Am J Physiol Renal Physiol 305: F1629–F1636, 2013.
First published October 9, 2013; doi:10.1152/ajprenal.00263.2013.
Review
Adipokines as a link between obesity and chronic kidney disease
Jessica F. Briffa,1,3 Andrew J. McAinch,1 Philip Poronnik,2 and Deanne H. Hryciw3
1
Biomedical and Lifestyle Diseases Unit, College of Health and Biomedicine, Victoria University, St Albans, Victoria,
Australia; 2School of Medical Sciences, The Bosch Institute, The University of Sydney, New South Wales, Australia;
and 3Department of Physiology, The University of Melbourne, Parkville, Victoria, Australia
Submitted 9 May 2013; accepted in final form 2 October 2013
keywords; adipokines; obesity; chronic kidney disease; leptin; adiponectin
of the kidney are to reabsorb nutrients,
excrete wastes, regulate blood volume and pressure, and secrete hormones (17). In a healthy individual, the proximal
tubule of the kidney is able to reabsorb the majority of protein
that enters the glomerular filtrate, with only traces being
excreted in the urine (51). In kidney disease, the filtration and
reabsorption of protein are altered, leading to a loss of protein
in the urine (proteinuria) (24, 61, 73). Importantly, an increase
in proteinuria is associated with an increase in renal damage
(nephropathy) (24).
Obesity rates in the Western world are increasing rapidly,
which mirrors the increase in comorbidities such as nephropathy (24). Obesity-related pathologies increase the health, economic, and social costs associated with this disease (13).
Importantly, the numbers of obese patients with end-stage
renal disease (ESRD) have significantly increased worldwide
in the last 10 years (40). In the obese state, there are two main
cellular targets that are associated with proteinuric renal disease. These are 1) structural changes to the glomerulus allowing more protein to enter the filtrate (73) and 2) the proximal
tubules are unable to endocytose the increase in protein load
(64). Thus, both the glomerulus and proximal tubules are sites
of dysfunction in proteinuric nephropathy.
Adipocytes are able to secrete a number of bioactive proteins, termed “adipokines” (50, 71), with dysregulation in the
THE MAIN FUNCTIONS
Address for reprint requests and other correspondence: D. H. Hryciw, Dept.
of Physiology, The Univ. of Melbourne, Parkville, VIC 3010, Australia
(e-mail: [email protected]).
http://www.ajprenal.org
production and secretion of a number of adipokines occurring
in the obese state (63). Many of these molecules have been
shown to alter renal cell function in vitro, which could increase
the risk of developing kidney damage associated with obesity
(45, 68).
Clinical Diagnosis, Progression, and Pathogenesis of
Chronic Kidney Disease
Chronic kidney disease (CKD) is the result of a decrease in
the kidneys’ ability to function (41, 61). The average glomerular filtration rate (GFR) is ⬃90 –120 ml/min (46), with a
reduction in GFR being associated with kidney disease (46).
Recent research has supported the inclusion of albuminuria as
an indicator for CKD either in the presence or absence of a
decrease in GFR (33, 46). Consequently, CKD stages 1 and 2
indicate kidney damage with either a reduction in GFR (33, 46)
and/or albuminuria. CKD stages 3–5 are associated with a
significant drop in GFR to below 60 ml/min, which is associated with albuminuria (33, 41, 46). CKD stage 5 is associated
with severe albuminuria and reduced GFR in addition to
interstitial fibrosis (33), with dialysis and renal replacement
required. It is estimated that 5–10% of the adult population in
the Western world has an estimated GFR (eGFR) similar to
those observed in CKD stages 3–5 (41).
