REVIEW
URRENT
C
OPINION
Physiology and pathophysiology of incretins in
the kidney
Karoline von Websky a,b, Christoph Reichetzeder a,b, and Berthold Hocher a
Purpose of review
Incretin-based therapy with glucagon-like peptide-1 receptor (GLP-1R) agonists and dipeptidyl peptidase-4
(DPP-4) inhibitors is considered a promising therapeutic option for type 2 diabetes mellitus. Cumulative
evidence, mainly from preclinical animal studies, reveals that incretin-based therapies also may elicit
beneficial effects on kidney function. This review gives an overview of the physiology, pathophysiology,
and pharmacology of the renal incretin system.
Recent findings
Activation of GLP-1R in the kidney leads to diuretic and natriuretic effects, possibly through direct actions
on renal tubular cells and sodium transporters. Moreover, there is evidence that incretin-based therapy
reduces albuminuria, glomerulosclerosis, oxidative stress, and fibrosis in the kidney, partially through GLP1R-independent pathways. Molecular mechanisms by which incretins exert their renal effects are
understood incompletely, thus further studies are needed.
Summary
The GLP-1R and DPP-4 are expressed in the kidney in various species. The kidney plays an important role
in the excretion of incretin metabolites and most GLP-1R agonists and DPP-4 inhibitors, thus special
attention is required when applying incretin-based therapy in renal impairment. Preclinical observations
suggest direct renoprotective effects of incretin-based therapies in the setting of hypertension and other
disorders of sodium retention, as well as in diabetic and nondiabetic nephropathy. Clinical studies are
needed in order to confirm translational relevance from preclinical findings for treatment options of renal
diseases.
Keywords
DDP-4 inhibition, diabetes, diabetic nephropathy, GLP-1 receptor, hypertension, incretins, kidney,
renal impairment
INTRODUCTION
The incretin hormones glucagon-like peptide-1
(GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are secreted from intestinal cells in
response to food intake. By enhancing insulin
secretion from pancreatic beta cells and reducing
glucagon secretion from alpha cells in a glucosedependent manner, these endogenous peptide hormones lower plasma glucose and regulate postprandial glucose homeostasis [1]. In vivo, GLP-1 and GIP
are degraded by the serine protease dipeptidyl
peptidase-4 (DPP-4) [2]. Apart from their actions
on the pancreas, incretins also have systemic effects
due to an expression of incretin receptors and DPP-4
in a variety of tissues such as kidney, heart, lung, the
central and peripheral nervous system, and the
digestive system [3,4].
Renal expression of GLP-1R and DPP-4 is
described in several publications for rats, mice [5],
www.co-nephrolhypertens.com
pigs [6], cattle [7], and humans [8]. GLP-1R mRNA
was found in the proximal tubular cells of rats [9]
and pigs [6]. Immunostaining of human kidney
cortex showed a GLP-1R signal predominantly in
proximal tubular cells [6]. Real-time PCR of microdissected rat nephron segments showed GLP-1R
mRNA expression in the glomerulus and proximal
convoluted tubule [9]. Summarized information
about the localization and physiology of DPP-4
and GLP-1R in the kidney are found in Table 1
and Fig. 1.
a
Institute of Nutritional Science, University of Potsdam, Potsdam and
Center for Cardiovascular Research, Charité, Berlin, Germany
b
Correspondence to Professor Dr Berthold Hocher, MD, PhD, Institute of
Nutritional Science, University of Potsdam, 14558 Nuthetal, Potsdam,
Germany. Tel: +49 33200 88 5508; e-mail: [email protected]
Curr Opin Nephrol Hypertens 2014, 23:54–60
DOI:10.1097/01.mnh.0000437542.77175.a0
Volume 23 Number 1 January 2014
Incretins in the kidney von Websky et al.
KEY POINTS
DDP-4 and the GLP-1R are expressed in the kidney of
various species including humans. A limited number of
studies show expression in the renal blood vessels,
glomerular cells, and tubular cells.
