Hypertension and kidney disease: is renalase a new player or an innocent bystander?

Abstract

Most patients on dialysis are hypertensive and their blood pressure (BP) control is often poor. Renalase is preferentially expressed in proximal tubules, but it is also present in glomeruli and distant tubules, as well as in cardiomyocytes, liver, and skeletal muscle. It had been proposed that renalase had a flavin adenine dinucleotide (FAD)-binding domain and that FAD was an essential cofactor for its stability and monoamine oxidase activity. It was reported that renalase, secreted by the kidney and circulating in the blood, degraded catecholamines and might play a role in the regulation of sympathetic tone and BP. It has been also proposed that renalase-coding gene is a novel susceptibility gene for essential hypertension and its variations may influence BP. In addition, polymorphisms of the renalase gene in hemodialysed patients were associated with hypertension. However, several unresolved and controversial issues still remain such as how to measure renalase and its physiological activity. Furthermore, there are few data on possible activators and/or inhibitors of renalase. We are at the very beginning of solving the problem of whether renalase is a causative factor of hypertension in kidney disease or just an innocent bystander. Therefore, more research is needed to establish whether renalase can become a useful therapeutic target.

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Hypertensionandkidneydisease:isrenalase
anewplayeroraninnocentbystander?
Jolanta Malyszkoa, Jacek S. Malyszkoa, Dimitri P. Mikhailidisb, Jacek Ryszc,
Marcin Zorawskid, and Maciej Banache
Most patients on dialysis are hypertensive and their blood
pressure (BP) control is often poor. Renalase is
preferentially expressed in proximal tubules, but it is also
present in glomeruli and distant tubules, as well as in
cardiomyocytes, liver, and skeletal muscle. It had been
proposed that renalase had a flavin adenine dinucleotide
(FAD)-binding domain and that FAD was an essential
cofactor for its stability and monoamine oxidase activity. It
was reported that renalase, secreted by the kidney and
circulating in the blood, degraded catecholamines and
might play a role in the regulation of sympathetic tone
and BP. It has been also proposed that renalase-coding
gene is a novel susceptibility gene for essential
hypertension and its variations may influence BP. In
addition, polymorphisms of the renalase gene in
hemodialysed patients were associated with hypertension.
However, several unresolved and controversial issues still
remain such as how to measure renalase and its
physiological activity. Furthermore, there are few data on
possible activators and/or inhibitors of renalase. We are at
the very beginning of solving the problem of whether
renalase is a causative factor of hypertension in kidney
disease or just an innocent bystander. Therefore, more
research is needed to establish whether renalase can
become a useful therapeutic target.
Keywords: blood pressure, hypertension, kidney diseases,
renalase
Abbreviations: BP, blood pressure; CKD, chronic kidney
disease; CVD, cardiovascular disease; ESRD, end-stage
renal disease; FAD, flavin adenine dinucleotide; LAD, left
anterior descending coronary artery; MAO, monoamine
oxidase; SSAO, semicarbazide-sensitive amine oxidase
INTRODUCTION
Hypertension and the sympathetic nervous
system in end-stage kidney disease
M
mortality [1]. The relationships between elevated BP and
cardiovascular mortality in patients with end-stage renal
disease (ESRD) are complex due to the high prevalence of
comorbid conditions and underlying vascular abnormal-
ities [1,2]. The rate of cardiovascular disease (CVD) is six to
ost patients starting dialysis are hypertensive,
suggesting that blood pressure (BP) control is
an important target to reduce cardiovascular
10 times higher in that population compared with those not
undergoing dialysis [3,4].
Worldwide, chronic renal failure and ESRD is increas-
ingly becoming a global public health problem [5,6]. It is
known that major established vascular risk factors (e.g.
hypertension, diabetes, dyslipidemia) occur more fre-
quently and with greater severity in those with a decreased
glomerular filtration rate [7]. Hypertension, the most preva-
lent controllable disease in developing countries, contrib-
utes to about 62% of all strokes and 49% of all causes of
heart disease in the adult population [8,9]. Most patients on
dialysis have hypertension, and BP control is often very
poor [10,11].
