NATURE REVIEWS | NEPHROLOGY ADVANCE ONLINE PUBLICATION | 1

Introduction
An outbreak of chronic kidney disease
(CKD) is ongoing in Central America,
pri marily in hot tropical agricultural com-
munities along the Pacific Coast.
14
The epi-
demic, which has been present since at least
the 1990s, primarily affects manual workers
(predominantly men) labouring under hot
conditions, among whom dehydration is
common.
5
Typically, these individuals are
asymptomatic but laboratory testing reveals
elevated levels of serum creatinine, often in
association with non-nephrotic protein-
uria. Affected individuals have normal
or only slightly elevated blood pressure,
normal levels of blood sugars and urinary
sediment that does not indicate glomerular
injury. In the few patients in whom kidney
biopsies have been performed, substantial
tubulointerstitial disease is apparent, with
some evidence of glomerular ischaemia and
secondary glomerulosclerosis (Figure1).
6
Numerous studies have looked for evi-
dence that nephrotoxins cause this form of
CKD, but to date, no pesticide, herbal toxin
or heavy metal has been identified as a likely
aetiological agent.
24,79
Use of NSAIDs and
leptospiral infection might be contributory
factors, but do not seem to be the primary
cause.
4
However, both epidemiological and
experimental studies suggest that recurrent
dehydration is the primary risk factor for
this type of CKD,
10,11
and similar mecha-
nisms might contribute to the ongoing
epidemic of CKD in Sri Lanka.
12
Under
extremely hot ambient temperatures, loss of
water (dehydration) and salt initially lead
to extracellular volume loss and a revers-
ible prerenal state. If dehydration persists,
acute kidney injury can develop as a result
of heat shock (owing to low blood pressure
and impaired renal perfusion) or rhabdo-
myolysis;
13
however, neither seems to be
a major factor in either the Sri Lankan or
Mesoamerican CKD outbreak. By con-
trast, studies in laboratory animals have
identified hyperosmolarityhigh levels of
solutes in the bloodas a novel mechanism
by which dehydration might cause kidney
disease. Interestingly, the discovery of how
hyperosmolarity causes renal injury pro-
vides new insights into the role of salt and
water in hypertension and CKD in general.
In this Perspectives article, we present
the hypothesis that changes in osmo larity
induced by an imbalance in water and salt
intake, rather than the amount of salt or
water ingested perse, drives the develop-
ment of dehydration-related hypertension
and kidney disease.
Dehydration and hyperosmolarity
Mechanisms
Workers in the sugarcane fields of Central
America labour under extremely hot con-
ditions (often exceeding 35C), and their
extensive sweating results in considerable
loss of water and salt during the course of
the day.
14
A study in Nicaragua revealed
that agricultural workers lost an average of
2.6 kg of body weight during the working
day.
10
This weight loss was associated
with increased serum levels of sodium,
rising to 145 mmol/l at the end of the day,
and increased serum osmolarity, rising to
301 mosm/l.
10
As expected, these changes
were also associated with concentration
of the urine, with increases in both urine
specific gravity and osmolarity.
10
The body responds to a rise in plasma
osmolarity by activating two major path-
ways (Figure2a). The first pathway involves
stimulation of vasopressin synth esis in the
hypothalamus and its sub sequent release
from the posterior pituitary into the circu-
lation, where it helps to promote reabsorp-
tion of water (and to a lesser extent, sodium)
in the kidney.
15,16
The second pro cess
involves activation of the polyol metabolic
pathway,
17,18
in which hyper osmolarity
increases the activity of aldose reductase,
which in turn converts glucose into sorbi-
tol. Sorbitol is an osmolyte that protects
tubular cells and interstitial medullary
cells from the hyperosmotic environments
that drive water reabsorption, especially
under conditions of dehydration and
plasmahyperosmolarity.