There is a strong correlation between obesity and hypertension, both of which are risk factors for CKD. In the initial
stages of obesity-related hypertension, there is afferent arteriole vasoconstriction, which is caused by an increase in solute
delivery to the distal tubules, detected by cells of the macula
1931-857X/13 Copyright © 2013 the American Physiological Society
F1629
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Briffa JF, McAinch AJ, Poronnik P, Hryciw DH. Adipokines as a link between
obesity and chronic kidney disease. Am J Physiol Renal Physiol 305: F1629 –F1636,
2013. First published October 9, 2013; doi:10.1152/ajprenal.00263.2013.—Adipocytes
secrete a number of bioactive adipokines that activate a variety of cell signaling
pathways in central and peripheral tissues. Obesity is associated with the altered
production of many adipokines and is linked to a number of pathologies. As an
increase in body weight is directly associated with an increased risk for developing
chronic kidney disease (CKD), there is significant interest in the link between
obesity and renal dysfunction. Altered levels of the adipokines leptin, adiponectin,
resistin, and visfatin can decrease the glomerular filtration rate and increase
albuminuria, which are pathophysiological changes typical of CKD. Specifically,
exposure of the glomerulus to altered adipokine levels can increase its permeability,
fuse the podocytes, and cause mesangial cell hypertrophy, all of which alter the
glomerular filtration rate. In addition, the adipokines leptin and adiponectin can act
on tubular networks. Thus, adipokines can act on multiple cell types in the
development of renal pathophysiology. Importantly, most studies have been performed using in vitro models, with future studies in vivo required to further
elucidate the specific roles that adipokines play in the development and progression
of CKD.
Review
F1630
ADIPOKINES IN OBESITY AND CKD
Adipose Tissue as an Endocrine Organ
Adipose tissue has been identified to secrete ⬎50 adipokines, including cytokines, chemokines, hormone-like factors,
and other signaling mediators (5). These adipokines can activate many signal transduction pathways that are essential for
the maintenance of energy homeostasis and metabolism (50,
71). Adipokines have various roles in vivo, including lipid
metabolism, inflammation, atherosclerosis, insulin resistance,
the immune-stress response, vascular homeostasis, and cell
adhesion and migration (39). Analysis of adipokine function in
vitro has provided an indicator for the molecular mechanisms
linking obesity and renal disease.
Increases in body mass index are tightly associated with an
increased risk in the development of obesity-related CKD (24).
Studies in vivo in obese animals as well as in healthy animals
injected with higher concentrations of adipokines have characterized the roles of leptin, adiponectin, resistin, and visfatin
in obesity-related renal pathophysiology. These adipokines are
associated with renal dysfunction by increasing the risk of
developing albuminuria by altering GFR and potentially by
modulating renal tubule function. In vitro studies have typically focused on the glomerulus, with altered adipokines acting
on specific cell types within this region of the nephron. Recent
research in our laboratory (12) has also demonstrated that leptin
can alter proximal tubular function, which may exacerbate the
pathophysiological changes in the obese. This review will specifically focus on leptin, adiponectin, resistin, and visfatin as links
between obesity-related CKD and renal failure.
Adipokines and CKD
Leptin. Leptin is a 16-kDa peptide product of the obese (ob)
gene and is predominantly secreted by white adipose tissue (3,
28, 42) but, under some circumstances, may be produced in
other tissues (the gastric mucosa, placenta, bone marrow, mammary epithelium, skeletal muscle, pituitary, hypothalamus, and
bone marrow) (3, 28, 42). Leptin is filtered across the glomerulus
and is taken up by the scavenger receptor megalin in the proximal
convoluted tubules (28). Megalin processes leptin from the filtrate, with negligible levels of leptin in the urine (56). Low leptin
in the urine is evident even in situations when serum leptin is
elevated, such as obesity (18, 47). In nonobese individuals, the
serum level of leptin is ⬃5.5 ng/ml, with 9.5% being transferred
from the blood to the filtrate (26). In nonobese individuals, the
renal clearance of leptin is ⬃0.0595 ␮g/ml (59.5 ng/ml) (26). The
glomerular concentration of leptin in obese individuals has not
been measured; however, obese individuals have ⬃5–10 times
higher serum levels of leptin than normal individuals (26), with
another group (48) determining that the maximum plasma leptin
level observed in the obese is likely to be 200 ng/ml. Interestingly,
individuals with CKD also present with hyperleptinemia, at levels
up to 490 ng/ml (19).
