structure to gp91phox [7–9]. Among them, Nox1 and
Nox3 show the closest homology to Nox2, while Nox4
is more distantly related to Nox2. Nox5 is larger than
Nox2 because it has four additional cytosolic EF hands
(motifs from the parvalbumin E & F helices) on its
N-terminus [10]. These motifs are responsible for the
regulation of proteins by Ca2þ. Duox1 and 2 are the
largest members of the Nox/Duox family [11]. They are
called Dual oxidases because they possess an
N-terminal peroxidase-homology domain in addition
to their C-terminal NADPH oxidase domain. Between
the NADPH oxidase portion and the peroxidase-like
domain there is an additional trans-membrane domain
and two EF-hand motifs, representing targets of
regulation by calcium ions.
Regulation
In phagocytic cells, in addition to flavocytochrome
b558, which consist of gp91phox and p22phox, there are
other regulatory components needed for ROS production: p47phox, p67phox, p40phox and the small guanosine
triphosphate (GTP) Rac2 [2] (Figure 1). P47phox,
p67phox and Rac2 are essential regulators of Nox2,
since a deficiency in any of these proteins results in
immunodeficiency with absent or diminished
ß The Author [2007]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.
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Nephrol Dial Transplant (2007) 22: Editorial Comments
A
B
.
–
O2
phox
p22phox
Nox4
+ H+ p22
Nox4
NADPH
NADP++ +H++
The phagocyte oxidase
The renal oxidase
Fig. 1. Molecular composition of the phagocyte- and renal-oxidase. (A) The phagocyte oxidase is a multicomponent enzyme which is
localized to the phagosomal membrane during phagocytosis. (B) The renal oxidase contains Nox4 and probably p22phox. The exact
intracellular localization of Nox4 is currently unknown.
superoxide production [3] Unstimulated phagocytes
have inactive cytochrome b558 stored within intracellular membranes; during activation, the cytosolic
regulators are translocated to the catalytic core.
P67phox and Rac seem to regulate catalysis directly,
while p47phox is a classical adapter protein, linking
p67phox to the gp91phox [2].
Our understanding of how other Nox/Duox proteins
are regulated is far from complete, although recently it
became evident that striking similarities exist between
the regulation of phagocytic and non-phagocytic
oxidases. First p22phox, which is an essential partner
of Nox2, can also form a functional complex with
Nox1, Nox3, and Nox4 [12–15]. This finding explains
previous studies, where high-level p22phox expression
was described in non-phagocytic tissues [16]. Nox5
and Duox proteins probably function independently of
p22phox, since Duox proteins are present and active
in lower species where p22phox homologues are not
expressed (Geiszt et al., unpublished data).
Based on the high structural homology between
Nox1 and Nox2, it seemed likely that Nox1 is also
regulated by cytosolic proteins. Indeed, the cytosolic
components of the phagocytic NADPH oxidase
(p47phox and p67phox) could also increase the enzymatic
activity of Nox1 [17]. Based on homology with p47phox
and p67phox two novel regulator proteins were identified in colon epithelial cells, which are now designated as NOXO1 and NOXA1 [12,18,19]. NOXO1 is
homologous to p47phox and NOXA1 is homologous
to p67phox. Their function in the regulation of Nox1
was confirmed in heterologous co-expression
experiments. The small GTPase Rac1 also regulates
Nox1, since Noxa1 binds Rac1 in a GTP-dependent
manner [12] and Nox1-mediated superoxide production is effectively reduced by mutant Rac1 proteins and
Rac1-specific siRNA [15,20,21]. The activity of Nox1
is probably also regulated at the transcriptional level.
In mesangial cells, nitric oxide (NO) inhibits the
expression of Nox1, suggesting a crosstalk between
NO and superoxide-generating systems [22].
