Post on 04-Mar-2023
AMPK in Diabetic Nephropathy SS Prabhakar
The Role of 5'-AMP-activated protein kinase (AMPK)
in Diabetic Nephropathy: A new direction?
K. Wyatt McMahon1, Dora I. Zanescu2, Vineeta Sood1,
Elmus G. Beale3, and Sharma Prabhakar1*
1 - Texas Tech University Health Sciences Center School of
Medicine, Department of Internal Medicine, Division
of Nephrology, Lubbock, TX 79430
2 - Texas Tech University Health Sciences Center School of Allied
Health, Department of Molecular Pathology, Lubbock,
TX 79430
3 -Texas Tech University Health Sciences Center Paul Foster
School of Medicine, Department of Medical
Education, El Paso, TX 79905
Address for correspondence
Sharma S Prabhakar MD, MBA, FACP, FASN.
Chief, Division of Nephrology and Hypertension
Department of Internal Medicine,
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AMPK in Diabetic Nephropathy SS Prabhakar
Texas Tech University Health Sciences Center
Lubbock, TX 79430 USA
Tel: (806)743-3155 Fax: (806)743-3148 E-mail:
sharma.prabhakar@ttuhsc.edu
Abstract
Diabetic nephropathy (DN) is a microvascular complication of
diabetes that is characterized by proteinuria,
glomerulosclerosis, and decreased kidney function ultimately
leading to end stage renal disease; in fact, DN is the
leading cause of end stage renal disease in the western
world. Glycemic and blood pressure control are currently the
most common forms of prevention and treatment of the
disease. However, despite good glycemic and blood pressure
control, many patients still progress to end stage renal
disease and require renal replacement therapy, leaving
investigators searching for novel DN therapy targets. The
AMP-activated protein kinase (AMPK) is a heterotrimeric
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AMPK in Diabetic Nephropathy SS Prabhakar
protein that serves as an energy regulator for the cell.
However, numerous extracellular factors that contribute to
DN progression (including glucose, vascular endothelial
growth factor, insulin, and AngII) may inhibit AMPK
activity. Two recent studies indicate that AMPK activity
decreases during DN progression (Lee et al., Am J Physiol Renal
Physiol 292(2):F617-27 and Cammisotto et al., Am J Physiol Renal
Physiol. 294(4):F881-F889). In order to better understand the
potential role that AMPK inhibition has in DN, we have
reviewed the mechanisms of AMPK regulation, how these
regulatory mechanisms are changed in DN, and what effect
that might have on AMPK activity. Additionally, we discuss
the downstream effects of AMPK signaling, and how diminished
AMPK activity would affect these events. It is our hope
that this review will stimulate future research into how
augmenting renal AMPK activity may be useful in alleviating
DN.
[word count: 240]
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AMPK in Diabetic Nephropathy SS Prabhakar
Key words: AMPK, diabetic nephropathy, enzyme regulation, molecular
pathogenesis
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AMPK in Diabetic Nephropathy SS Prabhakar
Introduction
The adenosine mono-phosphate activated protein kinase (AMPK)
has been known as the “metabolic master switch” (reviewed in
[19-21]). Over the past 35 years of AMPK research, one
important function of this enzyme has been actively
investigated: to generate ATP under conditions of low
energy. AMPK phosphorylates substrates that inhibit
anabolic pathways (like fat accumulation) and activate
catabolic pathways (like β-oxidation of fatty acids) in the
presence of even minor increases in the level of AMP, which
acts as an indicator for low energy in the cell. Research
on AMPK has mainly focused on its ability to respond quickly
and robustly to these slight increases in AMP levels and
thereby generate energy in response to metabolic stresses
like exercise. However, more recent studies have indicated
that AMPK is also regulated by extracellular cues, including
adiponectin, leptin, angiotensin (AngII), as well as others
(see below). In addition, AMPK is now known to regulate not
only fatty acid β-oxidation and ATP synthesis by
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AMPK in Diabetic Nephropathy SS Prabhakar
glycoloysis, but angiogenesis, cell division, feeding and
apoptosis. Therefore, our understanding of AMPK’s role has
expanded to include not only a regulator of cellular
metabolism, but a regulator of whole-body metabolism. In
this review, we highlight the importance of AMPK in the
kidney.