19,20
OPINION
Hyperosmolarity drives hypertension
andCKDwater and salt revisited
Richard J. Johnson, Bernardo Rodriguez-Iturbe, Carlos Roncal-Jimenez,
MiguelA.Lanaspa, Takuji Ishimoto, Takahiko Nakagawa, Ricardo Correa-Rotter,
Catharina Wesseling, Lise Bankir and Laura G. Sanchez-Lozada
Abstract | An epidemic of chronic kidney disease (CKD) in Mesoamerica is providing
new insights into the mechanisms by which salt and water might drive hypertension and
CKD. Increasingly, evidence suggests that recurrent dehydration and salt loss might be a
mechanism that causes CKD, and experimental studies suggest a key role for increased
plasma osmolarity in activating both intrarenal (polyolfructokinase) and extrarenal
(vasopressin) pathways that drive renal injury. Thus, we propose that water and salt
might influence blood pressure and kidney disease through the timing and combination
of their intake, which affect plasma osmolarity as well as intrarenal andextrarenal
mechanisms of renal injury. The type of fluid intake might also be important, as fluids
containing fructose can trigger activation of these pathways. Future studies should
investigate the effects of salt, sugar and fluid intake on plasma osmolarity as apotential
pathogenetic mechanism in renal injury and high blood pressure.
Johnson, R.J. etal. Nat. Rev. Nephrol. advance online publication 6 May 2014;
doi:10.1038/nrneph.2014.76
Competing interests
R.J.J. and M.A.L. are inventors on patent
applications related to blocking fructokinase in
the treatment of kidney disease and metabolic
syndrome from the University of Colorado
(US2013/0195886 and US2013/0224218).
R.J.J. is on the Scientific Advisory Board of
Amway, the Scientific Board of XORT Therapeutics
and of Rivermend Health. R.J.J. has also received
research funding from Danone Research and
Amway. R.J.J., C.R.-J., M.A.L. and L.G.S.-L. are
members of Colorado Research Partners. The
other authors declare no competing interests.
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Historically, the activation of the vaso-
pressin and aldose reductase pathways
during dehydration was strictly viewed as
a beneficial adaptive response, as they both
promote urinary concentration under con-
ditions of water shortage or depriva tion.
This view is of course correct on a short-
term basis; however, new research sug-
gests that chronic overactivation of these
pathways might be deleterious (as has also
been observed in many other physiological
processes) resulting in kidney injury.
11
The vasopressin pathway
Vasopressin is used clinically to treat severe
hypotension, to block variceal bleeding
(through its vasoconstrictive effects) and
to stimulate the concentration of urine in
patients with central diabetes insipidus.
Vasopressin is not normally thought of
as being nephrotoxic under physiological
conditions or when used pharmacologi-
cally. However, experimental studies have
clearly shown that vasopressin is a mediator
of CKD, and that suppression of vaso pressin
can slow the progression of renal dysfunc-
tion in both diabetic and non diabetic
models of kidney disease.
21,22
The anti-
diuretic effects of vasopressin are mediated
by the vasopressin V2 receptor, and include
substantial hyperfiltration (comparable to
that induced by high-protein diets)
23
and
increased urinary albumin excretion in rats
and humans.
17,18
Elevated levels of vaso-
pressin might also be a risk factor for hyper-
tension.
16
Haemodynamic effects might
also be involved in vasopression-mediated
kidney damage, including the induction of
glomerular hypertension and stimulation of
the reninangiotensinaldosterone system
(RAAS).
17
Kidney damage might also result
from the increased metabolic demand
required for reabsorption of the extra solutes
filtered by the kidneys,
24
which leads to cel-
lular hypertrophy and interstitial inflam-
mation.
15
Additionally, vaso pressin causes
mitochondrial dysfunction;
25,26
how ever,
whether this is the mechanism by which
vasopressin causes renal injury remains
unknown. Further information on this topic
can be found elsewhere.
15,27
The fructokinase pathway
Initial interest in the role of aldose reductase
in dehydration focused largely on the polyol
pathway as a means of generating sorbi-
tol to protect cells in the renal medulla.
19,28

However, sorbitol is metabolized to fructose
by sorbitol dehydrogenase, and fructose is
in turn metabolized by fructokinase (also
known as KHK), which exists as two isoforms
(KHK-C and KHK-A).
29
KHK-C metabolizes
fructose rapidly, resulting in transient deple-
tion of intracellular phosphate and ATP,
which leads to local oxidative stress, inflam-
mation and uric acid generation.
30,31
By con-
trast, KHK-A meta bolizes fructose slowly,
resulting in limited ATP consumption.
31

Metabolism of other sugars, such as glucose,
does not result in transient ATP depletion.
KHK-C is present primarily in the liver and
small intestine, where it has a central role in
metabolizing dietary fructose, provided pri-
marily in the form of sucrose (a disaccharide
of fructose and glucose) or high-fructose
corn syrup (a monosaccharide mixture of
fructose and glucose in varying proportions).