The major physiological role of leptin is to regulate hunger
and satiety (21); it does this by crossing the blood-brain barrier
and inhibiting neuropeptide Y neurons in the arcuate nucleus of
the basomedial hypothalamus (10, 21, 70, 80). Leptin also acts
on the ventromedial hypothalamus, where it activates the SNS
and increases circulating epinephrine and norepinephrine levels (70, 80). Although the effect of leptin on the basomedial
hypothalamus is diminished in obesity, its effects on the
ventromedial hypothalamus remain the same (70, 80). Typically, obese individuals have an increased sympathetic output
(70), with a study (38) in dogs showing that renal denervation
ameliorates obesity-associated hypertension. Animal studies
(8, 32) have shown that lean animals acutely infused with
leptin have no changes in blood pressure and an increased Na⫹
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densa (60), which activates tubuloglomerular feedback. However, in the obese state, there is an increase in Na⫹ retention by
the kidney (14, 27, 34, 64). The increase in Na⫹ retention is
caused by increased renal sympathetic nervous system (SNS)
activation, activation of the renin-angiotensin system (RAS),
and altered intrarenal physical forces (2, 27, 57). However, the
main factor contributing to the changes in Na⫹ retention is
caused by an increase in the extracellular matrix mass of the
kidneys, which compresses the loop of Henle, decreasing blood
flow to the vasa recta and increasing Na⫹ reabsorption in the
loop of Henle (2, 27), resulting in renal vasodilatation, increasing GFR and activating the RAS. Current data suggest that
adipose tissue contains all components of the RAS and is
capable of producing both angiotensinogen and ANG II, which
increases their plasma levels (2, 27, 57). Therefore, the adipose
tissue surrounding the kidneys of obese individuals may be
contributing to the increase in RAS proteins that are observed
in the obese state. Increased RAS activation further compounds
the increase in Na⫹ and water retention, resulting in an expansion of the extracellular matrix driving hypertension (27). Ultimately, the kidney attempts to compensate for the increase in Na⫹
retention by increasing renal plasma flow, increasing GFR, and
causing hypertension (2, 27), resulting in glomerular hyperfiltration. Glomerular hyperfiltration is caused by the decrease in Na⫹
and Cl⫺ delivery to the macula densa cells of the distal tubules, as
a result of their increased reabsorption in the loop of Henle (60).
This switches off the tubuloglomerular feedback mechanism,
reducing afferent arteriole vasoconstriction, resulting in an increased GFR (60) to normalize solute delivery to the distal tubule.
Persistent glomerular hyperfiltration ultimately causes glomerular
sclerosis and renal failure (2).
Proteinuria and albuminuria are hallmark characteristics of
renal damage. The increase in protein filtration through the
glomerulus is primarily due to basement membrane thickening
(77, 79), which is further compounded with an impairment of
the protein endocytic pathway by proximal tubule cells (PTCs),
which are unable to remove excess proteins from the glomerular filtrate (73). Exposure to elevated levels of protein in the
renal tubule has been linked to the enhancement of proinflammatory and profibrotic changes in the tubulointerstitium in vivo
(79). Specifically, exposure to high levels of albumin induces
the production of proinflammatory, profibrotic, and vasoactive
factors in vitro (79). For example, the profibrogenic cytokine
transforming growth factor (TGF)-␤ is increased in the glomerular filtrate, which upregulates extracellular matrix production, leading to basement membrane thickening (79). Exposure
of renal cells to elevated protein increases the secretion of collagen types I, III, and IV, resulting in tubulointerstitial fibrosis and
also leading to basement membrane thickening (77). Despite our
understanding of the pathophysiological changes in albuminuria,
in general, the molecular and cellular targets that are altered in
obesity-related nephropathy are not as well understood; however,
studies in vivo have supported the role of adipokines in the
pathogenesis of obesity-related renal disease.
Review
F1631
ADIPOKINES IN OBESITY AND CKD
A
elevated leptin results in an accumulation of collagen and an
upregulation of TGF-␤1 secretion from glomerular endothelial
cells in vitro (78). In vivo, increased TGF-␤1 could cause
thickening of the basement membrane, leading to the development of glomerulosclerosis (Fig. 1) (78). However, the direct
link between leptin and TGF-␤1 secretion in the glomerulus in
vivo has not been demonstrated. In vitro, TGF-␤ has been
shown to increase collagen synthesis, which could cause extracellular matrix accumulation and, ultimately, fibrosis (79).