Cumulative evidence from functional and mechanistic
studies supports a role of a renal incretin system in the
modulation of sodium and water homeostasis and in
kidney function. Diuretic and natriuretic actions of
GLP-1R agonists and DPP-4 inhibitors may offer
renoprotection in the setting of hypertension and other
disorders of sodium retention.
Preclinical studies with GLP-1R agonists and DPP-4
inhibitors show functional and histological
improvements in the diabetic kidney, effects elicited
above and beyond glucose-lowering.
Clinical studies addressing renal endpoints in patients
with diabetic and nondiabetic kidney diseases are
urgently needed.
The membrane-bound form of DPP-4 is present
on many cell types, including kidney epithelial cells,
endothelial cells, and T cells [22], where it functions
as a binding protein and transmits intracellular
signals [23]. The circulating, soluble form of
DPP-4 in the plasma accounts for the degradation
of GLP-1, and its inhibition leads to the glucoselowering effect utilized with DPP-4 inhibitors in
clinical use. Mentlein [12] found a high concentration of DPP-4 in the mammalian kidney where
it is involved in the degradation of filtered proteins
[13,14]. Expression in brush border microvilli of the
proximal tubules and glomerular podocytes is
described for rodents [11,24,25]. Jackson et al. [10]
found expression of DPP-4 mRNA and protein in the
preglomerular microvascular smooth muscle cells
and glomerular mesangial cells of rats. The expression of DPP-4 is up-regulated in cultured human
renal glomerular epithelial cells during inflammation [26] and in a rat model of type 2 diabetes
mellitus (T2DM) [27]. Increased DPP-4 activity in
the kidney or urine is said to be a hallmark for
human glomerular diseases [28,29]. We recently
detected DPP-4 immunoreactivity in glomeruli of
patients with diabetic nephropathy and nephrotic
syndrome, but not in healthy kidneys (unpublished
data).
The data about DPP-4 and GLP-1R expression in
the kidney are still incomplete and speculation of
low specificity and sensitivity of existing antibodies
gives reason for the discussion about the validity of
immunostaining data [30,31]. However, cumulative
evidence from functional and mechanistic studies
supports a role of a renal incretin system in the
modulation of sodium and water homeostasis and
kidney function. The natriuretic and diuretic properties of GLP-1 were proved in infusion studies: in a
rat model of salt sensitivity, chronic intravenous
infusion of GLP-1 increased glomerular filtration
rate (GFR), inhibited proximal tubular reabsorption,
and increased urinary flow and sodium excretion
[17]. The effect on GFR was not present in rats with
denervated kidneys, which shows that renal GLP-1
signalling seems to be a complex mechanism, also
depending on functional neurotransmission [18].
For healthy humans, it was shown that infusion
of GLP-1 has a dose-dependent effect on urinary
sodium excretion without changing GFR [19]. In
obese, insulin-resistant men, there was a significant
increase in urinary sodium excretion, a decrease in
urinary Hþ secretion, and a decrease in the GFR [20].
The role for GLP-1 in modulating the renal Naþ/Hþ
exchange was therefore examined more closely in
rat [21] and porcine [6] renal proximal tubule cells.
GLP-1 infusion significantly reduced Naþ/Hþ
Table 1. Cellular localization of the DPP-4 and the GLP-1 receptor in the kidney
Preglomerular
Mesangium
Glomerulus/podocyte
Proximal tubule
DPP-4
X
X
X
X
Method
RT-PCR
RT-PCR
EM
EM
Year/Author/Journal
2012/Jackson
et al./Hypertension [10]
2012/Jackson
et al./Hypertension [10]
1992/Kettmann
et al./Acta Histochem [11]
1992/Kettmann et al./
Acta Histochem [11]
GLP-1R
–
–
X
X
Method
–
–
RT-PCR
RT-PCR
Year/Author/Journal
–
–
2011/Crajoinas et al./
Am J Physiol Renal
Physiol [9]
2011/Crajoinas et al./
Am J Physiol Renal
Physiol [9]
–
–
2007/Schlatter et al./
Regul Pept [7]
DPP-4, dipeptidyl peptidase 4; EM, electron microscopy; GLP-1R, glucagon-like peptide 1 receptor; RT-PCR, real-time PCR.