Several factors are involved in BP control and in CVD
that develops in ESRD [4,10]. These include sodium and
volume excess, activation of the renin–angiotensin–
aldosterone system, an overactive sympathetic nervous
system, increased activity of vasoconstrictive systems and
decreased activity of vasodilator systems, increased intra-
cellularcalcium, increased arterialstiffness,oxidativestress,
hyperparathyroidism, the administration of erythropoiesis-
stimulating agents, inflammation, sleep apnea, renovascu-
lar disease, and pre-existing hypertension [1,10–12].
Enhanced sympathetic activity is frequently reported in
ESRD [13] and correlates with the increase in both vascular
resistance and systemic BP [14] through unknown mech-
anisms. It seems that the afferent signal may arise within the
kidney, as sympathetic activation is not seen in anephric
patients [14]. Such activation declines, but does not normal-
ize, after successful kidney transplantation [15]. Thus, it has
been proposed that activation of chemoreceptors within
the kidney by uremic metabolites leads to a neural reflex
that through afferent pathways reached the central nervous
Journal of Hypertension 2012, 30:457–462
aDepartment of Nephrology and Transplantology, Medical University, Bialystok,
Poland,
School, University College London (UCL), London, UK,cDepartment of Nephrology,
Hypertension and Family Medicine, Medical University of Lodz, Lodz,dDepartment of
Pharmacology, Medical University, Bialystok and
Medical University of Lodz, Lodz, Poland
bDepartment of Clinical Biochemistry, University College London Medical
eDepartment of Hypertension,
Correspondence to Maciej Banach, MD, PhD, FAHA, FESC, FASA, FRSPH, Head,
DepartmentofHypertension,ChairofNephrologyandHypertension,WAMUniversity
Hospital in Lodz, Medical University of Lodz, Zeromskiego 113, 90-549 Lodz, Poland.
Tel: +48 42 639 3771; fax: +48 42 639 3782; e-mail: maciejbanach@aol.co.uk
Received 23 August 2011 Revised 2 October 2011 Accepted 9 November 2011
J Hypertens 30:457–462 ? 2012 Wolters Kluwer Health | Lippincott Williams &
Wilkins.
DOI:10.1097/HJH.0b013e32834f0bb7
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system, resulting in increased efferent sympathetic tone
[15]. Sympathetic nervous system activation in chronic
kidney disease (CKD) is an early event in the pathophysi-
ology of CKD, not a consequence of ESRD [14,15]. Acti-
vation of the sympathetic nervous system contributes
substantially to cardiovascular events in persons with
CKD, resulting in the poor prognosis for that population
[13]. Increased concentrations of catecholamines and
enhanced sensitivity to norepinephrine are the first
indicators ofoveractivity of the sympathetic nervoussystem
in CKD [16,17]. The elevated level of catecholamines in
patients with ESRD is the result of not only reduced
catecholamine clearance but also overspill involving the
mechanisms that inhibit nitric oxide (NO) and that are
associated with increased angiotensin II and increased
sympathetic afferent outflow from diseased kidneys [18].
Norepinephrine clearance is reduced by 20% in mild renal
failure and by up to 40% in patients receiving hemodialysis
[19]. Norepinephrine affects cardiomyocytes and could be
responsible for left ventricular hypertrophy [20]. Activation
of the sympathetic nervous system and vagal withdrawal
are closely linked to rhythm disturbances [21], which may
lead to sudden cardiac death, a common cause of mortality
in CKD [22].