However, others (44) have shown that elevated leptin induces
the expression of matrix metalloproteinase-2 in mesangial cells
without altered expression of collagen types I and IV. Importantly, in vivo, Wolf et al. (78) demonstrated that leptin
infusion into rats for 3 wk caused an increase in collagen type
IV expression in the glomerulus. Despite the obvious differences between in vitro and in vivo experimentation, the study
by Wolf et al. (78) may not represent a true pathophysiological
condition as the levels of leptin that were infused were significantly higher than those detected in obesity. Conversely, in
PTCs, acute leptin exposure reduces cellular metabolic activity
by the activation of the mammalian target of rapamycin and
also reduces the protein content per cell (Fig. 1) (12). Research
by Hama et al. (28) identified that megalin is the sole receptor
responsible for leptin reuptake in the kidney, with histological
sections of kidneys from rats that were infused with a radioactive labeled leptin showing that leptin uptake occurs in the
proximal convoluted tubule, which lacks Ob-R. Importantly,
research by Zou et al. (82) identified that another megalin
ligand, vitamin D-binding protein, is able to cause regulated
intramembrane proteolysis of megalin with the cytosolic fragment translocating to the nucleus, which may be able to
activate signal transduction pathways. Recently, another group
(66) has determined that megalin is trafficked to the endocytic
recycling compartment in L2 rat yolk sac cells for proteolytic
B
Afferent arteriole
Basement membrane
Efferent arteriole
Adipokine
Glomerulus
Proximal
Tubule
Result
↑ leptin
Mesangial cell
hypertrophy;
Basement
membrane
thickening
↓ metabolic
activity; ↓
protein
content per
cell
Albuminuria;
Glomerular
sclerosis;
Activation of
apoptotic
pathways
↓ adiponectin
Fusion of
podocytes
↓ AMPK
Albuminuria; ↓
GFR; Tubular
inflammation
↑ resistin
?
?
↓ GFR; Tubular
inflammation
↑ visfatin
Oxidative
stress
?
Altered GFR
Mesangial cells
Capillaries
Podocytes
Proximal tubule
Protein/albumin
Fig. 1. Adipokine-induced changes to the glomerulus and proximal tubule. A: a normal glomerulus and proximal tubule in the nephron with key cells identified.
B: changes in the plasma concentrations of each adipokine observed in obesity. The effects that these changes in adipokine levels have on the structure of the
glomerulus and proximal tubule cells are shown. All of these adipokines in obesity lead to changes in the glomerular filtration rate (GFR) and/or an increase in
albuminuria or proteinuria. These changes are characteristic of chronic kidney disease. AMPK, AMP-activated protein kinase.
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excretion and urine output. The ability of leptin to increase
natriuresis is caused by a decrease in Na⫹ transport in the
tubules, with work by Bełtowski et al. (8) identifying that acute
leptin exposure decreases Na⫹/K⫹ pump (Na⫹-K⫹-ATPase)
activity. Several studies have now demonstrated that acute
leptin infusion stimulates the release of nitric oxide (NO) in
endothelial cells and blood vessels (74), with NO being shown
to decrease Na⫹ reabsorption in the tubules by decreasing
Na⫹-K⫹-ATPase (58). Therefore, acute leptin exposure in the
kidney may increase NO expression in an attempt to regulate
obesity-associated hypertension. However, chronic leptin exposure further compounds hypertension in the obese by increasing renal sympathetic activity. Chronic hyperleptinemia
has been shown to increase the activity of Na⫹-K⫹-ATPase,
causing Na⫹ retention (7) by either increased renal SNS
activity and/or decreased NO production (7). Bełtowski et al.
(9) identified that hyperleptinemia causes NO deficiency primarily due to increased renal oxidative stress, which inhibits
the protective role of NO in increasing Na⫹ excretion (9).