Diabetic nephropathy (DN) is the leading cause of end stage
renal disease (ESRD) in the western world, and an important
complication of diabetes. Nearly 180,000 people are
suffering from kidney failure as a direct result of
diabetes. In addition, there is a recent explosion in the
number of individuals with diabetes, indicating that a
similar increase in DN is close at hand. Therefore, the
necessity of developing novel therapies is becoming a more
pressing issue.
DN is characterized by increasing proteinuria, expansion of
the mesangium, glomeruluar sclerosis and fibrosis, leading
to a diminished glomerular filtration rate [43, 56]. While
the disease is well-characterized at the clinical and
histological levels, the molecular mechanisms of this
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AMPK in Diabetic Nephropathy SS Prabhakar
disease remain unclear. Current therapies for DN such as
AngII converting enzyme inhibitors and AngII receptor
blockers show some efficacy, but eventually patients
progress to ESRD regardless, and therefore improved
therapies are needed to prevent further increases in the
incidence of this debilitating disease. A better
understanding of the molecular mechanisms of this disease
could lead to such improvements in DN therapeutics.
AMPK regulation and activity have been extensively studied
in insulin-responsive tissues such as skeletal muscle,
adipose, and liver; therefore, little is known about the
role of AMPK in the kidney. However, two recent papers have
suggested that inhibition of the AMPK enzyme may be an
important step in the pathogenesis of DN [6, 24]. These
papers both suggest that there is a loss of AMPK activity in
DN, and that this loss of activity leads to some of the
observed histological aberrations that characterize DN —
glycogen accumulation in renal tubules [6] and podocyte
hypertrophy [24]. These observations led us to speculate
about the importance of such a proposed loss of AMPK
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AMPK in Diabetic Nephropathy SS Prabhakar
activity in DN, and what potential mechanisms could explain
this loss.
The basis of this review article is that that the decrease
contributes to DN pathophysiology. In this article we
review the factors that activate and inhibit AMPK activity,
with special attention to those factors that may be
responsible for the inhibition (or lack of activation) of
AMPK in DN. Subsequently, we describe the possible
ramifications of loss of AMPK signaling in DN. Finally, we
review known phrarmacological activators of AMPK, and the
possible usefulness of these drugs in DN treatment. It is
our hope that this article will initiate further research
into the role of AMPK in DN, and lead to better therapies
for the growing number of people with this disease.
AMPK structure and enzymology
AMPK is a heterotrimeric enzyme, consisting of α, β, and γ
subunits (for an excellent review of the enzyme, see[5,
51]), the sequences of which are all highly conserved,
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AMPK in Diabetic Nephropathy SS Prabhakar
underscoring the physiological importance of the enzyme
[5]The α subunit is the catalytic subunit, and the γ subunit
binds AMP via its CBS domains. The β subunit serves to
bridge between the two subunits. In mammals, there are two
α subunits which are encoded by separate genes: α1 and α2.
The α2 subunit is expressed predominantly in skeletal muscle
and liver [49].There is little difference in the catalytic
abilities of either form of the α protein. However, the α1
subunit (expressed in most tissues [49], including the
kidney) seems to be slightly less responsive to fluctuations
in AMP [44], indicating that the activity of this protein is
more likely to be regulated by extracellular signals.
AMPK is also regulated by phosphorylation of threonine 172
(T172) on the α-subunit; more precisely, AMPK is regulated
via a continuous phosphorylation/dephosphorylation cycle.
The constituitively active proto-oncogene LKB1 and the
calcium-calmodulin kinase are responsible for constantly
phosphorylating AMPK at T172, which increases the activity
of AMPK by >100-fold. However, the PP2C phosphatase is
responsible for constantly de-phsophorylating the α-subunit,
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AMPK in Diabetic Nephropathy SS Prabhakar
thereby inactivating AMPK. What breaks the tie between the
two opposing forces may be the binding of AMP to the CBS
domains of the γ subunit, which prevents the
dephosphorylation of the α subunit. Therefore, binding of
AMP not only activates the protein but also prevents
dephosphorylation, leading to a combinatorial effect on the
enzyme’s activity. The corollary to this is that
extracellular cues that activate AMPK must not only lead to
an increase in T172 phosphorylation, but also an increase in
cellular AMP.