Another concept regarding the pathogenesis of hyper-
tension in ESRD is abnormal endothelial release of hemo-
dynamically active compounds, that is, vasoconstrictors
and vasodilators [21,22]. NO is produced in endothelial
cells from L-arginine. In uremic plasma, there is a high
concentration of an endogenous compound, asymmetrical
dimethylarginine, which inhibits NO synthesis [23]. In
addition, in an animal model of CKD, NO synthase activity
progressively declines in the kidney [24]. This consequently
leads to oxidative stress due to enhanced production of
superoxide, which can stimulate sympathetic nerve activity
[25]. Thus, NO deficiency may contribute to the develop-
ment of hypertension in ESRD.
RENALASE AND THE KIDNEY
Discovery and properties of renalase
The kidney, among its various functions, is also an endo-
crine organ [26]. In 2005, Xu et al. [27] described the history
ofthediscoveryofrenalaseanditspossiblerole.Identifying
and characterizing renalase represents an impressive illus-
tration of the effective use of postgenomic technologies.
The renalase gene, according to information available in
the GenBank, is located on chromosome 10 at q23.33,
contains seven exons (NC_000010), and has two transcrip-
tion variants (1 and 2). It encodes four alternatively spliced
isoforms (hRenalase 1–4) [28], which can be tissue-specific
and reflect the particular function of renalase in these
tissues. Only hRenalase1 is detected in human blood
samples, which suggests that hRenalase2–4probably differ
in function from hRenalase 1 [28]. The calculated molecular
mass is approximately 38kDa. The mouse renalase gene,
residing on chromosome 19 C1, was also characterized [29].
Mouse renalase (mRenalase) is closely related to human
renalase 1 with 72% amino acid identity [29]. Xu et al. [27]
reported that renalase had a flavin adenine dinucleotide
(FAD)-binding domain and that FAD was an essential
cofactor for its stability and monoamine oxidase (MAO)
activity. However, the amino acid sequence of renalase
markedly differs from MAOs A and B, the main FAD-
dependent enzymes catalyzing oxidative deamination of
catecholamine in the body [27]. Renalase only shares 13.2%
of its identity with MAO-A [27]. Renalase is preferentially
expressed in proximal tubules, but it is also present in
glomeruli and distant tubules, as well as in cardiomyocytes,
liver, and skeletal muscles [27]. Recently, others have also
identified renalase expression in peripheral nerves, adre-
nals, endothelium, and the central nervous system, as well
as in adipose tissues in 12.5-day-old rat embryos and
humans [28,30].
Renalase function: experimental data
Xu et al. [27] indicated that the new hormone, renalase,
secreted by the kidney and circulating in blood, degrades
catecholamines and may play a role in the regulation of
sympathetic tone and BP [27].
Renalase administered intravenously to Sprague–Daw-
ley rats caused a fall in BP by 25%, as well as a decrease in
heart rate and cardiac contractility [27]. These effects lasted
only minutes and were dose-dependent. They resembled
massive a-receptor and b-receptor blockade; however, no
positive control was studied. A renalase knock-out mouse
was generated to better understand the role of this peptide
[27]. Wu et al. [31] reported no difference between the wild-
type mouse and renalase knock out mouse in regard to
renal function, but the knock-out mouse was hypertensive,
having tachycardia, and had higher catecholamines levels
than the wild-type animal. Then, the researchers tested the
hypothesis that the knock-out mouse was more susceptible
to myocardial ischemia [31]. They found that renalase
deficiency worsened myocardial damage during acute
ischemia and that treatment with recombinant renalase
could ameliorate cardiac injury. These authors concluded
that cardiac renalase deficiency may contribute to the
increased susceptibility to myocardial injury due to ische-
mia and rhythm disturbances frequently found in CKD. In
addition, they also reported [32] that circulating renalase
lacked sufficient amine oxidase activity under basal con-
ditions (prorenalase), but after a brief surge of epinephrine
for less than 2min, they observed a significant rise in
renalase activity in normotensive rats. Simultaneously, pro-
renalase became maximally activated with a rise in BP more
than 5mmHg. In five of six nephrectomized rats (5/6 Nx) (a
model of CKD), the authors found severe blood renalase
deficiency 2–3 weeks after the surgery [32]. In addition,
kidney renalase migrated as a dimer with a molecular
weight of approximately 70kDa, whereas heart renalase
ran as a monomer (35kDa) in SDS-PAGE gels [32]. Epi-
nephrine infusion in these rats resulted in a shorter and less
pronounced activation of renalase. The authors concluded
that renalase deficiency might contribute to the elevated
catecholamine levels in 5/6 Nx rats [32].