1062-4821 ß 2013 Wolters Kluwer Health | Lippincott Williams & Wilkins
www.co-nephrolhypertens.com
55
Hormones, autacoids, neurotransmitters and growth factors
Localization and physiology
of DPP-4 in the nephron
Localization and physiology
of GLP-1R in the nephron
GLP-1R localization
DPP-4 localization
Involved in NPY and PYY
metabolism and subsequent
proliferation and collagen
production by
preglomerular/mesangial
cells.
[10]
Natriuretic and diuretic
properties.
[17–20]
Final degradation of peptides
produces by other endoand exo-peptidases.
[12–14]
Independent NHE3 mediated
effects on natriuresis
and diuresis.
[15,16*]
Involved in renal Na+/H+
exchange by modulating
NHE3. Influences on renal
hemodynamics.
[6,9,21]
FIGURE 1. Localization and physiology of the DPP-4 and GLP-1 receptor in the nephron. DPP-4, dipeptidyl peptidase-4;
GLP-1, glucagon-like peptide-1; NHE3, Naþ/Hþ exchanger isoform 3; NPY, neuropeptide Y; PYY, peptide YY.
exchanger isoform 3 (NHE3)-mediated bicarbonate
reabsorption via a protein kinase A-dependent
mechanism in rat renal proximal tubule, thus influencing renal hemodynamics. The down-regulation
of NHE3 activity in the renal proximal tubule by
GLP-1 infusion led to an increased renal plasma flow
and GFR [9].
PHARMACOKINETICS OF GLUCAGON-LIKE
PEPTIDE-1 ANALOGS AND DIPEPTIDYL
PEPTIDASE-4 INHIBITORS IN RENAL
FAILURE
It is known that GLP-1 and GIP are eliminated in the
kidneys [32], which could affect the plasma levels of
incretins in patients with impaired kidney function.
Studies with small groups of patients showed that
serum incretin levels were significantly increased in
uremic patients in comparison with healthy persons
[33,34]. However, the kidney does not seem to be of
much importance for the degradation and inactivation of GIP and GLP-1. Apparently, intact incretin
hormones are inactivated by hepatic DPP-4 and
further degraded in peripheral tissues [35]. Thus,
the initial DPP4-mediated degradation of both hormones is almost unaffected by an impaired renal
56
www.co-nephrolhypertens.com
function [35]. Meier et al. [35] showed that the
kidneys are the major site for excretion of incretin
metabolites like GIP (3–42) and GLP-1 (9–36). It is
important to learn more about what physiologic
effects incretin metabolites may have, given the
increasing importance of GLP-1R agonist and
DPP-4 inhibitor treatment in routine clinical routine [36]. In-vitro studies showed an antagonistic
effect of GLP-1 (9–36) to the GLP-1R, but affinity is
very low, and at the moment there is no evidence of
an effect of GLP-1 (9–36) on insulin secretion [37].
Still, it has to be kept in mind that accumulation of
metabolites because of decreased elimination in
renal insufficiency could influence the binding of
GLP-1 agonists to the GLP-1R. Therefore, special
consideration has to be given when treating patients
with impaired renal function with an incretin-based
therapy. As the pharmacokinetics of incretin therapies differ greatly between drugs of the same class,
no general guidance can be given.
