The Role of 5'-AMP-activated protein kinase (AMPK) in Diabetic Nephropathy: A new direction?

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,

1


Texas Tech University Health Sciences Center

Lubbock, TX 79430 USA

Tel: (806)743-3155 Fax: (806)743-3148 E-mail:

[email protected]

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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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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Key words: AMPK, diabetic nephropathy, enzyme regulation, molecular

pathogenesis

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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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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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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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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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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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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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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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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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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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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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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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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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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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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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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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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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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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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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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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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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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.

References

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[1] Adler, S. (1994) Structure-function-relationships associated with extracellular-matrix alterations in diabeticglomerulopathy. Journal of the American Society of Nephrology, 5, 1165-1172.[2] Akerstrom, T.C.A., Birk, J.B., Klein, D.K., Erikstrup, C., Plomgaard, P., Pedersen, B.K., Wojtaszewski, J.F.P. (2006) Oral glucose ingestion attenuates exercise-induced activation of 5 '-AMP-activated protein kinase in human skeletal muscle. Biochemical and Biophysical Research Communications,342, 949-955.[3] Axelsson, J., Stenvinkel, P. (2008) Role of fat mass and adipokines in chronic kidney disease. Current Opinion in Nephrology and Hypertension, 17, 25-31.[4] Ballerman, B., Korecki, K., Brenner, B. (1984) Reduced glomerular angiotensinII receptor density in early untreateddiabetes mellitus in the rat. American Journal of Physiology, 247.[5] Beale, E.G. (2008) 5 '-AMP-activated protein kinase signaling in Caenorhabditis elegans. Experimental Biology and Medicine, 233, 12-20.[6] Cammisotto, P.G., Londono, I., Gingras, D., Bendayan, M. (2008) Control of glycogen synthase through ADIPOR1-AMPK pathway in renal distal tubules of normal and diabetic rats.American Journal of Physiology-Renal Physiology, 294, F881-F889.[7] Chen, H., Charlat, O., Tartaglia, L.A., Woolf, E.A., Weng, X., Ellis, S.J., Lakey, N.D., Culpepper, J., Moore, K.J., Breitbart, R.E., Duyk, G.M., Tepper, R.I., Morgenstern, J.P. (1996) Evidence that the diabetes gene encodes the leptin receptor: Identification of a mutation inthe leptin receptor gene in db/db mice. Cell, 84, 491-495.[8] Chen, M.B., McAinch, A.J., Macaulay, S.L., Castelli, L.A., O'Brien, P.E., Dixon, J.B., Cameron-Smith, D., Kemp, B.E., Steinberg, G.R. (2005) Impaired activation of AMP-kinase and fatty acid oxidation by globular adiponectin in cultured human skeletal muscle of obese type 2 diabetics. Journal of Clinical Endocrinology and Metabolism, 90, 3665-3672.[9] Chen, Z.P., Mitchelhill, K.I., Michell, B.J., Stapleton, D., Rodriguez-Crespo, I., Witters, L.A., Power, D.A., Ortiz de Montellano, P.R., Kemp, B.E. (1999) AMP-

26


activated protein kinase phosphorylation of endothelial NO synthase. FEBS Lett, 443, 285-289.[10] Choi, S.L., Kim, S.J., Lee, K.T., Kim, J., Mu, J., Birnbaum, M.J., Kim, S.S., Ha, J. (2001) The regulation of AMP-activated protein kinase by H2O2. Biochemical and Biophysical Research Communications, 287, 92-97.[11] Cooper, M.E., Vranes, D., Youssef, S., Stacker, S.A., Cox, A.J., Rizkalla, B., Casley, D.J., Bach, L.A., Kelly, D.J., Gilbert, R.E. (1999) Increased renal expression of vascular endothelial growth factor (VEGF) and its receptor VEGFR-2 in experimental diabetes. Diabetes, 48, 2229-2239.[12] Dagher, Z., Ruderman, N., Tornheim, K., Ido, Y. (1999) The effect of AMP-activated protein kinase and its activatorAICAR on the metabolism of human umbilical vein endothelial cells. Biochemical and Biophysical Research Communications, 265, 112-115.[13] Dagher, Z., Ruderman, N., Tornheim, K., Ido, Y. (2001) Acute regulation of fatty acid oxidation and AMP-activated protein kinase in human umbilical vein endothelial cells. Circulation Research, 88, 1276-1282.[14] El-Mir, M.Y., Nogueira, V., Fontaine, E., Averet, N., Rigoulet, M., Leverve, X. (2000) Dimethylbiguanide inhibits cell respiration via an indirect effect targeted on the respiratory chain complex I. Journal of Biological Chemistry, 275, 223-228.[15] Fioretto, P., Mauer, M. (2007) Histopathology of diabetic nephropathy. Seminars in Nephrology, 27, 195-207.[16] Guerre-Millo, M. (2008) Adiponectin: An update. Diabetes & Metabolism, 34, 12-18.[17] Halaas, J.L., Gajiwala, K.S., Maffei, M., Cohen, S.L., Chait, B.T., Rabinowitz, D., Lallone, R.L., Burley, S.K., Friedman, J.M. (1995) WEIGHT-REDUCING EFFECTS OF THE PLASMA-PROTEIN ENCODED BY THE OBESE GENE. Science, 269, 543-546.[18] Hanefeld, M., Brunetti, P., Schernthaner, G.H., Matthews, D.R., Charbonnel, B.H., Grp, Q.S. (2004) One-year glycemic control with a sulfonylurea plus pioglitazone versus a sulfonylurea plus metformin in patients with type 2diabetes. Diabetes Care, 27, 141-147.