In another study on nephrectomized pups, Ghosh et al.
[30] found that norepinephrine transporter protein and
renalase protein expression in cardiac tissue were signifi-
cantly lower than sham-operated and pair-fed controls, but
norepinephrine levels were two times higher in nephrec-
tomized pups. Those authors suggested that animals
Malyszko et al.
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nephrectomized at an early age had increased circulating
catecholamines due to decreased norepinephrine metab-
olism [30]. Desir et al. [33] reported that subcutaneous
renalase significantly decreased SBP and DBP for up to
12h in Dahl salt-sensitive rats.
Renalase and hypertension: clinical data
A link between renalase and hypertension was also dem-
onstrated byZhao etal.[34], who pioneeredthefinding that
the renalase-coding gene in the Han Chinese population is
anovelsusceptibilitygeneforessentialhypertensionandits
genetic variations may influence BP. This is probably con-
nected with sex differences in autonomic nervous system
activity, which is higher in males [35]. Polymorphisms of the
renalase gene in hemodialysed patients were described, as
well as their associations with hypertension in this popu-
lation [36]. Hypertension was defined in this study as SBP of
at least 140mmHg, DBP of at least 90mmHg, or taking
hypotensive medication. rs2576178 polymorphism was
genotyped in 369 hemodialysed patients, including 200
who were hypertensive and 169 who were normotensive,
but rs10887800 polymorphism was genotyped in 421
hemodialysed patients, including 278 with hypertension
and 143 controls [36]. The authors found that not only
theG-allelefrequenciesofrs2576178 showed asignificantly
higher incidence, but those of rs10887800 also showed a
significantly higher incidence in hypertensive, hemodia-
lysed patients. The carrier state of the G-allele of rs2576178
polymorphism was associated with a 1.55 times greater risk
of hypertension, whereas the carrier state of the G-allele of
rs10887800 polymorphism was associated with 1.76 times
greater risk of hypertension [36]. Because the number of
patients is only slightly different for each group, it seems
that the studies may have been performed on overlapping
populations. It would be more interesting to know the
prevalence of both polymorphisms in the same population,
as the prevalence of hypertension was 54% and 66% in
these two hemodialysed populations, respectively [36].This
is the first molecular analysis of renalase variants in hemo-
dialysed patients, which we believe is paving the way to
gaining a deeper insight into the origin of hypertension and
its complications.
Farzaneh-Far et al. [37] reported that a functional mis-
sense polymorphism (C-allele) in renalase (Glu37Asp) was
associated with left ventricular hypertrophy, both systolic
and diastolic dysfunction, and poor exercise capacity and
inducible ischemia in whites included in the Heart and Soul
Study; however, no association between this CC genotype
and BP was found in the population with stable coronary
artery disease [37].
Renalase in kidney and heart diseases
In a study by Gu et al. [38], a model of unilateral renal artery
stenosis was demonstrated in an experimental animal
model. The study showed that renalase expression in the
ischemic kidney was lower than in the nonischemic one,
indicating that renal blood flow might influence renalase
synthesis [38]. Moreover, when Gu et al. studied the model
of heart failure in rats [ligation of the left anterior descend-
ing coronary artery (LAD)], they found that renal renalase
expression increased and reached a peak at 1 week post-
LAD ligation, gradually decreasing in weeks 3 and 4; they
provided no data on the serum creatinine [38]. Renalase
activity was measured with the Amplex Red Monoamine
Oxidase Assay Kit from Invitrogen (Carlsbad, California,
USA); this measurement was based on the detection of
H2O2in a horseradish peroxidase-coupled reaction and
was the same assay used by the Desir group (Xu et al. [27]).