Mechanisms for the loss of AMPK activity in DN
As described above, two separate reports have indicated a
decrease in AMPK activity during DN progression. While both
groups have made suggestions as to what a possible mechanism
for this loss of activity might be, the issue is complicated
by the large number of stimuli present in the diabetic
milieu which could play a role in changing renal AMPK
activity. Below are a number of such factors that could be
responsible for changes in AMPK activity.
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AMPK in Diabetic Nephropathy SS Prabhakar
Hyperglycemia
The distinguishing characteristic of all poorly-controlled
diabetics is high levels of blood glucose; therefore, it is
likely that any changes in AMPK activity that occurs in
diabetics would be at least partially accounted for by
hyperglycemia. AMPK activity had been studied as a
regulator of metabolism for 24 years before any studies
focused on the effect that high glucose might have on AMPK.
Then, Salt et al. (1998), observed that removal of glucose
from the media of two different insulin-producing pancreatic
β-cell lines led to an increase in AMPK activity [45]. This
activation is due to both an increase in intracellular AMP
levels and increased AMPK phosphorylation. Subsequently,
numerous studies have found that AMPK activity is inhibited
by high glucose in numerous tissues and organisms [2, 23,
34], indicating a central role for extracellular glucose in
the regulation of AMPK activity.
As described above, Lee et al. grew thick ascending tubule
cells in a high glucose medium and observed a precipitous
decrease in the level of AMPK activity [24]. While the
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AMPK in Diabetic Nephropathy SS Prabhakar
mechanism of this downregulation is currently unclear (i.e.
– decreased AMP, decreased AMPK phosphorylation, or both)
these data indicate that high glucose is likely a central
player in the theorized downregulation of AMPK activity in
the diabetic kidney.
Decreased adiponectin
Adiponectin (Ad - also called adipocyte complement-related
protein of 30 kDa and adipo Q) is a peptide hormone produced
exclusively by adipose tissues that is both anti-atherogenic
and anti-diabetic [3, 16, 54]. Ad’s main function is to
sensitize tissues to insulin, and it does this by 1)
increasing β-oxidation and thereby lower the fat content of
these tissues, and 2) preventing gluconeogenesis in the
liver. Since these primary functions are precisely the same
as the functions of AMPK, it was reasonable to speculate
that AMPK may be regulated by adiponectin. Indeed,
treatment of cells with adiponectin causes a fast increase
in the activity of AMPK [50, 57]. Furthermore, low levels
of adiponectin are associated with a predisposition for type
II diabetes [48]; therefore, the relative absence of
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AMPK in Diabetic Nephropathy SS Prabhakar
adiponectin from the serum of type II diabetics could be at
least partially responsible for the proposed decrease in
AMPK activity in the kidney during DN.
Additionally, uncoupling of adiponectin and AMPK activation
is a common feature of diabetes. Hyperglycemia, a
characteristic of DN patients, prevents the adiponectin-
mediated upregulation of AMPK activity in distal tubular
cells [6], and adiponectin-based AMPK activation attenuated
in type II diabetics [8]. While the mechanism of this
uncoupling has not been elucidated, these data indicate that
a decrease in adiponectin - along with a decrease in
adiponectin’s ability to stimulate AMPK - may play an
important role in mediating the downregulation of AMPK
activity in DN.
Leptin-resistance
Another important adipocyte-derived metabolic hormone is
leptin. This hormone not only regulates fat metabolism (as
does adiponectin), but also regulates energy intake [35].