Leptin predominantly binds to the leptin receptor (Ob-R) in
most tissues, which is capable of activating downstream signal
transduction pathways (3). The long isoform of the leptin
receptor (Ob-Rb) has been shown to activate JAK/STAT (10)
and MAPK pathways (3, 6). However, leptin can activate a
number of cell signaling pathways in a cell-specific manner,
and, thus, the effect of altered levels of leptin on the kidney is
an emerging area of research. In vitro, leptin can alter glomerular cell size via activation of the MAPK pathway through
ERK1/2 (15, 45). Specifically elevated levels of leptin cause
hypertrophy in glomerular mesangial cells via activation of
phosphoinositide 3-kinase and ERK1/2 (Fig. 1) (45). Glomerular mesangial hypertrophy increases the amount of filtered
protein and albumin reaching the PTCs activating fibrotic and
inflammatory pathways (77, 79). In addition, exposure to
Review
F1632
ADIPOKINES IN OBESITY AND CKD
mediator AMP-activated protein kinase (AMPK) (1, 68), a key
regulator of energy homeostasis. Adiponectin also activates the
downstream signaling mediator peroxisome proliferator-activated
receptor-␣ as well as the MAPK pathway in vitro (43).
Hypoadiponectinemia has been associated with renal dysfunction and CKD. Research by Doumatey et al. (22) identified
an inverse relationship between circulating adiponectin levels
and renal function, which was further supported by Sharma et
al. (68), who identified that adiponectin is an independent
predictor of moderate CKD. Specifically, adiponectin can be
used as a predictor of eGFR and CKD (22), with circulating
adiponectin being negatively associated with eGFR (Fig. 1)
(22). A potential mechanism for this has been identified in
mice with hypoadiponectinemia. These mice exhibit podocyte
fusion with adiponectin treatment improving the glomerular
podocyte foot processes via activation of AMPK, which downregulates podocyte NADPH oxidase (Nox)4 production (Fig.
1) (68). Importantly, these mice exhibit albuminuria (45),
clearly demonstrating a link between hypoadiponectinemia and
kidney dysfunction.
AdipoR1 is localized to the podocytes, which suggests that
at the molecular level, altered adiponectin receptor activity
may lead to obesity-related dysfunction (68). Importantly,
adiponectin has been shown to downregulate Nox4 production
in podocytes (68), which is an important mediator in oxidative
stress. Furthermore, research by Sharma et al. (68) demonstrated that the low adiponectin levels in obesity cause an
upregulation of podocyte production of Nox4, which suggests
that the role for AdipoR1 may be by the modulation of
oxidative stress associated with renal damage.
Interestingly individuals with established kidney disease and
patients with type 2 diabetes mellitus (DM) have a significant
increase in the urinary excretion of both the low- and highmolecular-weight isoforms of adiponectin (69, 76). The cause
of this association was determined by von Eynatten et al. (76),
who identified that glomerular adiponectin is diminished in
diabetic nephropathy, which is caused by glomerular sclerosis.
Importantly, AdipoR1 and AdipoR2 have been identified in
vitro in PTCs (HK2 cells) (69), with adiponectin treatment
increasing AMPK activation and decreasing the secretion of
monocyte chemotactic protein (MCP)-1 (a mediator of inflammation) (69). Research by Declèves et al. (20) further identified
significant increases in urinary excretion of MCP-1 and H2O2
after only 1 wk of high-fat feeding in vivo that proceeded
albuminuria, identifying that MCP-1 and H2O2 are involved in
the onset of inflammation in the kidney. Importantly, treatment
with an AMPK activator prevented the increase in urinary
MCP-1 and H2O2, which also prevented the decrease in adiponectin levels associated with obesity, suggesting that adiponectin is the main modulator of these inflammatory proteins
via AMPK activation (20). Therefore, hypoadiponectinemia
results in tubular inflammation by decreasing tubular AMPK
activation, resulting in an accumulation of MCP-1. Despite this
finding, limited research exists on the effect hypoadiponectinemia has on the tubules, with most studies investigating patients
with normal adiponectin levels who have kidney disease and
DM. As elevated glucose, which is observed in DM, may alter
tubular function independently of obesity, future studies are
required to clarify the specific roles that AdipoR1 and AdipoR2
play in the tubules, including the effect that obesity has on the
downstream signaling targets of these receptors.