The authors found that plasma renalase activity was the
highest in the operated group [38], and when they
measured the renalase concentration in control, sham-
operated, and operated rats, the highest concentration of
this protein was found in the operated rats. The same
applied to the concentration of norepinephrine. To deter-
mine the renalase concentration, the researchers used an
ELISA with antirenalase antibody [1:32000, Abcam (Cam-
bridge, Massachusetts, USA)]. Both the activity and concen-
tration of renalase were higher in association with heart
failure, suggesting that more highly activated renalase
degraded the increased norepinephrine levels [38]. The
authors proposed that the kidney synthesized and secreted
more renalase to compensate for the increased catechol-
amine levels in the early phase of acute myocardial infarc-
tion in the animal model [38]. When renal blood flow falls to
a critical level, renalase expression in the kidney fails to
keep up with the elevated catecholamine concentration.
This could be a decompensation phase; however, the
activity and concentration of renalase measured in the
plasma 4 weeks after ligation were elevated [38]. Thus,
the problem of kidney function and renalase activity and
levels needs further study.
There is virtually no data on renalase concentration and/
or activity in humans. Xu et al. [27] found that in hemodia-
lyzed patients (n¼8) renalase expression was decreased
compared with healthy volunteers (n¼4). Similar findings
were presented by Wang et al. [39]. They reported a
decreased renalase expression in one CKD patient and
one hemodialysis patient compared with two healthy con-
trols. In a recent study [40], serum renalase was significantly
higher in kidney transplant recipients relative to healthy
volunteers. In this study, predictors of serum renalase were
kidney function, age, time after transplantation, and DBP.
Przybylowski et al. [41] showed similar findings in heart
transplant recipients; however, only kidney function
(serum creatinine level) was a predictor of serum renalase.
Serum renalase was not affected by sex, diabetic status, and
presence of hypertension. In addition, a recent study [42]
reported highly elevated serum renalase in patients on
peritoneal dialysis compared with healthy volunteers. In
addition, renalase was positively related to the duration of
peritoneal dialysis and negatively to residual renal function.
No correlation between serum renalase concentration and
BP, age, sex, or adequacy of dialysis was found.
In only a clinical study presented as an abstract, Schlaich
et al. [43] found that in patients with resistant hypertension
(n¼22), arterial renalase (measured by western blot
analysis using a monoclonal antibodies and quantified
using a gel documentation system) was significantly higher
in four normotensive control participants relative to 22
hypertensive patients (P<0.05), whereas, whole body
noradrenaline spillover tended to be higher in hypertensive
patients, but without reaching statistical significance
Hypertension and kidney disease
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(P¼0.12). Arterial renalase correlated negatively in uni-
variate analysis with SBP in the entire cohort.
UNRESOLVED ISSUES
Theplasma-specificenzymesemicarbazide-sensitiveamine
oxidase (SSAO) catalyzes the oxidative deamination of
primary amines (methylamine, aminoacetone, benzyla-
mine, and 2-phenylamine are preferential and physio-
logical substrates) to form the corresponding aldehydes
with H2O2and ammonia [44]. Dopamine and, to a lesser
extent, norepinephrine are oxidized by SSAO, but epineph-
rine is not. Vascular adhesion protein-1 is a copper-con-
taining SSAO secreted by vascular smooth muscle cells,
adipocytes, and endothelial cells with functional MAO
activity [45]. It may function as a scavenger enzyme to assist
MAO, but it is insensitive to MAO inhibitors. The oxidation
processgenerates harmful products that maybe involved in
causing atherosclerosis and vascular damage in diabetes.