Exendin-4 is contraindicated in patients with
moderate renal impairment and above. Experiments
with pigs showed it is solely cleared by glomerular
filtration [38] and in the current available doses it is
not suitable for patients with end-stage renal disease
[39]. In patients with mild and moderate renal
Volume 23 Number 1 January 2014
Incretins in the kidney von Websky et al.
impairment, it was well tolerated and it did not need
dose adjustment with a creatinine clearance of
50–80 ml/min [40]. Liraglutide is not eliminated
via the kidneys; the drug is degraded by DPP-4 in
the same manner as endogenous GLP-1, but at a
much slower rate [41]. The pharmacokinetics of
liraglutide seems to be independent of renal function, as varying degrees of renal impairment were
not associated with changes in liraglutide exposure
[42]. Despite this, the use of liraglutide in moderate
to severe renal impairment is not recommended
because of lack of long-term safety data [43].
Dipeptidyl peptidase-4 inhibitors have been
proven to be well tolerated in patients with renal
impairment, but accumulation of the pharmaceuticals in the plasma may represent a potential risk for
unknown adverse events. Saxaglitptin, sitagliptin,
and vildagliptin are allowed to be prescribed in renal
impairment. A dose adjustment according to the
patient’s estimated GFR is necessary with these
drugs because they are mainly excreted in the urine
[44–46]. Linagliptin is the only DPP-4 inhibitor
which does not need a dose adjustment in renal
impairment because excretion happens predominantly via bile and gut, whereas renal excretion is
low. Metabolites of linagliptin do not play a major
role in its elimination, as most of the substance is
excreted unchanged [47]. Previous studies showed
that linagliptin exposure does not vary in patients
with normal, mild, moderate, or severe renal insufficiency [48].
PHARMACOLOGIC APPROACHES
TARGETING THE RENAL INCRETIN
SYSTEM: GLUCAGON-LIKE PEPTIDE-1
AGONISTS
The effects of GLP-1 on the kidney and its function
have been investigated in several studies with degradation-resistant GLP-1R agonists, such as exendin-4
or liraglutide. Many observations suggest that GLP-1
exerts pleiotropic actions via its receptor, independent of the glucose-lowering effects. Preclinical
research with GLP-1R agonists focuses on animal
models of hypertension and diabetes as leading
causes of chronic kidney disease.
There is growing evidence that treatment with
GLP-1R agonists may be effective in decelerating the
progression of diabetic nephropathy by improving
endothelial function and inhibiting inflammatory
and profibrotic actions [49 ,50,51]. It was shown
that the expression of GLP-1 receptors in the
glomeruli of diabetic mice is reduced [49 ,50]. Treatment with exendin-4 led to an increased number
of GLP-1R-positive cells in the glomeruli and
ameliorated glomerular pathology. GLP-1R agonist
&
&
treatment might influence diabetic nephropathy by
increasing GLP-1R expression in the glomerulus,
thus accounting for a restored GLP-1 protective
action on the renal endothelium. In rats with insulin-deficient diabetes mellitus (T1DM), exendin-4
treatment led to reduced albuminuria, prevention
of glomerular hypertrophy, macrophage infiltration
in the glomeruli, and decreased glomerular and
tubulointerstitial fibrosis without influencing blood
glucose levels [51]. As microinflammation is a
common mechanism in the pathogenesis of diabetic
nephropathy, these effects might in part be
explained by the in-vitro observed anti-inflammatory properties of exendin-4 via the GLP-1R and
subsequent activation of the cyclic AMP pathway
[51]. The activation of the GLP-1R pathway with
both GLP-1R agonists – exendin-4 and liraglutide –
led to a protection against oxidative stress and albuminuria in several rodent models of diabetes. A
protein kinase A-mediated inhibition of renal
NAD(P)H oxidase [52] and a protection against
effects of advanced glycation end-products (AGEs)
by reducing receptor for AGE (RAGE) expression
[53 ] may play a role. By increasing the expression
of the oxidative defense gene heme oxygenase-1,
exendin-4 showed protective effects against reactive
oxygen species in a rat model of renal ischemia–
reperfusion injury [54]. In-vitro studies showed
renoprotective effects of exendin-4 on human
mesangial cells, cultured in a high glucose medium.
GLP-1R agonist treatment inhibited the overproliferation of high-glucose treated cells. The decreased
mRNA and protein expression of transforming
growth factor-b, a major fibrogenic growth factor,
suggests a possibilty to improve renal interstitial
fibrosis in diabetic nephropathy with GLP-1R agonist treatment [55].