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processing and the modulation of cellular gene expression for
the activation of signal transduction pathways. Research from
our laboratory (12) has shown that leptin alters signalingmediated expression in opossum kidney cells, a cell line that
has characteristics of the proximal tubule and appears to lack
protein expression of Ob-R. Therefore, we speculate that in the
proximal tubule, leptin signaling may occur via megalin. To
add to our knowledge in this area, long-term exposure to leptin
results in the activation of apoptotic pathways in PTCs (30),
which is absent after acute exposure to leptin (12, 15). Recently, we (12) have also demonstrated that acute exposure to
leptin activates ERK1/2 and mammalian target of rapamycin
phosphorylated at serine reside 2481. These few studies clearly
highlight a need for further research into leptin-megalin signaling pathways so that potential targeted molecules can be
identified for future therapeutics.
Leptin is linked to the development of CKD in the absence
of obesity, as patients with ESRD have an estimated 4- to
7.5-fold increase in plasma leptin concentration (hyperleptinemia) compared with healthy control subjects (19, 55, 67).
However, this finding has only been investigated in ESRD
patients undergoing hemodialysis and may be an artifact of the
dialysis itself. To investigate if the identified hyperleptinemia
in ESRD patients is caused by hemodialysis or by altered leptin
excretion or production, Dagogo-Jack et al. (19) investigated
this association in ESRD patients undergoing continuous ambulatory peritoneal dialysis. They determined that hyperleptinemia is still observed in patients undergoing continuous
ambulatory peritoneal dialysis, suggesting that the hyperleptinemia may be the result of terminal renal failure (19). Interestingly, Sharma et al. (67) identified in patients with renal
insufficiency that leptin uptake by the kidneys is diminished.
These data, taken together, suggest that in ESRD, hyperleptinemia may be the result of altered leptin production as well as
terminal renal failure. However, the mechanism for this link is
poorly understood, and, as such, future studies are required to
further investigate this association.
Adiponectin. Adiponectin is a 30-kDa plasma protein that is
predominantly secreted by adipose tissue (63, 68). Physiological plasma concentrations of adiponectin are between 5 and 30
␮g/ml (63, 68), which constitute 0.01% of total plasma protein
(63). In healthy individuals, both a low- and high-molecularweight isoform of adiponectin are detected in the urine in trace
amounts, with the low-molecular-weight isoform being the
most abundant form of urinary adiponectin (69, 76). Adiponectin has a number of functional roles, including acting as a
cardioprotective protein, improving insulin sensitivity, and acting
as a vascular protective agent via the suppression of ROS production (68). Secreted adiponectin exists in many stable complexes of different molecular weights (23). Adiponectin levels are
negatively correlated with percent body fat, with adiponectin
levels decreasing significantly in obesity (1, 68, 81). Adiponectin
binds to two receptors that have varied distributions and different
affinities to the molecular weight complexes of adiponectin. Adiponectin receptor (AdipoR)1 is abundantly expressed in skeletal
muscle and moderately expressed in other tissues, including the
brain and heart (37, 68); in the kidney, AdipoR1 is located in the
glomerulus and proximal tubule (68). AdipoR2 is predominantly
expressed in the liver (37); however, AdipoR2 has also been
identified in PTCs (69). Adiponectin binding to both AdipoR1 and
AdipoR2 increases the activation of the downstream signaling
Review
ADIPOKINES IN OBESITY AND CKD
the gene discovered in 1994 (65). Visfatin is a 52-kDa protein,
which makes it one of the largest adipokines (23). Adipocytes
are the primary source of visfatin, with leucocytes, hepatocytes, and skeletal muscle also producing the adipokine at
lower levels (50, 72). The estimated physiological plasma
concentration of visfatin is 15 ng/ml (23), with plasma concentrations of visfatin increasing with adiposity (71, 72). Controversy exists between the classification of visfatin as an
adipokine, with some researchers suggesting that it should be
classified as a marker of inflammation (50, 71), as elevated
visfatin levels in obesity are potentially caused by renal failure
or inflammation (50). Nonetheless, visfatin has been shown to
increase the production of the inflammatory cytokines TNF-␣,
IL-6, and IL-1␤ as well as increasing ROS generation (50).