The activity of Nox3 is also subject to regulation by
cytosolic proteins. Data obtained from experiments
with transfected cell lines suggest that Nox3 is able
to produce low amounts of superoxide in the absence
of cytosolic regulators [14]; however, its enzymatic
activity is effectively stimulated by p47phox and p67phox
[14,23,24]. NOXO1 is able to increase ROS production
in Nox3-expressing cells, and this stimulatory effect
seems to depend on p22phox [16,24,25]. Recent genetic
evidence supports the role of NOXO1 in the regulation
of Nox3 [26]. Similarly to its role in the regulation
of Nox1 and Nox2, Rac1 also regulates the activity of
Nox3 [15].
We have little information on the regulation of
Nox4. Nox4 seems to be constitutively active even in
the absence of the cytosolic regulators, and expression
of cytosolic Nox regulators in various combinations
had no effect on the ROS output of Nox4-expressing
cells [27]. As mentioned above, p22phox can form a
complex with Nox4, but it does not appear to serve as
a docking point for the known cytosolic regulators [25]
(Figure 1).
Nephrol Dial Transplant (2007) 22: Editorial Comments
Nox5 and Duox proteins all contain calcium-binding
EF-hand motifs, suggesting that calcium signals that
can arise in cells through several mechanisms regulate
the activity of these enzymes. In fact, Nox5-expressing
cells produce ROS when stimulated by calcium
ionophores [10,28] and calcium is also an effective
stimulus of different Duox-expressing cells [29,30].
Both Nox5 and Duox2 can be activated in cell-free
systems by calcium [28,30]; in the case of Nox5, this
appears to involve a direct intramolecular interaction
of the calcium-binding EF-hands with the C-terminal
domain [28]. It is possible that Nox5 and Duox
proteins also have cytosolic regulators, but the identity
of such proteins remains unknown. Grasberger and
Refetoff [31] have recently identified Duox maturation
factors (DUOXA1 and DUOXA2) which are necessary
for the expression of functional Duox proteins.
Expression pattern
A common feature of the Nox/Duox family of oxidases
is their widespread expression pattern, although they
frequently exhibit their highest expression within
specific tissues and cell types. Nox1 is highly expressed
in colon epithelial cells, where it is readily detected by
Northern blotting, in situ hybridization, and immunohistochemistry [7,17,32]. Besides its primary site of
expression, Nox1 was also detected in several other cell
types, including gastric mucosal cells [33], smooth
muscle cells [7] and osteoclasts [34] The primary site of
Nox3 expression is in the inner ear [23,35], where the
enzyme is present in vestibular and cochlear epithelial
cells and also in spiral ganglions [23]. The expression
pattern of human Nox3 is currently unknown, but
based on the high sequence homology between human
and murine homologues, it is likely that in humans,
Nox3 is also present in the inner ear. Lower level of
Nox3 expression was detected in human fetal tissues,
including fetal kidney [9]. Nox5 is expressed in
lymphoid tissues such as spleen and lymph nodes
and it is also present in the testis, where pachytene
spermatocytes seem to express Nox5 [10]. Dual
oxidases 1 and 2 were originally described in the
thyroid gland [36,37], but subsequent studies have
demonstrated that their expression is not limited to the
thyroid, since they are present in many other tissues
including the airways, salivary glands and gastrointestinal system [38–40]. In all of these tissues epithelial
cells are the primary sites of Duox expression.
The expression pattern of Nox4 will be detailed in
a separate chapter.
Functional aspects
While Nox2 has a key role in antimicrobial host
defense, the function of other Nox/Duox isoforms
is far less understood. Many observations indicate
that Nox1 could also have a role in host defense.