In-vitro [56] and in-vivo [49 ] experiments
showed a GLP-1-mediated inhibition of angiotensin
2 (Ang II) signaling and its proinflammatory action
in glomerular endothelial cells. In Ang II-induced
salt-sensitivitve hypertensive mice, a rise in blood
pressure was attenuated with exendin-4 treatment
[57]. As Ang II-induced hypertension is caused by
fluid retention via excess sodium reabsorption [58],
and infusion of GLP-1 enhances sodium excretion
[17], the observed effect of exendin-4 might be due
to a regulation of sodium excretion. Treatment with
a peptide analog of exendin-4 attenuated saltinduced hypertension, cardiac morbidity, insulin
resistance, and renal dysfunction in Dahl salt-sensitive rats [59]. Micropuncture studies in hydropenic
rats revealed vasodilatatory effects leading to an
increase in GFR following an infusion of exentanide.
At the same time, reabsorption in the proximal
tubule was inhibited [60]
1062-4821 ß 2013 Wolters Kluwer Health | Lippincott Williams & Wilkins
&
&
www.co-nephrolhypertens.com
57
Hormones, autacoids, neurotransmitters and growth factors
PHARMACOLOGIC APPROACHES
TARGETING THE RENAL INCRETIN
SYSTEM: DIPEPTIDYL PEPTIDASE-4
INHIBITION
Expression of DPP-4 in renal glomeruli during
inflammation [26] suggests a role of the enzyme
in the development of glomerulosclerosis. Expression of DPP-4 in the kidney of rats treated with a
high-fat diet and streptozotocin is increased [27].
DPP-4 deficiency in rats made them more resistant
to streptozotocin-induced T1DM, but predisposed
the animals to dyslipidemia and a reduction of GFR
[61]. These observations suggest a role of DPP-4 in the
development of diabetes and diabetic nephropathy.
Treatment with DPP-4 inhibitors may thus be effective in slowing the progression of diabetic nephropathy. In fact, literature provides some data about
renoprotective effects of DPP-4 inhibition in diabetic
nephropathy. In rats with T1DM, a reduction of
albuminuria and an improvement in the histological
changes in the kidney were observed with vildagliptin treatment [62]. Similar renoprotective effects of
DPP4 inhibition were shown in rats with T2DM and
sitagliptin [63]. Significant reduction in urinary albumin excretion was also seen in diabetic endothelial
nitric oxide synthase knockout mice treated with
linagliptin on top of Ang II receptor antagonist medication [64 ]. In humans, it was shown that the DPP-4
inhibitor linagliptin significantly reduced urinary
albumin excretion after 24 weeks of treatment in
patients with T2DM [65]. Another randomized trial,
the MARLINA (Efficacy, Safety & Modification of
Albuminuria in Type 2 Diabetes Subjects with Renal
Disease with Linagliptin) study (ClinicalTrials.gov
Identifier: NCT01792518) [66], has recently been
initiated in order to specifically evaluate the albumin-lowering potential of linagliptin in patients with
T2DM and renal impairment. The renal effects of
DPP-4 inhibitor treatment might be indirect benefits
from changes in blood glucose, insulin levels, or
weight loss. Nonetheless, the observed effects in
those studies could as well be attributed to GLP-1Rmediated, blood sugar-independent effects of the
incretin therapy [67]. Moreover, there might be
GLP-1R-independent mechanisms of DPP-4 inhibitor
treatment, as the DPP-4 has a wide range of other
substrates apart from GLP-1 and GIP. The enzyme
also cleaves peptide hormones such as brain/atrial
natriuretic peptides, neuropeptide Y, peptide YY, and
stromal-derived factor 1a, thus exerting cardio-renal
effects [67]. Another beneficial effect of DPP-4 inhibition might be a reduction of oxidative stress. In a
very recent study, it was shown that DPP-4 inhibitor
treatment led to a reduction of lipid and protein
oxidation in a rat model of renovascular hypertension [68].