Rats and mice lacking functional receptors for leptin
(Zucker diabetic fat rats [40] and db/db mice [7, 58]) are
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AMPK in Diabetic Nephropathy SS Prabhakar
obese and show no evidence of satiety, leading to the
hypothesis that leptin is the “satiety hormone”. Since
leptin regulates fat metabolism in skeletal muscle the same
as AMPK, it was not surprising to find that AMPK is
activated by leptin in soleus muscle [30] which leads to an
phosphorylation and inhibition of acetyl Co-A carboxylase
(the enzyme that converts acetyl-CoA to malonyl Co-A and
thereby inhibits β-oxidation). Leptin levels are elevated
in obesity [26], which would be expected to elevate AMPK
activity. In contrast, leptin-resistance is a feature of
diabetes ensues, leading to a decrease in AMPK activity and
fatty acid accumulation in the liver [17, 35]. A similar
resistance may also be present in the kidney, which would
lead to a decrease in renal AMPK activity and progression of
DN. However, leptin inhibits AMPK in the arcuate and
paraventricular hypothalamus leading to a decrease in food
intake and body weight [29]. This indicates that leptin has
tissue-specific effects on AMPK activity. It is possible,
therefore, that renal AMPK activity could be decreased as a
result of leptin-based repression, or as a result of leptin-
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AMPK in Diabetic Nephropathy SS Prabhakar
resistance due to diabetes. Further experimentation will be
necessary to understand the effects of leptin on renal AMPK
activity.
Angiotensin activation
Angiotensin is a short peptide that is known to mediate an
increase in vascular tone and thereby increase local
pressure within an arteriole, and it also plays a key role
in the progression of DN [28]. Within the kidneys of
diabetics, there is an elevated level of locally-produced
AngII [4, 22], which is believed to be more relevant to the
pathogensis of DN than the systemic AngII [55].
Interestingly, treatment of rat vascular smooth muscle cells
with AngII initiated an increase in AMPK activity,
approximately half the power as what the specific AMPK
activator 5-Aminoimidazole-4-carboxyamide ribonucleoside
(AICAR) initiated, indicating that AMPK is activated by
AngII [37]. This activation was blocked by treatment with
valsartan, the AngII type I receptor, but not by PD 123319,
the AngII type II receptor. However, AMPK activation was
also blocked by antioxidants and NADPH oxidase inhibitor, in
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AMPK in Diabetic Nephropathy SS Prabhakar
line with previous reports that AMPK is redox-sensitive
[10]. Together, these data indicate that the primary source
of AMPK activation occurs as a result of reactive oxygen
species produced as a result of AngII type I receptor
activation.
Like hypoxia, the AngII-based activation of AMPK is
contradictory to what might be expected in DN, since AngII
is higher in DN and AMPK activity is lower. There are two
possible explanations for this discrepancy: first, it is
possible that the downregulatory effects of other
contributing factors such as hyperglycemia, leptin
resistance, and diminished adiponectin may surpass the Ang
II-mediated upregulation of AMPK. Alternatively, it is
possible that within the kidney, specifically, Ang II and
reactive oxygen species work to downregulate rather than
upregulate AMPK activity. Either way, it would not be
surprising if the elevated AngII levels are shown to play
some role in loss of AMPK activity in DN, since AngII is
known to play such an important role already. This
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AMPK in Diabetic Nephropathy SS Prabhakar
interaction between Ang II and AMPK in the diabetic kidney
may merit further investigation.
Possible effects of AMPK inhibition in DN
As described above, early data suggest that AMPK activity is
diminished in the kidney in diabetics, likely as a result of
multiple diabetic factors. However, beyond the important
question of how AMPK activity might be suppressed in DN is
what impact loss of AMPK activity might have on the diabetic
kidney. As described below, a number of the known
consequences of DN may result from AMPK activity loss. We
have already discussed the publications of Lee et al., and
Camissotto et al. which showed that AMPK activity loss may
play a role in podocyte hypertrophy and tubular cell
glycogen accumulation, respectively. However, these
phenomena are a small sample of the known symptoms of DN; it
is possible that AMPK plays a key role in mediating many
other tissue/cellular aberrations that occur in diabetic
renal disease.