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[19] Hardie, D.G. (2003) Minireview: The AMP-activated protein kinase cascade: The key sensor of cellular energy status. Endocrinology, 144, 5179-5183.[20] Hardie, D.G., Sakamoto, K. (2006) AMPK: A key sensor offuel and energy status in skeletal muscle. Physiology, 21, 48-60.[21] Hardie, D.G., Scott, J.W., Pan, D.A., Hudson, E.R. (2003) Management of cellular energy by the AMP-activated protein kinase system. Febs Letters, 546, 113-120.[22] Hollenberg, N.K., Price, D.A., Fisher, N.D.L., Lansang,M.C., Perkins, B., Gordon, M.S., Williams, G.H., Laffel, L.M.B. (2003) Glomerular hemodynamics and the renin-angiotensin system in patients with type 1 diabetes mellitus. Kidney International, 63, 172-178.[23] Itani, S.I., Saha, A.K., Kurowski, T.G., Coffin, H.R., Tornheim, K., Ruderman, N.B. (2003) Glueose autoregulates its uptake in skeletal muscle - Involvement of AMP-activatedprotein kinase. Diabetes, 52, 1635-1640.[24] Lee, M.J., Feliers, D., Mariappan, M.M., Sataranatarajan, K., Mahimainathan, L., Musi, N., Foretz, M., Viollet, B., Weinberg, J.M., Choudhury, G.G., Kasinath, B.S. (2007) A role for AMP-activated protein kinase in diabetes-induced renal hypertrophy. American Journal of Physiology-Renal Physiology, 292, F617-F627.[25] Lehir, M., Kriz, W. (2007) New insights into structuralpatterns encountered in glomerulosclerosis. Current Opinion in Nephrology and Hypertension, 16, 184-191.[26] Maffei, M., Halaas, J., Ravussin, E., Pratley, R.E., Lee, G.H., Zhang, Y., Fei, H., Kim, S., Lallone, R., Ranganathan, S., Kern, P.A., Friedman, J.M. (1995) LEPTIN LEVELS IN HUMAN AND RODENT - MEASUREMENT OF PLASMA LEPTIN AND OB RNA IN OBESE AND WEIGHT-REDUCED SUBJECTS. Nature Medicine, 1, 1155-1161.[27] Matthews, D.R., Charbonnel, B.H., Hanefeld, M., Brunetti, P., Schernthaner, G. (2005) Long-term therapy withaddition of pioglitazone to metformin compared with the addition of gliclazide to metformin in patients with type 2 diabetes: a randomized, comparative study. Diabetes-Metabolism Research and Reviews, 21, 167-174.