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The colon, where Nox1 is highly expressed, is inhabited
by a variety of microorganisms and must therefore
maintain an effective epithelial barrier against invasion
of the host. In guinea pig gastric cells, Helicobacter
pylori lipopolysacharides (LPS) induce elevated
Nox1 and thereby produce higher ROS levels through
toll-like receptor 4 (TLR) pathways [33]. Although
colon epithelial cells lack this receptor, and do not
react to LPS, Nox1-mediated ROS production in
response to flagellin from Salmonella enteritides
is mediated through TLR5 in these cells [33]. Viral
introduction of Nox1 into Nox2-lacking CGD
neutrophils can partly replace Nox2, and thereby
partially rescue the deficiency in superoxide production, suggesting a role in innate immunity [17]. Nox1
expression in different colon epithelial cell lines is
effectively up-regulated by the inflammatory cytokine
IFN-gamma [17,41], which further supports a role
for Nox1 in mucosal host defense.
Originally Nox1 was described as a ROS source that
stimulates mitogenesis when over-expressed in NIH
3T3 cells [7]. Experiments performed on other cell lines
did not support this early claim and found no effect
of elevated Nox1 expression on mitogenesis [17].
Furthermore, studies on Nox1 expression in colon
cancer samples found no positive correlation between
Nox1 expression levels and proliferation or malignancy
[17,42,43]; in two studies the more differentiated colon
tumours were found to express higher Nox1 levels
[17,42]. On the other hand, Lim et al. [44] found
increased Nox1 expression and hydrogen peroxide
production in prostate cancer samples.
Another intensively studied area of Nox1 function
is its role in the vascular smooth muscle cells.
Many agonists such as platelet-derived growth factor
(PDGF), angiotensin II, prostaglandin F2a up-regulate Nox1 expression, whereas suppression of Nox1 by
antisense techniques inhibits superoxide production in
cultured smooth muscle cells [7]. Overproduction of
ROS by Nox1 could lead to cell proliferation,
hypertrophy, and, partly through degradation of NO,
to increased blood pressure. Recently, three studies
using transgenic animals suggested that Nox1 might be
involved in the development of angiotensin II-induced
hypertension [45–47]. Since Nox1 is also expressed in
the kidney [22,48] future studies should focus on the
potential role of renal Nox1 in the development of
angiotensin II-induced hypertension.
Nox3 was recently shown to have a role in otoconia
formation in the utricle and saccule of the inner ear
[35]. Nox3-deficient mice are characterized by impaired
balance and the lack of otoconia in the inner ear.
The exclusive expression in inner ear (sensory epithelia
and ganglia) corresponds with this observation [23].
Nox5 mRNA is expressed in testis, in pachytene
spermatocytes, and in spleen, where it localizes to the
B-cell rich mantle zone, surrounding germinal centers,
and to periarterial lymphoid sheets [10]. Interestingly,
lymphocytes from circulating blood are Nox5 negative. In lymphoid tissues, the physiological role of
this calcium-regulated ROS production is unclear.
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Nephrol Dial Transplant (2007) 22: Editorial Comments
Since host defense can be excluded, function in
redox regulation of signalling pathways is the most
likely explanation. In spermatocytes, a function in
oxidative changes associated with sperm capacitation
or the acrosomal reaction is suggested.
Duox1 and 2 were cloned from thyroid glands and
were named at first as thyroid oxidases (thOX or tox)
[36,37]. In the thyroid gland, the enzymes are used in
iodide organification during thyroid hormone biosynthesis. The significance of two highly homologous
Duox enzymes in the thyroid gland is not yet known.
Patients with Duox2 deficiency have congenital hypothyroidism, which illustrates the essential role of
Duox2 in thyroxine synthesis [49]. Duox enzymes are
also present in other locations in the human body,
where a role in hormone biosynthesis is not likely.
It was proposed that in these tissues, Duox proteins
would represent the missing, ROS-producing arm of
the lactoperoxidase host defense system [38].
Nox 4, the renal oxidase
Nox 4 was first described as a renal-specific oxidase
[8,50], and was thus originally named Renox. In situ
hybridization experiments localized Nox4 mRNA
expression to renal cortex in murine kidney, while
the medulla showed much lower expression. Within
the cortex, epithelial cells of proximal tubules express
Antisense
Nox4. Interestingly, in human kidney we detected
Nox4 mRNA in medullary collecting ducts
and also in epithelium on renal papillas (Figure 2).