Extracellular matrix deposition
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AMPK in Diabetic Nephropathy SS Prabhakar
One of the hallmarks of DN is a significant increase in the
deposition of extracellular matrix, particularly by
mesangial cells within the glomerulus [1, 15, 25]. The
transforming growth factor-β (TGF-β) is said to play an
important role in the deposition of this matrix expansion
[47]. A recent study aimed at understanding the role of
AMPK in myofibroblast transdifferentiation indicated that
human mesangial cells treated with the AMPK activator AICAR
were resistant to TGF-β-induced collagen production, a major
contributor to the mesangial expansion seen in DN [31].
Further, expression of a kinase-dead mutant of AMPK
prevented the AICAR-induced inhibition, verifying that AMPK
is directly responsible for the observed suppression of
mesangial matrix expansion. Finally, the authors also
showed that fibroblasts from AMPK-/- mice secreted higher
levels of collagen in response to TGF-β than wild type
fibroblasts. Together, these recent data indicate that AMPK
is a negative regulator of TGF-β-induced collagen secretion.
In light of these data, it is interesting to speculate that
AMPK may also play a role in mesangial expansion in DN. If
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AMPK in Diabetic Nephropathy SS Prabhakar
this is the case, then AMPK activators would likely play a
very important role in preventing the glomerular sclerosis
and fibrosis seen in DN.
Reduction in nitric oxide levels
There was a recent important finding that AMPK
phosphorylates the endothelial nitric oxide synthase (eNOS)
on serine 1177 [9, 60]. This phosphorylation event is
shared by a number of other enzymes [33], and is an
important step in the activation of eNOS. Additionally,
eNOS is known to be the enzyme responsible for a majority of
the changes in nitric oxide (NO) fluctuations that occur
during DN [42], and loss of eNOS protein entirely leads to
precocious DN in a mouse model of the disease [38, 59]. It
is therefore interesting to suggest that a decrease in AMPK
activity during DN progression may play an important role in
the loss of NO bioavailability that occurs during DN.
However, decreases in eNOS protein levels have been seen in
models of DN, suggesting another mechanism by which NO
levels may diminish [41].
Angiogenesis
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AMPK in Diabetic Nephropathy SS Prabhakar
Recently, there has been an exponential increase in the
amount of research being performed to understand the role of
angiogenesis in DN. Angiogenesis is highly stimulated in
DN, and multiple research groups have shown a corresponding
increase in the secretion of the potent pro-angiogenic
factor vascular endothelial growth factor (VEGF) in diabetic
kidneys (O. Iznaola, J. Simoni, and S.P., unpublished) [11,
52]. AMPK activation with AICAR has been shown to elevate
VEGF protein and RNA expression, as well as vascular
infiltration, suggesting that AMPK likely plays an important
role in angiogenesis [36]. This is in contrast to the
observed decrease in AMPK activity that early evidence
suggests occurs in DN; therefore, it is possible that the
angiogenesis that occurs during DN occurs via an AMPK-
independent mechanism. Preliminary results from our
laboratory indicate that the expression of the pro-
angiogenic kinase Akt are upregulated during early-stage DN
(K.W.M., D. Z., S. Selhi, and S.P, unpublished); this may
indicate that the angiogenesis seen in DN is via a
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AMPK in Diabetic Nephropathy SS Prabhakar
wortmannin-sensitive (Akt-dependent) pathway, rather than a
compound C-sensitive (AMPK-dependent) pathway.
Expression of AMPK within the kidney
A number of potential mechanisms for AMPK activity loss in
DN have been described in this article, and it is likely
that AMPK plays a role in many features of DN, but the
practicality of AMPK’s role in these features is founded
largely on AMPK’s expression within the different cell
types. Activated AMPK is distributed throughout much of the
kidney, including various regions of the thick ascending
limb, distal convoluted tubule, the collecting duct, and the
macula densa. While this particular study did not look at
AMPK expression in the endothelium and mesangial cells,
AMPK has been detected in the endothelium [12, 13, 32] and
in mesangial cells [31] in other studies. Overall, these
data indicate that that AMPK is expressed in most of the
cell types of the kidney. Therefore, it is likely that all
of the above renal functions attributed to AMPK are
possible, given AMPK’s wide distribution of expression
within the kidney.