&
58
www.co-nephrolhypertens.com
Preclinical studies suggest that DPP-4 inhibitors
may enhance urinary flow and sodium excretion,
and influence blood pressure [69]. Treatment with
the DPP-4 inhibitor sitagliptin preserved the GFR in
an animal model of heart failure, thereby preventing
the development of cardio-renal syndrome [70].
DPP-4 is expressed in association with the NHE3
in the proximal tubular cells [71]. Therefore, DPP4 inhibition may affect NHE3 activity and the
excretion of sodium, bicarbonate, and water reabsorption in the proximal tubule. Pharmacologic
DPP-4 inhibition reduced NHE3 activity in kidney
proximal tubule cells in vitro [72]. Hence, the functional relationship between NHE3 and DPP-4 in
the intact proximal tubule in vivo was investigated
in rats. Inhibition of DPP-4 catalytic activity was
associated with inhibition of NHE3-mediated
NaHCO3 reabsorption in rat renal proximal tubule
[15]. Rieg et al. [16 ] used GLP1R-deficient mice
to show that alogliptin-induced natriuresis and
diuresis were in part independent of the GLP1R.
In contrast to alogliptin, the natriuretic action of
exendin-4 observed in wild-type mice was not
detected in the GLP-1R-deficient mice.
&
CONCLUSION
Current literature suggests that GLP-1R agonists and
DPP-4 inhibitors may reduce renal disease progression by directly acting on the kidney. Clinical
studies addressing renal endpoints in patients
with diabetic and nondiabetic kidney diseases are
warranted to provide information whether the
promising preclinical findings can be translated into
clinical benefit for patients with renal diseases.
Acknowledgements
None.
Conflicts of interest
Our research work cited in this work (’DPP-4 inhibition
on top of angiotensin receptor blockade offers a new
therapeutic approach for diabetic nephropathy’) was
supported by Boehringer Ingelheim with money for the
institution.
REFERENCES AND RECOMMENDED
READING
Papers of particular interest, published within the annual period of review, have
been highlighted as:
&
of special interest
&& of outstanding interest
1. Baggio LL, Drucker DJ. Biology of incretins: GLP-1 and GIP. Gastroenterology 2007; 132:2131–2157.
2. Mentlein R, Gallwitz B, Schmidt WE. Dipeptidyl-peptidase IV hydrolyses
gastric inhibitory polypeptide, glucagon-like peptide-1(7-36)amide, peptide
histidine methionine and is responsible for their degradation in human serum.
Eur J Biochem FEBS 1993; 214:829–835.
Volume 23 Number 1 January 2014
Incretins in the kidney von Websky et al.
3. Campbell RK. Clarifying the role of incretin-based therapies in the treatment of
type 2 diabetes mellitus. Clin Ther 2011; 33:511–527.
4. Masajtis-Zagajewska A, Kurnatowska I, Wajdlich M, et al. Influence of hemodialysis on incretin hormones and insulin secretion in diabetic and nondiabetic
patients. Int Urol Nephrol 2013. [Epub ahead of print]
5. Campos RV, Lee YC, Drucker DJ. Divergent tissue-specific and developmental expression of receptors for glucagon and glucagon-like peptide-1 in
the mouse. Endocrinology 1994; 134:2156–2164.
6. Schlatter P, Beglinger C, Drewe J, Gutmann H. Glucagon-like peptide 1
receptor expression in primary porcine proximal tubular cells. Regul Pept
2007; 141:120–128.
7. Pezeshki A, Muench GP, Chelikani PK. Short communication: expression of
peptide YY, proglucagon, neuropeptide Y receptor Y2, and glucagon-like
peptide-1 receptor in bovine peripheral tissues. J Dairy Sci 2012; 95:5089–
5094.