28


[28] McMahon, W., Iznaola, O., Prabhakar, S. (2008) Angiotensin-Nitric Oxide Interactions. In: Miurna, H., Sasaki, Y. Eds, Angiotensin Research Progress. Hauppauge, NY, Nova Publishers.[29] Minokoshi, Y., Alquier, T., Furukawa, N., Kim, Y.B., Lee, A., Xue, B.Z., Mu, J., Foufelle, F., Ferre, P., Birnbaum, M.J., Stuck, B.J., Kahn, B.B. (2004) AMP-kinase regulates food intake by responding to hormonal and nutrientsignals in the hypothalamus. Nature, 428, 569-574.[30] Minokoshi, Y., Kim, Y.B., Peroni, O.D., Fryer, L.G.D., Muller, C., Carling, D., Kahn, B.B. (2002) Leptin stimulatesfatty-acid oxidation by activating AMP-activated protein kinase. Nature, 415, 339-343.[31] Mishra, R., Cool, B.L., Laderoute, K.R., Foretz, M., Viollet, B., Simonson, M.S. (2008) AMP-activated Protein Kinase Inhibits Transforming Growth Factor-{beta}-induced Smad3-dependent Transcription and Myofibroblast Transdifferentiation. J Biol Chem, 283, 10461-10469.[32] Morrow, V.A., Foufelle, F., Connell, J.M.C., Petrie, J.R., Gould, G.W., Salt, I.P. (2003) Direct activation of AMP-activated protein kinase stimulates nitric-oxide synthesis in human aortic endothelial cells. Journal of BiologicalChemistry, 278, 31629-31639.[33] Mount, P.F., Kemp, B.E., Power, D.A. (2007) Regulation of endothelial and myocardial NO synthesis by multi-site eNOS phosphorylation. J Mol Cell Cardiol, 42, 271-279.[34] Mountjoy, P.D., Rutter, G.A. (2007) Glucose sensing by hypothalamic neurones and pancreatic islet cells: AMPle evidence for common mechanisms ? Experimental Physiology, 92, 311-319.[35] Myers, M.G., Cowley, M.A., Munzberg, H. (2008) Mechanisms of leptin action and leptin resistance. Annual Review of Physiology, 70, 537-556.[36] Nagata, D., Mogi, M., Walsh, K. (2003) AMP-activated protein kinase (AMPK) signaling in endothelial cells is essential for angiogenesis in response to hypoxic stress. J Biol Chem, 278, 31000-31006.[37] Nagata, D., Takeda, R., Sata, M., Satonaka, H., Suzuki,E., Nagano, T., Hirata, Y. (2004) AMP-activated protein

29


kinase inhibits angiotensin II-stimulated vascular smooth muscle cell proliferation. Circulation, 110, 444-451.[38] Nakagawa, T., Sato, W., Glushakova, O., Heinig, M., Clarke, T., Campbell-Thompson, M., Yuzawa, Y., Atkinson, M.A., Johnson, R.J., Croker, B. (2007) Diabetic endothelial nitric oxide synthase knockout mice develop advanced diabetic nephropathy. J Am Soc Nephrol, 18, 539-550.[39] Owen, M.R., Doran, E., Halestrap, A.P. (2000) Evidence that metformin exerts its anti-diabetic effects through inhibition of complex 1 of the mitochondrial respiratory chain. Biochemical Journal, 348, 607-614.[40] Phillips, M.S., Liu, Q.Y., Hammond, H.A., Dugan, V., Hey, P.J., Caskey, C.T., Hess, J.F. (1996) Leptin receptor missense mutation in the fatty Zucker rat. Nature Genetics, 13,18-19.[41] Prabhakar, S., Starnes, J., Shi, S., Lonis, B., Tran, R. (2007) Diabetic nephropathy is associated with oxidative stress and decreased renal nitric oxide production. Journal of the American Society of Nephrology, 18, 2945-2952.[42] Prabhakar, S.S. (2004) Role of nitric oxide in diabeticnephropathy. Seminars in Nephrology, 24, 333-344.[43] Remuzzi, G., Bertani, T. (1998) Pathophysiology of progressive nephropathies. New England Journal of Medicine, 339, 1448-1456.[44] Salt, I., Celler, J.W., Hawley, S.A., Prescott, A., Woods, A., Carling, D., Hardie, D.G. (1998) AMP-activated protein kinase: greater AMP dependence, and preferential nuclear localization, of complexes containing the alpha 2 isoform. Biochemical Journal, 334, 177-187.[45] Salt, I.P., Johnson, G., Ashcroft, S.J.H., Hardie, D.G.(1998) AMP-activated protein kinase is activated by low glucose in cell lines derived from pancreatic beta cells, and may regulate insulin release. Biochemical Journal, 335, 533-539.[46] Schernthaner, G., Matthews, D.R., Charbonnel, B., Hanefeld, M., Brunetti, P., Grp, Q.S. (2005) Efficacy and safety of pioglitazone versus metformin in patients with type 2 diabetes mellitus: A double-blind, randomized trial