Immunohistochemical studies also showed Nox4
expression in distal portions of the human nephron
[50]. Nox4 is also found in mesangial cells of rat kidney
[51]. Nox4 is expressed in many other tissues and cells
including fetal liver, vascular endothelial cells, murine
osteoclasts [8,52–54]. When over-expressed in NIH3T3 fibroblasts, Nox4 increased superoxide production
and decreased cell proliferation and induced the
phenotype of cellular senescence [8]. The physiological
function of Nox4 is currently unknown. Nox4 may
serve different roles depending on the tissue where it is
expressed and its function as a ROS producer. The
expression pattern of Nox4 in the kidney is consistent
with several renal-specific functions. We originally
suggested that Nox4 might be the long-sought oxygen
sensor that could regulate erythropoietin (EPO)
production in the kidney. This hypothesis is supported
by several findings. The potassium channel TASK-1,
which is expressed in oxygen-sensing cells, is inhibited
by hypoxia and the oxygen sensitivity of TASK-1
seems to be modulated by the activity of Nox4 [55].
Nox2, the phagocytic homologue of Nox4, was
described as an oxygen sensor in the lung [56]. In the
murine kidney, EPO synthesis occurs in the proximal
tubules [57] or in close proximity to proximal tubules
[58], which would make Nox4 an ideally located sensor
Sense (control)
A
B
C
D
Fig. 2. Detection of Nox4 mRNA in the human kidney medulla by in situ hybridization. Antisense (A, C) and sense (B, D) probes
demonstrate specific expression of Nox4 mRNA in cells of medullary collecting ducts (A) and in epithelial cells of renal papilla (C).
Superimposed polarized epi-illumination and bright-field images (in which the hybridization signal appears green).
Nephrol Dial Transplant (2007) 22: Editorial Comments
1285
Table 1. Tissue distribution, protein interactions and functions of Nox/Duox enzymes [4–6]
Enzyme
Other names
Site of expression
Protein interactions
Function
Nox2
gp91phox
Myeloid cells
Host defense Signalling?
Nox1
Mox1, NOH-L
Colon, VSMC, prostate, uterus
p22phox, p47phox,p67phox,
Rac1,Rac2
p22phox, NOXO1,
NOXA1, Rac1
p22phox, NOXO1, Rac1
p22phox
Nox3
Nox4
Nox5
Duox1& 2
Renox
Thox, Tox, LNOX
Inner ear, fetal tissues
Kidney, endothelium, osteoclast
Lymph nodes, spleen, testis
Thyroid, lung, salivary glands,
gastro-intestinal tract
Host defense?
Blood pressure regulation
Otoconia Biosynthesis
Oxygen sensing?, Vasoregulation?
Signalling?
Hormone synthesis Host defense?
Bold types mark functions and protein interactions which are supported by genetic evidence.
to regulate this process. Although proline hydroxylases
are now considered the primary sensors of oxygen and
regulators of hypoxia-inducible factor-1alpha (HIF)
levels [59], recent observations suggest that Nox4 can
also regulate HIF through ROS production [60].
Furthermore, there are transcription factors such as
GATA-2 that are H2O2-sensitive targets, that regulate
EPO expression in a HIF-independent manner [61].
Finally, it was shown in recent studies that superoxide dismutase 3, which is also present in the
proximal tubules, has a role in the regulation of EPO
production [62].
It is also possible that Nox4, similar to its phagocytic
counterpart, has a role in host defense. The expression
pattern detected in the human kidney (Figure 2)
would support such a function, since Nox4 is mainly
expressed in the medullary part of the human kidney.