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AMPK in Diabetic Nephropathy SS Prabhakar
Clinical use of metformin in DN – clues to the importance of AMPK in DN?
While the data described above implicate AMPK in DN
progression in in vitro and rodent studies, clinical data
obtained by using AMPK-activating drugs also indicate that
activation of AMPK may ameliorate various aspects of DN.
There are three different well-known AMPK activators, and
the mechanisms of their activation are being made clear.
First, AICAR (5-aminoimidazole-4-carboxamide
ribonucleoside), an analogue of AMP, which activates AMPK
through allosteric activation; however, this has thus far
not been used in a clinical setting, and therefore will not
be discussed further here. Another family of AMPK activators
is the PPAR activators, rosiglitazone and pioglitazone,
which also activate AMPK not by direct binding but by
increasing cellular AMP/ATP ratio. Finally, the best known
AMPK activator is metformin, which has been used as an anti-
diabetic drug for 40 years. Metformin inhibits the
mitochondrial electron transporting enzyme complex I of the
respiratory chain, and thereby activates AMPK [14, 39].
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AMPK in Diabetic Nephropathy SS Prabhakar
Promising data about the use of AMPK activators come from
studies involving thiazolidines in DN. Data from several
animal and human studies support the concept that
thiazolidines reduce urine albumin excretion and may prevent
development of renal injury [46]. This is associated with a
reduction of glomerular hyperfiltration, prevention of
intrarenal arteriolosclerosis, and prevention of
glomerulosclerosis and tubulointerstitial fibrosis [18, 27,
46].
It is difficult to speculate about the possible effects of
metformin on DN because patients with sub-optimal glomerular
filtration rates are rarely treated with metformin, given a
propensity for such individuals to develop acidosis.
However, metformin has also been found to improve both
endothelial function and insulin resistance in patients with
metabolic syndrome [53]. With the high proportion of
endothelium that exists in the kidney, it is likely that
metformin would benefit DN, were it not for the
contraindications of this drug in DN. Therefore, indirect
AMPK activation via inhibition of the mitochondrial electron
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AMPK in Diabetic Nephropathy SS Prabhakar
transporting enzyme complex I may be a possible mechanism of
improving AMPK activity in the kidney and thereby improving
renal function in diabetics. Therefore, evidence exists that
thiazolidines and metformin improve endothelial function,
decrease albuminuria and prevent tubulointerstitial
fibrosis. It can be speculated that the beneficial effects
seen in halting glomerulosclerosis may be through AMPK and
thus brings forth the hypothesis that AMPK activators like
metformin and thiazolidines can be used in future in
patients with diabetic nephropathy, provided they do not
have another contraindication for the use of metformin.
Conclusions
Clearly, little is currently known about the role of AMPK in
DN. However, the current state of understanding of AMPK
suggests that it might play a critical role in the
pathogenesis of DN (Figure 1). Since AMPK has been an
effective target for diabetic complications previously, it
is an attractive target for novel DN therapies. To make
such treatments viable, It will be especially important to
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AMPK in Diabetic Nephropathy SS Prabhakar
test the role of AMPK in an animal model of DN to determine
1) whether there is a decrease in AMPK activity during DN
progression in other models of the disease and 2) whether
activation/inhibition of AMPK can alleviate/worsen the
symptoms of DN, prior to extending studies to humans. If
studies conclude that AMPK plays an important role in DN
progression, then future studies can be performed to
identify which drugs might be best suited for increasing
AMPK activity, and thereby alleviating some of the
pathogenesis of DN.
Acknowledgements
The authors would like to thank Enusha Karunasena, Parastoo
Momeni, Raffaele Ferrari, and Ganesh Shankarling for
critical review of this manuscript. This work is supported
by the Jane and Larry Woirhaye Renal Research Endowment to
S. P.
Disclosure: The authors disclose that there are no conflicts
of interest from the financial contributions to the work
being submitted.
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AMPK in Diabetic Nephropathy SS Prabhakar
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