In the small intestine and liver, metabolism
of fructose is associated with local inflam-
mation, as shown by increased intestinal per-
meability
32,33
and the development of hepatic
steatosis andinflammation.
31,34
KHK-C is also expressed in proximal
tubules, with the highest concentration in
the S3 segment.
35,36
Even though relatively
small amounts of dietary fructose escape
first-pass hepatic metabolism, some fruc-
tose is filtered by the kidney. Indeed, urinary
fructose is a fairly accurate biomarker for
dietary fructose intake.
37,38
Some of the fil-
tered fructose is taken up by the proximal
tubules. At variance with glucose transport,
which involves energy-dependent sodium/
glucose co- transporters1 and 2, fructose
transport occurs primarily through the
fructose- specific passive facilitated trans-
porter, GLUT-5.
36
In turn, the metabolism
of fructose by the proximal tubule results
in local oxidative stress that causes release
of inflammatory cytokines (such as CC
motif chemokine 2, also known as MCP-1)
and uric acid.
30
High dietary intake of fruc-
tose might lead to sufficient local fructose
metabolism for proximal tubular injury to
become prominent.
36,39,40
As already mentioned, a rise in plasma
osmo larity increases the expression and
activ ity of aldose reductase.
19,41
In a mouse
model of recurrent dehydration caused by
inter mittent exposure to heat with or with-
out water deprivation, dehydrated ani mals
exhibited plasma hyperosmolarity and evi-
dence of polyol pathway activation in their
renal cortex, leading to increased renal
levels of sorbitol and fructose, despite the
absence of fructose in their diet.
11
Inthis
case, KHK-C, which is constitutively present
in the proximal tubule but relatively inactive
owing to a lack of substrate, is now presented
with fructose that has been generated by the
polyol pathway. Metabolism of the fructose
by KHK-C in the proximal tubule results
in local oxidative stress and mitochondrial
injury, resulting in renal injury, inflam-
mation and fibrosis.
30
Indeed, dehydrated
mice lacking KHK have been shown to be
protected from renal injury.
11
Activation
of the polyolKHK pathway also occurs in
mouse models of diabetic nephropathy, and
is associated with substantial albuminuria,
mesangial expansion and tubulointerstitial
injury; renal injury is also largely prevented
by knockout of KHK, suggesting that the
polyolKHK pathway might be a medi ator
of diabetic nephro pathy.
42
Thus, KHK is
a Trojan horsedormant in the proximal
tubule unless it is activated by local increases
in fructose levels.
Collectively, these observations suggest
that hyperosmolarity might activate adap-
tive pathways that are initially protective,
but if continuously activated, will have
negative downstream effects on the organ-
ism (Figure 2b). The observation that
dehydration- induced hyper osmolarity results
in renal injury mediated by endo genous
fructose (which is produced by the polyol
pathway) also raises the question of whether
rehydration with fructose- containing drinks,
Figure 1 | Chronic tubulointerstitial fibrosis in
Mesoamerican nephropathy. In one study,
eight patients were evaluated, all having
worked in sugar plantations in El Salvador.
Laboratory findings were estimated
glomerular filtration rate between 27 ml/
min/1.73 m
2
and 79 ml/min/1.73 m
2
and
hypokalaemia was present insix of the eight
patients. Urine tests showedelevated levels
of tubular injury biomarkers, butlow levels of
albuminuria. Pictured here, light microscopic
changes in kidney biopsy specimens were
evaluated inSchiffs periodicacid-stained
sections and showedglomerulosclerosis
(2978% global glomerulosclerosis), changes
indicating glomerular ischaemia, mild to
moderate tubular atrophy and chronic
interstitial inflammation. Bar = 500 m.
Permission to reproduce obtained from
Elsevier Wijkstrom,J. etal. Am. J.Kidney
Dis. 62, 908918 (2013).
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NATURE REVIEWS | NEPHROLOGY ADVANCE ONLINE PUBLICATION | 3
or the chewing of sugarcane (which is rich
in fructose), might exacerbate renal injury.
Studies are ongoing to assess not only the
role of dehydration, but also the type of rehy-
dration fluid, in renal damage associated
withMesoamericannephropathy.
The concept that overactivation of the
vasopressin and polyolKHK pathways can
be injurious might be analogous to the role of
RAAS activation in protecting renal vascula-
ture in conditions of volume depletion, and
its injurious effects when hyperactivatedin
hypertension and cardiovasculardisease.