Producing microbicidal ROS at that locus of the
kidney would provide an effective defense against
infectious pathogens, which usually originate from the
lower urinary tract. In support of this idea, it has been
known for years that the urine contains hydrogen
peroxide in relatively high concentrations [63].
Nox4 might also have a role in the development
of the renal complications of diabetes mellitus. Etoh
et al. [64] showed increased expression of Nox4 and
p22phox (both mRNA and protein) in the kidney of
streptozotocin-induced diabetic rats. The localization
of the two proteins was in parallel with the accumulation of 8-hydroy-deoxyguanosine (8-OHdG),
which is a marker for ROS-induced DNA damage.
In the same animal model of diabetes, antisense
oligonucleotides targeting Nox4 mRNA were effective
in reducing the hypertrophy and fibronectin expression
[65], which are characteristic markers of diabetic
nephropathy. These data point to a signalling role
for Nox4-derived ROS in the development of diabetic
nephropathy, but the specific target(s) of ROS remain
to be identified.
Nox4 was suggested to participate in insulin receptor
signal transduction [66]. In many cells, growth factors
and insulin stimulate low-level hydrogen peroxide
production. Hydrogen peroxide then inhibits tyrosine
phosphatases, thus enhancing the tyrosine phosphorylation induced by the receptor agonists [67]. Recently,
it was suggested that Nox4 is responsible for insulininduced H2O2 production in 3T3-L1 adipocytes [66].
Gorin et al. [51] showed that Nox4 is involved in
angiotensin II-induced ROS production in kidney
mesangial cells. Since PDGF receptor stimulation
also involves ROS production and enhanced cellular
protein phosphotyrosine levels, a role for Nox4 in this
receptor pathway was also suggested recently [68]; the
decreased growth factor responses of fibroblasts from
patients with Leprechaunism was attributed to downregulation of Nox4.
Nox4 may have important roles in the cardiovascular system. According to expression studies
performed on vascular endothelial cells, Nox4 seems
to be the dominant ROS source in endothelial
cells [53,69]. This localization is particularly exciting,
because it would mean that Nox4-produced superoxide
could effectively antagonize the effect of NO produced
in the same cell type. A recent publication [53] has
located endogenous Nox4 within the nucleus of human
umbilical endothelial cells (HUVECs). The nuclear
fraction of HUVEC cells produced superoxide in
a NADPH-dependent way. Earlier reports already
pointed to the nucleus as an intracellular site of ROS
production in endothelial cells [70], and NADPH
oxidase components were detected in nuclear fraction
of endothelial cells [70] and B lymphocytes [71]. The
nuclear localization of Nox4 suggests that it could
convey redox signals altering gene expression. This
suggestion is now supported by some experimental
evidence [53], but the idea requires more rigorous
testing. In blood vessels, Nox4 is also present
in smooth muscle cells, where it localizes to
the endoplasmic reticulum and nucleus [72,73].
7-ketocholesterol, a major oxysterol component in
low-density lipoprotein, stimulates the expression of
Nox4 in smooth muscle cells, thus, ROS production by
Nox4 might be responsible for the oxidative stress
induced by 7-ketocholesterol [72].
Nox4 is also present in the heart, where cardiac
fibroblasts express the enzyme. Transforming growth
factor (TGF)-b stimulates the conversion of fibroblasts
into myofibroblasts in a ROS-dependent manner.
Nox4 is the likely source of oxidants in this process,
since down-regulation of Nox4 expression by siRNA
1286
inhibited both ROS-production and the TGF-b
induced expression of smooth muscle actin [74].
The involvement of Nox4 in TGF-b signalling was
recently described in human pulmonary artery smooth
muscle cells and also in HUVECs [75,76].