Currently, the role that visfatin plays in the kidney in vivo is
not well understood; however, after renal transplantation, visfatin levels are positively correlated with proteinuria and the
production of markers of inflammation (50). Analysis of visfatin in cultured glomerular endothelial cells in vitro has
determined that visfatin stimulation causes a significant increase in superoxide production via lipid raft clustering (11).
As superoxide production increases oxidative stress, it alters
the permeability of the cell (11), suggesting that visfatin may
activate oxidative stress pathways leading to renal pathology
(Fig. 1).
In vitro visfatin administration at levels associated with obesity
have been shown to upregulate components of the intrarenal
RAS (31). Specifically, in glomerular mesangial cells, exposure to elevated visfatin resulted in increased renin mRNA
expression in addition to increased mRNA and protein expression of angiotensinogen (31). As the RAS plays an important
role in the regulation of GFR (31), any changes in renin or
angiotensinogen levels are likely to alter GFR (31), contributing to nephropathy (Fig. 1). Song et al. (71) identified that
glomerular mesangial cells in vitro express visfatin protein in
normal glucose conditions, with minimal visfatin secretion
from these cells. Interestingly, high glucose (30 mM) conditions significantly increase mesangial visfatin production and
secretion (71). The increase in visfatin production under high
glucose conditions could contribute to the increased influx of
glucose into mesangial cells, accelerating the progression of
diabetic nephropathy (71). Furthermore, there is a correlation
between plasma visfatin levels and the severity of DM (16, 71).
However, the role that visfatin plays in obesity-related CKD is
poorly understood. Future studies should investigate the effect
that elevated visfatin has on the glomerulus and proximal
tubules, specifically, the downstream signaling mediators it
activates under physiological and pathophysiological conditions, to characterize the effect of visfatin in CKD and diabetic
nephropathy.
Conclusions
Obesity rates worldwide are increasing rapidly, with obesity
being associated with a number of pathologies, including CKD.
CKD is the result of a decrease in the kidney’s ability to
function and is associated with albuminuria and proteinuria.
Both albuminuria and proteinuria cause basement membrane
thickening and fibrosis in the glomerulus (77, 79), and, in the
tubules, it actives the tubuloglomerular feedback mechanism,
resulting in glomerular hyperfiltration and hypertrophy, lead-
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While obesity is typically associated with hypoadiponectinemia, in contrast to this, adiponectin levels have been demonstrated to increase in type 1 diabetic patients with diabetic
nephropathy and later stages of CKD (35, 53). To help possibly
explain the rational for this increase, a recent study by Martinez Cantarin et al. (52) identified that elevated adiponectin in
ESRD is caused by an increased production of adiponectin
from adipose tissue. Despite the generally protective actions of
adiponectin on health, interestingly, elevated adiponectin is a
predictor for mortality in patients with CKD stages 3 and 4
(53); however, the mechanisms behind this observation remain
unclear. Future studies are therefore required to determine why
adiponectin levels rise in CKD stages 3 and 4 and how
adiponectin is a predictor of mortality in these patients.
Resistin. Resistin is a 12.5-kDa adipokine that is predominantly produced by macrophages, with lower levels released
from adipocytes (4, 54). Resistin circulates in the blood in two
forms (minor and major) (59), with increasing resistin levels
associated with adiposity (54). The minor form of resistin has
a significantly increased bioactivity compared with the major
form, indicating that it is the major active form of the molecule
(59). The pathophysiological role that high resistin levels has
in obesity has been poorly investigated. Resistin levels are
linked to the albumin-to-creatinine ratio as well as GFR (4, 54),
with increased resistin levels associated with a decrease in
GFR (Fig. 1). This may be due to the activation of inflammatory pathways, with elevated resistin levels being associated
with an enhanced inflammatory response (4), which is likely to
be due to the activation of macrophages in CKD, the primary
source of resistin production (4, 54).