Inflammation, hypertension and CKD
The observation that recurrent dehydra-
tion and periodic hyperosmolarity acti-
vate processes that lead to renal injury and
inflammation
11
suggests the possibility
of a general mechanism leading to CKD.
Indeed, evidence has been accumulating for
some time that elevated plasma osmolarity
is proinflammatory and prohypertensive
in its own right.
43
In turn, low-grade vas-
cular and intrarenal inflammation has a
major role in driving CKD.
44
For example,
hyper osmolarity is a potent stimulus for
the release of inflammatory cytokines from
peripheral blood mononuclear cells.
45,46
Cell
culture studies have also shown that the
increased plasma osmolarity resulting from
high dietary sodium intake stimulates pro-
fibrotic factors, such as transforming growth
factor ,
47
and induces hypertrophy of vas-
cular smooth muscle cells.
48
An increase in
plasma osmolarity also activates the central
sympathetic nervous system,
49
stimulating
intracerebral activation of angiotensinII.
50

Elevations in plasma sodium levels also
increase lumbar sympathetic nervous sys tem
activity and blood pressure in rats with
deoxy corticosterone acetate salt-induced
hypertension.
51
High plasma sodium levels
increase blood pressure, both acutely and
chronically.
52
In humans, administration of
6 g of salt (provided in soup) to normo tensive
volunteers led to an acute increase in serum
sodium levels of 3 mmol/l in associ ation
with an acute rise (5.7 mmHg) in systolic
bloodpressure.
53
By contrast, other studies have not been
able to show acute effects of hyperosmo-
larity on blood pressure, but they have
shown an effect on arterial stiffness (aug-
mentation index),
54
baroreflex control of
sympatheticactivity
55
and muscle sympa-
thetic nerve activity,
56
suggesting activa-
tion of processes that can lead to increased
blood pressure. Indeed, the effects (if any)
might simply relate to a dose effect, which
is supported by the fact that the changes in
serum osmolarity in these studies was small
(approximately 3 mmol/l). Furthermore,
in one of these studies increasing doses
of hypertonic saline did lead to a rise in
bloodpressure.
56
Collectively, these studies indicate that
salt-sensitive hypertension results from a
Vasopressin pathway Polyol pathway
ER
Synaptic vesicle
Prohormone Hypothalamic-posterior
pituitary stalk
Osmosensitive
neuron
Hypothalamus
a
b
Golgi
apparatus
NADPH
NADP
+
NAD
+
NADH
XO
ATP ADP
Fructo-
kinase
pathway
Polyol
pathway
Proximal
tubule
Vasopressin mRNA (in hypothalamus)
Vasopressin (in blood)
Recurrent dehydration
Uric acid
Fructose
Sorbitol
Water and sodium reabsorption in kidney
Water conservation Blood pressure
Oxidative stress, NO, infammation, endothelial dysfunction,
vasoactive substances, arteriolopathy and glomerular hypertension
SDH
Glucose
Protection against
hyperosmolar environment
in renal medula
Glucose
Sorbitol
Plasma osmolarity
Acute dehydration
Vesicle
Water conservation
Vasopressin (in blood)
Water reabsorption in kidney
Aldose reductase
Aldose reductase
KHK
Plasma osmolarity
Posterior pituitary
Figure 2 | Physiological and pathophysiological effects of water depletion on the kidney.
a|Thenormal response to acute dehydration involves activation of two major pathways
(vasopressin and polyol), leading to urine concentration and water conservation. Aldose
reductase is normally expressed in the renal medulla; the sorbitol produced by this enzyme
hasa protective effect against the hyperosmolar enviroment. b | Recurrent dehydration induces
chronic vasopressin secretion and abnormal activation of polyol pathway in the proximal
tubules. Fructose produced by the latter is further metabolized by fructokinase, leading to renal
injury. Abbreviations: ER, endoplasmic reticulum; KHK, fructokinase; NO, nitric oxide; SDH,
sorbitol dehydrogenase; XO,xanthine oxidase.
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variety of haemodynamic effects, derived not
only from extracellular volume expansion
but also from modest increments in sodium
concentration in plasma and cerebro spinal
fluid. Indeed, new mechanisms are being
unravelled as to the mecha nisms by which
increased extra cellular volume is partitioned
in the body. Specifically, salt intake in
animals with salt-sensitive hypertension
results in sodium-related hyper osmolarity
in subdermal locations that causes lymph-
angiogenesis and compartmentalization of
sodium outside the circulation. Amelio ration
of salt-induced hypertension is driven by
vascular endo thelial growth factor, produced
by macrophages in response to stimulation of
nuclear factor of activated Tcells(NFAT-5).