Nox4 is also expressed in cells of haematopoietic
origin. CD34þ cells exhibit significant extra-mitochondrial oxygen consumption, which might be explained
by the activity of Nox2 and Nox4, which are both
detected by reverse transcriptase PCR [77]. The
significance of Nox2 expression in haematopoietic
stem cells is unclear, since no defect in blood cell
formation was described in Nox2-deficient CGD
patients or in animal models of CGD. Another extrarenal site of Nox4 expression is the murine osteoclast,
where Nox2 is also detected [54]. It is possible that
Nox4 and Nox2 together provide oxidative support for
bone resorption, although this hypothesis requires
further investigation.
Conclusion
With the discovery of novel NADPH oxidase
isoforms, a very exciting area has began in ROS
research. On the one hand, in tissues where the
production of ROS has already been described
(thyroid gland), we can now attribute this biological
response to the activity of specific enzymes, allowing
a more thorough understanding of the ROS-production process. On the other hand, the expression of
these enzymes at sites where ROS-production has
not been studied before expands our knowledge of
the importance of ROS signalling. The exact function
of the non-phagocytic Nox/Duox proteins remains
to be explored; however, it now seems likely that
different epithelial cells, particularly along mucosal
surfaces, use these proteins—especially Nox1, Duox1
and 2—for ROS-based host defense. High-level ROS
production at specific sites by non-phagocytic oxidases
suggests that they have additional unique functions,
such as hormone biosynthesis in thyrocytes (Duox2)
or formation of otoconia (Nox3). The involvement
in signalling is also an important question that must
be studied further. Among new challenges are the
collection of more data on the molecular assembly of
these novel enzymes and the identification of their
role in disease pathogenesis. It is likely that with
broader knowledge we will be able to define the role
of these novel ROS-sources in different disease
processes, which can arise from either under- or overproduction of ROS.
Acknowledgements. Experimental
work
in
the
authors’
laboratory was financially supported by grants from the
Hungarian Research Fund (OTKA 042573) and the Cystic
Fibrosis Foundation. M.G. is recipient of a Wellcome Trust
International Senior Fellowship.
Conflict of interest statement. None declared.
Nephrol Dial Transplant (2007) 22: Editorial Comments
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Received for publication: 2.1.06
Accepted in revised form: 26.1.07
Nephrol Dial Transplant (2007) 22: 1288–1292
doi:10.1093/ndt/gfl846
Advance Access publication 27 January 2007
Prorenin and the (pro)renin receptor—an update
A. H. Jan Danser, Wendy W. Batenburg and Joep H. M. van Esch
Department of Pharmacology, Erasmus MC, Dr Molewaterplein 50, 3015 GE Rotterdam, The Netherlands
Keywords: angiotensin; diabetes; fibrosis; heart;
hypertrophy; kidney; MAP kinase; prorenin;
(pro)renin receptor; renin
Introduction
Blockers of the renin–angiotensin system (RAS) are
widely used for the treatment of cardiovascular and
renal diseases. It is generally assumed that the
beneficial effects of these drugs are due, at least in
part, to blockade of the generation or action of
angiotensin (Ang) II at tissue sites [1]. According to
this concept, Ang II is generated at tissue sites rather
Correspondence and offprint requests to: Prof. Dr A. H. J. Danser,
PhD, Department of Pharmacology, Room EE1418b, Erasmus
MC, Dr Molewaterplein 50, 3015 GE Rotterdam, The Netherlands.
Email: [email protected]
than in circulating blood. Multiple lines of evidence
support this idea [2–5]. Remarkably, however,
although several RAS components are locally
expressed [e.g. ACE, Ang II type 1 (AT1) and type 2
(AT2) receptors] [6–8], thereby allowing such local
activity, renin is not [9,10]. Thus, the renin required
for local Ang production is sequestered from the
circulation, i.e. is kidney-derived. Importantly, renin
has an inactive precursor, prorenin. Prorenin is
released constitutively from the kidney, and its blood
plasma levels are 10-fold higher than those of
renin [11].
What does prorenin do?
For many years, prorenin was simply considered to be
the inactive precursor of renin, without having a
function of its own. Chronic stimulation of the RAS