Elevation of SSAO activity is observed in atherosclerosis,
diabetes mellitus, and obesity [46–48]. The SSAO level in
human plasma is very low and exerts a minor influence on
catecholamines in in-vitro incubation [44]. In addition,
SSAO overexpression in transgenic mice has had no influ-
enceonBP afteradrenalineadministration incontrasttothe
wild-type animals [49]. On the contrary, the administration
ofgeraniin(hydrolysabletannin from Phyllantusurinaria),
which possesses SSAO inhibitory and antioxidant proper-
ties, resulted in a fall in BP [50]. Taking all these data
together, Medvedev et al. [51] concluded that SSAO was
not involved in the degradation of catecholamines in the
circulation. Boomsma and Tipton [44] questioned the
method used by Xu et al. [27] to measure renalase activity.
Xu et al. [27] measured MAO activity and extrapolated the
results to renalase. In addition, Boomsma and Tipton [44]
considered that the pathophysiological concentrations of
catecholamines are lower than the concentrations used
in the experiments. They further concluded that it was
unlikely that renalase is a catecholamine-metabolizing
enzyme. They suggested that it may have important car-
diovascular functions, but through another mechanism [44].
In another study, Pandini et al. [52] reported expression of
human renalase in Escherichia coli cells and its purification
to homogeneity. Moreover, this renalase contained non-
covalently bound FAD, which dissociated easily in the
presence of SDS (0.2% concentration). However, using
two different methods, the authors were unable to prove
that renalase exhibited MAO activity. Nevertheless, when
administered to rats, it exerted its hypotensive properties,
despite being catalytically inactive [52]. Therefore, is the
question whether renalase is really a MAO still valid? Luft
[53] noted that dopamine is associated with lower BP and
decreased cardiovascular risk, and that is why diminishing
dopaminergic tone (by renalase, for example) would
increase BP and cardiovascular risk. Eikelis et al. [54] also
questioned the hypothesis that renalase could degrade
catecholamines because of the lack of definitive evidence
in the literature to directly support this hypothesis. In
addition, authors’ own sequencing of renalase transcripts
from various mouse strains demonstrated that renalase in
these animals was shorter than rat and human renalase and
did not contain the N-terminal flavin adenosine dinucleo-
tide-binding site characterized by a GxGxxG motif, as
described by Wu et al. [31]. Therefore, it is difficult to
comprehend how renalase normally functions in mice if
the protein does not possess this supposedly essential
active site. In addition, Milani et al. [55] pointed out that
renalase is not a MAO and most probably is not an oxidase.
The absence of a recognizable NADP-binding site in the
protein structure and its poor affinity for, or poor reactivity
toward, NADH and NADPH suggest that these are not
physiological ligands of renalase.
Xu et al. [27], using western blot technique with poly-
clonal antibodies, found that renalase expression in eight
hemodialysed patients was diminished when compared
with four healthy controls. In another study by Wang
et al. [39], recombinant renalase and monoclonal antibody
were obtained. The human renalase gene was amplified
from nephrectomized human kidney (no cause for neph-
rectomy was given) by specific primer, and DNA fragments
into pET22b, the gene was transformed to E. coli BL21.
Upon induction by IPTG, BL-21 transformed bacteria pro-
duced 38kDa protein as shown on SDS-PAGE electropho-
resis, whereas, according to Li et al. [32], renal renalase was
run as a dimer with a mass of 70kDa on SDS-PAGE. The
Balb/c mouse was immunized with purified protein to
prepare the monoclonal antibody by hybridoma technique.
The monoclonal antibody could react with the both
recombinant and human serum renalase. Wang et al. [39]
also showed renalase expression in patient with CKD,
patient with hemodialysis, and healthy controls. However,
in the methods section, the information on the patients was
as follows: ‘the serum of both healthy persons and chronic
renal failure patients was incubated with the recombinant
renalase monoclonal antibody, followed by soaking in the
HRP-IgG (Sigma) and visualized by ECL kits (GE Co. Ltd)’
[39]. However, no further data were given.
Western blot is only a semiqualitative method, whereas
an ELISA assay with a monoclonal antibody specific to
renalase is commercially available from at least two com-
panies. The assays measure the total level of renalase 1,
independent of whether this peptide is active or inactive.