57
A clear example of the importance of
osmolarity in the inflammatory response is
demonstrated by the results of a prospective
randomized controlled study of the effect of
reducing sodium dialysate levels in patients
on haemodialysis from 138 mmol/l to
135 mmol/l over a 16-week period. Despite
having similar fluid and sodium intake
throughout the study to those of controls
(whose dialysate sodium levels were held
at 138 mmol/l), patients in the sodium-
reduction group displayed significantly
lower levels of markers of systemic inflam-
mation, such as tumour necrosis factor and
IL-6.
58
These studies highlight the impor-
tance of even mild changes in osmolarity for
human health and disease.
At this time, we do not know whether
the mechanism by which hyperosmolarity
affects individual cells involves the polyol
pathway and/or other pathways. A variety
of receptors present in the central nervous
system and target organs are activated by
hyperosmolarity, including transient recep-
tor potential cation channel subfamily V
member 4 (TRPV4) and others.
59,60
The
function of many of these receptors is still
being elucidated.
59,60
The role of water and salt
The observation that increased plasma
osmolarity raises blood pressure, induces
renal injury and stimulates inflammation
raises the question of whether the benefi-
cial effects of limiting dietary salt intake in
patients with hypertension and CKD are
mediated by changes in plasma osmolarity
as well as effects on extracellular volume.
Indeed, high-salt diets tend to worsen
hypertension and CKD, whereas low-
saltdiets seem to be protective.
6165
Low-salt
diets reduce cardiovascular events,
66
and
sodium restriction potentiates the effects of
RAAS blockade, which is currently oneof
the favoured approaches to slow the pro-
gression of CKD.
67
However, some excep-
tions are notable. A low-sodium diet in
hypertensive patients receiving antihyper-
tensive medication might be associated with
increased cardiovascular mortality, perhaps
driven by increased activation of the RAAS
in response to sodium restriction.
68
Low
urinary sodium excretion (consistent with
a reduced dietary sodium intake) is associ-
ated with poor cardiovascular outcomes in
patients with diabetes
69,70
and, in one of these
studies, with an increased risk of end-stage
renal disease.
70
These observations have
shaken the belief in sodium restriction as a
general protective mechanism for preventing
hypertension and cardiovasculardisease.
Although high-salt diets are gener-
ally viewed as promoting hypertension
and CKD, abundant reports indicate that
increased water intake might have a protec-
tive role.
7173
This concept originated from
the demonstration that increased water
intake in rats with CKD reduced vasopres-
sin levels and slowed the progression of
kidney disease.
21
However, just as in the
studies involving high dietary salt intakes,
not all studies have documented a protective
effect of high fluid intake (or the resulting
high urine volume) on kidney function.
74,75

Several groups concluded that increased
fluid intake offered no protection against
CKD, but this interpretation was limited
by the failure to identify the composition of
ingested fluids. Clearly, clinical studies are
needed to directly address the hypothesis
that high water intake (resulting in a urine
volume 2.5 l) can slow the progression
ofCKD.
Components of fluid intake
We propose that the balance of salt, water
and sugary drinks, and the timing of their
intake, might be critical factors in the
development of renal injury. A major role
of the kidneys is to help preserve a stable
extracellular milieu, in which electrolyte
and glucose concentrations are maintained
within a tightly regulated range. Studies of
Mesoamerican nephropathy have led to new
insights into how recurrent dehydration-
induced hyperosmolarity can activate several
pathways (vasopressin, aldose reductase
fructokinase and others) that lead to renal
injury and systemic vasoconstriction.
11
Mild
changes in plasma osmolarity occur rapidly
following ingestion of meals that are high in
salt.
53
Currently, most people on a western
diet eat 1012 g of salt daily, including
patients with CKD,
63
and as a consequence,
low-salt diets are commonly recommended
for both patients with CKD and those with
hypertension. Unfortunately, low-salt diets
can be hard to maintain, with typical adher-
ence rates of only 1020%.