30


(vol 89, pg 6068, 2004). Journal of Clinical Endocrinology and Metabolism, 90, 746-746.[47] Sharma, K., McGowan, T.A. (2000) TGF-beta in diabetic kidney disease: role of novel signaling pathways. Cytokine & Growth Factor Reviews, 11, 115-123.[48] Spranger, J., Kroke, A., Mohlig, M., Boeing, H. (2003) Adiponectin and protection against type 2 diabetes mellitus (vol 361, pg 226, 2003). Lancet, 361, 1060-1060.[49] Stapleton, D., Mitchelhill, K.I., Gao, G., Widmer, J., Michell, B.J., Teh, T., House, C.M., Fernandez, C.S., Cox, T., Witters, L.A., Kemp, B.E. (1996) Mammalian AMP-activatedprotein kinase subfamily. Journal of Biological Chemistry, 271, 611-614.[50] Tomas, E., Tsao, T.S., Saha, A.K., Murrey, H.E., Zhang,C.C., Itani, S.I., Lodish, H.F., Ruderman, N.B. (2002) Enhanced muscle fat oxidation and glucose transport by ACRP30 globular domain: Acetyl-CoA carboxylase inhibition and AMP-activated protein kinase activation. Proceedings of the National Academy of Sciences of the United States of America, 99, 16309-16313.[51] Towler, M.C., Hardie, D.G. (2007) AMP-activated proteinkinase in metabolic control and insulin signaling. Circulation Research, 100, 328-341.[52] Tsuchida, K., Makita, Z., Yamagishi, S., Atsumi, T., Miyoshi, H., Obara, S., Ishida, M., Ishikawa, S., Yasumura, K., Koike, T. (1999) Suppression of transforming growth factor beta and vascular endothelial growth factor in diabetic nephropathy in rats by a novel advanced glycation end product inhibitor, OPB-9195. Diabetologia, 42, 579-588.[53] Vitale, C., Mercuro, G., Cornoldi, A., Fini, M., Volterrani, M., Rosano, G.M.C. (2005) Metformin improves endothelial function in patients with metabolic syndrome. Journal of Internal Medicine, 258, 250-256.[54] Wang, Z.V., Scherer, P.E. (2008) Adiponectin, cardiovascular function, and hypertension. Hypertension, 51, 8-14.[55] Wiecek, A., Chudek, J., Kokot, F. (2003) Role of angiotensin II in the progression of diabetic nephropathy -

31


Therapeutic implications. Nephrology Dialysis Transplantation, 18, 16-20.[56] Wolf, G., Ziyadeh, F.N. (1999) Molecular mechanisms of diabetic renal hypertrophy. Kidney International, 56, 393-405.[57] Yamauchi, T., Kamon, J., Minokoshi, Y., Ito, Y., Waki, H., Uchida, S., Yamashita, S., Noda, M., Kita, S., Ueki, K.,Eto, K., Akanuma, Y., Froguel, P., Foufelle, F., Ferre, P., Carling, D., Kimura, S., Nagai, R., Kahn, B.B., Kadowaki, T.(2002) Adiponectin stimulates glucose utilization and fatty-acid oxidation by activating AMP-activated protein kinase. Nature Medicine, 8, 1288-1295.[58] Zhang, Y.Y., Proenca, R., Maffei, M., Barone, M., Leopold, L., Friedman, J.M. (1994) POSITIONAL CLONING OF THEMOUSE OBESE GENE AND ITS HUMAN HOMOLOG. Nature, 372, 425-432.[59] Zhao, H.J., Wang, S., Cheng, H., Zhang, M.Z., Takahashi, T., Fogo, A.B., Breyer, M.D., Harris, R.C. (2006)Endothelial nitric oxide synthase deficiency produces accelerated nephropathy in diabetic mice. J Am Soc Nephrol, 17,2664-2669.[60] Zou, M.H., Hou, X.Y., Shi, C.M., Nagata, D., Walsh, K.,Cohen, R.A. (2002) Modulation by peroxynitrite of Akt- and AMP-activated kinase-dependent Ser1179 phosphorylation of endothelial nitric oxide synthase. J Biol Chem, 277, 32552-32557.

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The Role of 5'-AMP-activated protein kinase (AMPK) in Diabetic Nephropathy: A new direction?

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