Moreover, it is possible that the antibody in the assay binds
to common fragments of different isoforms; therefore, the
measured level could be very high and not related to
activity. As Xu et al. [27] assessed the activity of the enzyme
using a commercially available assay, it is not possible to
compare the activity with the antigen due to the fact that
renalase has isoforms. The manufacturers of the assay
claimed that only renalase 1 levels were measured, and
there are no data on the possible cross-reactivity. As rena-
lase is secreted not only by the kidney but also by cardi-
omyocytes, liver, and adipose tissue, in the case of ESR
failure, other organs and tissues may oversecrete renalase
and,therefore,thelevelscouldbeveryhighaswas foundin
clinical studies [40–42]. When expression of the renalase is
assessed, we cannot be sure that the protein is active. In
addition, as Xu et al. [27] suggested, there is an inhibitor of
renalase in plasma. Therefore, the level of the enzyme can
be high, but its activity can be low or negligible.
Li et al. [32] have shown that the infusion of catechol-
amines causes an increase in blood renalase activity in
Malyszko et al.
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experimental animals. They also found that renalase circu-
lates as a proenzyme that lacks enzymatic activity, but is
rapidly activated by elevated plasma catecholamines. For
more than 30 years, it has been known that plasma levels of
norepinephrineareelevatedinchronicrenalfailure, leading
to increased sympathetic nerve activity. The kidneys make a
15–24%contributiontotheclearanceofcirculatingcatechol-
amines [19]. Most circulating catecholamines are actively
removed from the circulation by nonneuronal monoamine
transporters in other tissues and organs in which the amines
are subsequentlymetabolized
Although decreases in circulatory clearance resulting from
impaired renal function may contribute to increased plasma
concentration of catecholamines, these increases in patients
with renal failure probably result mainly from activation of
the sympathetic nervous system [18]. Therefore, we may
speculate that in the state of catecholamine excess, that is,
in ESRD, the activation of proenzyme renalase into active
renalase is more rapid and efficient in several tissues.
Much progress has been achieved in the study of the
expression of renalase, but, with the wide tissue distri-
bution, the function may be tissue-specific. There are
few data on the possible activators and/or inhibitors of
renalase. It seems that urinary and serum renalase are not
identical, as the experimentally determined molecular mass
of the urinary enzyme (35kDa) [32] is lower than the
calculated molecular mass (37.8kDa) [27,29,55].
before excretion [18].
CONCLUSION
Further studies are needed to prove or disprove the
possible role of renalase in the pathogenesis of hyperten-
sion in patients with kidney diseases. Regulation of BP and
development of cardiovascular complications are complex
processes [56–58], and the contribution of renalase is far
from clear. It should also be stressed that there is a lack of
information on renalase concentration and activity in
specific conditions in humans, and publications are scarce
and often only in abstract form [33,43,59–61]. Whether
renalase will become a novel therapeutic target for hyper-
tension, as suggested by Paulis and Unger [62], remains an
open question. Recombinant renalase or renalase anti-
bodies could be attractive therapeutic option, providing
that renalase does really participate in the regulation of BP.
Therefore, ‘proof of concept’ studies are urgently needed.
In addition, a basic question whether renalase is a MAO
should also be addressed and how this may be related to
catecholamines. Renalase is ‘an interesting protein’ with, so
far, poorly defined biochemical functions. We are at the
very beginning of solving the problem of whether renalase
isacausativefactorofhypertensioninkidneydiseaseorjust
an innocent bystander. We know for sure that it is an
intriguing protein with, so far, poorly defined biochemical
functions. Whether renalase will be a novel therapeutic
target for hypertension, as suggested by Paulis and Unger
[62], remains an open question.
ACKNOWLEDGEMENT
The authors have not received any payments in connection
with the preparation of this review. No medical or
pharmaceutical company was involved with the pre-
paration of this article.
Conflicts of interest
There are no conflicts of interests.
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