76
However, if the
principal mechanism of renal protection
afforded by a low-salt diet is prevention of
hyperosmolarity, these individuals could
simply be encouraged to increase their
water intake, rather than having to impose
major dietary salt restrictions. As shown in
healthy volunteers, increased fluid intake
improves the ability of the kidneys to
excrete sodium,
77
whereas the antidiuretic
action of vasopressin results in substantial
sodiumretention.
16
Fluid intake, as well as urine osmolarity,
can dramatically vary among individuals,
78

and the type of fluid ingested is potentially
very important. As mentioned earlier,
drinks (as well as foods) containing fructose
can result in increased delivery offruc-
tose to the kidneys, where it can activate
the KHK-C pathway in proximal tubules.
Rehydration of dehydrated animals with
fructose- containing solutions can leadto
worsening of renal injury, possibly owing
to the additive effect of dietary fructose in
accelerating KHK-dependent renal damage
(unpublished work, L.G. Sanchez-Lozada).
Additionally, infusions of fructose (but not
equimolar glucose) stimulate vasopres-
sin release in humans.
79,80
Individuals who
consume high dietary levels of fructose
also develop water retention and increased
urineconcentration.
81
The results of these studies provide key
insights into understanding the role of
salt and water intake in CKD and hyper-
tension. Specifically, plasma osmolarity
will be affected by both the amount of salt
ingested and the timing of ingestion. For
example, drinking water followed by eating
salty food might have worse consequences
than the reverse. Eating salty foods and then
drinking fluids to quench the resulting thirst
might not be ideal, as the thirst response
occurs after vasopressin is released.
82,83
We,
therefore, suggest that studies be conducted
to evaluate the role of water and salt intake
on volume status and plasma osmolarity, as
reflected not only in fasting morning blood
samples but also during periods of activity.
These factors might be as important as the
actual amount of salt and water ingested
daily. We suggest that preventing the induc-
tion of hyperosmolarity by providing suffi-
cient hydration throughout the day might be
the key to preventing CKD in the ongoing
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NATURE REVIEWS | NEPHROLOGY ADVANCE ONLINE PUBLICATION | 5
Mesoamerican nephropathy epidemic
and perhaps also to slowing the progression
ofother types of CKD and reducing the
riskof primary hyper tension. The Ameri-
can poet Emily Dickinson once wrote, I
dwell in Possibility. This is good advice.
As nephrologists, we need to continu ously
review the scientific evidence of our clinical
practice, and always be open to the possibil-
ity that there might be a time when classic
paradigms needrevision.
Division of Nephrology, Eastern Colorado Health
Care System, Department of Veteran Affairs,
12700 East 19
th
Avenue, Room 7015, Aurora,
CO 80045, USA (R.J.J.). Universidad del Zulia,
Instituto Venezolano de Investigaciones
Cientficas (IVIC)-Zulia, Maracaibo, Venezuela
(B.R.-I.). Division of Renal Diseases and
Hypertension, University of Colorado, Denver,
CO, USA (C.R.-J., M.A.L., T.I.). Mitsubishi Tanabe-
Kyoto (TMK) project, Kyoto University Graduate
School of Medicine, Kyoto,Japan (T.N.).
Department of Nephrology and Mineral
Metabolism, Instituto Nacional de Ciencias
Mdicas y Nutricin Salvador Zubirn,
MexicoCity, Mexico (R.C.-R.). Program on Work,
Environment and Health in Central America
(SALTRA), Central American Institute for Studies
on Toxic Substances (IRET), Universidad
Nacional, Heredia, Costa Rica (C.W.). INSERM
Unit Mixte de Recherche (UMR)-S 1138/
Equipe 2, Centre de Recherche des Cordeliers,
Paris, France (L.B.). Laboratory of Renal
Physiopathology, Intituto Nacional de
Cardiologa Ignacio Chavez, Mexico City, Mexico
(L.G.S.-L.).
Correspondence to: R.J.J.
richard.johnson@ucdenver.edu
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Acknowledgements
R.J.J.s research work is funded by the University of
Colorado, Denver, CO, USA, and NIH grant funding.
L.G.S.-L.s work is funded by CONACyT Mexico
(No.133232).
Author contributions
R.J.J., L.B. and L.G.S.-L. researched the data for the
article. All authors contributed to the discussion of
the articles content, after which R.J.J., B.R.-I., L.B.
and L.G.S.-L. wrote the manuscript. R.J.J., B.R.-I.,
T.I., T.N., R.C.-R., C.W., L.B. and L.G.S.-L. edited the
manuscript before submission.
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