Several studies (36, 49, 75) have investigated the role that
resistin plays in the development of cardiovascular disease
(CVD), where high resistin levels correlate with increased
endothelin (ET)-1 expression. ET-1 is a potent vasoactive factor that causes endothelial dysfunction in CVD and has also
been linked to obesity-related hypertension. A study by Jung et
al. (36) identified macrophages that infiltrated atherosclerotic
aneurysms secreted resistin and that resistin increases ET-1 and
causes vascular smooth muscle cell infiltration. In vitro experiments have also shown that resistin significantly increases the
expression of MCP-1 and VCAM (75). Physiological levels of
ET-1 are responsible for the maintenance of normal renal
function (62). A study (29) in transgenic mice overexpressing
ET-1 in the kidney developed glomerulosclerosis and tubulointerstitial fibrosis in an aging-induced manner and have noted
decreases in GFR. These studies, taken together, suggest that in
obesity, there is an increase in macrophage invasion in the
endothelium of the kidney, which increases renal expression of
ET-1 and MCP-1, causing inflammation, with the increase in
ET-1 causing endothelial dysfunction, ultimately resulting in
glomerulosclerosis and tubulointerstitial fibrosis, suggesting a
role for ET-1 in the development of CKD. However, such
studies have not been carried out looking at obesity-related
changes to macrophage infiltration and ET-1 levels in the
kidney. Currently, the specific molecular targets in the nephron
that are activated after exposure to elevated resistin is unknown, and further studies are required to characterize the
specific role that resistin has in macrophage infiltration and
inflammation in the kidney.
Visfatin. Visfatin (also known as pre-B cell colony-enhancing) is an adipokine that was first identified in 2005 (25), with
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Review
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ADIPOKINES IN OBESITY AND CKD
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
GRANTS
J. F. Briffa is supported by an Australian Postgraduate Award scholarship.
D. H. Hryciw and A. J. McAinch were funded by Helen McPherson Smith
Trust Grant 6662. A. J. McAinch is supported by the Australian Government’s
Collaborative Research Networks program.
DISCLOSURES
18.
19.
20.
No conflicts of interest, financial or otherwise, are declared by the author(s).
AUTHOR CONTRIBUTIONS
21.
Author contributions: J.F.B., A.J.M., P.P., and D.H.H. conception and
design of research; J.F.B., A.J.M., and D.H.H. prepared figures; J.F.B., A.J.M.,
P.P., and D.H.H. drafted manuscript; J.F.B., A.J.M., P.P., and D.H.H. edited
and revised manuscript; J.F.B., A.J.M., P.P., and D.H.H. approved final
version of manuscript.
22.
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ing to renal fibrosis and progressive nephropathy (64). Our
understanding of the roles that adipokines play in obesity and
CKD is an emerging field of research. The link between
adipokines and changes in glomerular filtration have been
observed; however, for most adipokines, the molecular mechanism(s) have not been determined. Most research has been
performed on leptin, with elevated levels of leptin resulting
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tubular apoptosis (12, 15, 30). These changes to the nephron
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cells.
Studies investigating a number of other adipokines have
been more limited. Hypoadiponectinemia in the obese state
increases the production of ROS, leading to oxidative stress in
the podocytes (68), which is likely to alter GFR. Importantly,
adiponectin may also play a role in tubular inflammation (69),
which may further compound the development of nephropathy.
However, research into the roles that resistin and visfatin play
in obesity-related nephropathy is limited, with both adipokines
being associated with declining GFR. Currently, the mechanism behind the role of resistin in declining GFR is unknown.
Interestingly, glomerular mesangial cells have been shown to
secrete visfatin under high glucose conditions (71), with visfatin being shown to increase angiotensinogen protein expression, which may increase RAS activation, which would alter
GFR (31).
Overall, there appears to be an emerging link between
adipokine dysregulation in obesity and the development of
CKD. Largely, these studies have demonstrated that adipokines
can alter glomerular function, with emerging research also
identifying a tubular link. More extensive mechanistic studies
in vivo are required to clarify the role(s) that these adipokines
play in CKD and other obesity-related pathologies. Furthermore, the characterization of the molecular downstream signaling targets in altered renal cells is essential in developing
effective therapeutics for obesity-related nephropathy.
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