8. Körner M, Stöckli M, Waser B, Reubi JC. GLP-1 receptor expression in human
tumors and human normal tissues: potential for in vivo targeting. J Nucl Med
Off Publ Soc Nucl Med 2007; 48:736–743.
9. Crajoinas RO, Oricchio FT, Pessoa TD, et al. Mechanisms mediating the
diuretic and natriuretic actions of the incretin hormone glucagon-like peptide1. Am J Physiol Renal Physiol 2011; 301:F355–F363.
10. Jackson EK, Kochanek SJ, Gillespie DG. Dipeptidyl peptidase IV regulates
proliferation of preglomerular vascular smooth muscle and mesangial cells.
Hypertension 2012; 60:757–764.
11. Kettmann U, Humbel B, Holzhausen HJ. Ultrastructural localization of dipeptidyl peptidase IV in the glomerulum of the rat kidney. Acta Histochem 1992;
92:225–227.
12. Mentlein R. Dipeptidyl-peptidase IV (CD26): role in the inactivation of regulatory peptides. Regul Pept 1999; 85:9–24.
13. Tiruppathi C, Miyamoto Y, Ganapathy V, et al. Hydrolysis and transport of
proline-containing peptides in renal brush-border membrane vesicles from
dipeptidyl peptidase IV-positive and dipeptidyl peptidase IV-negative rat
strains. J Biol Chem 1990; 265:1476–1483.
14. Tagore DM, Nolte WM, Neveu JM, et al. Peptidase substrates via global
peptide profiling. Nat Chem Biol 2009; 5:23–25.
15. Girardi ACC, Fukuda LE, Rossoni LV, et al. Dipeptidyl peptidase IV inhibition
downregulates Naþ–Hþ exchanger NHE3 in rat renal proximal tubule. Am J
Physiol Renal Physiol 2008; 294:F414–F422.
16. Rieg T, Gerasimova M, Murray F, et al. Natriuretic effect by exendin-4, but not
&
the DPP-4 inhibitor alogliptin, is mediated via the GLP-1 receptor and
preserved in obese type 2 diabetic mice. Am J Physiol Renal Physiol
2012; 303:F963–F971.
Interestingly, the studies from Rieg et al. are indicating that alogliptin-induced
natriuresis and diuresis are in part independent of the GLP1 receptor.
17. Yu M, Moreno C, Hoagland KM, et al. Antihypertensive effect of glucagonlike peptide 1 in Dahl salt-sensitive rats. J Hypertens 2003; 21:1125–
1135.
18. Moreno C, Mistry M, Roman RJ. Renal effects of glucagon-like peptide in rats.
Eur J Pharmacol 2002; 434:163–167.
19. Gutzwiller J-P, Hruz P, Huber AR, et al. Glucagon-like peptide-1 is involved
in sodium and water homeostasis in humans. Digestion 2006; 73:142–
150.
20. Gutzwiller J-P, Tschopp S, Bock A, et al. Glucagon-like peptide 1 induces
natriuresis in healthy subjects and in insulin-resistant obese men. J Clin
Endocrinol Metab 2004; 89:3055–3061.
21. Carraro-Lacroix LR, Malnic G, Girardi ACC. Regulation of Naþ/Hþ exchanger
NHE3 by glucagon-like peptide 1 receptor agonist exendin-4 in renal proximal
tubule cells. Am J Physiol Renal Physiol 2009; 297:F1647–F1655.
22. Lone AM, Nolte WM, Tinoco AD, Saghatelian A. Peptidomics of the prolyl
peptidases. AAPS J 2010; 12:483–491.
23. Lambeir A-M, Durinx C, Scharpé S, De Meester I. Dipeptidyl-peptidase IV from
bench to bedside: an update on structural properties, functions, and clinical
aspects of the enzyme DPP IV. Crit Rev Clin Lab Sci 2003; 40:209–
294.
24. Hartel S, Gossrau R, Hanski C, Reutter W. Dipeptidyl peptidase (DPP) IV in
rat organs. Comparison of immunohistochemistry and activity histochemistry.
Histochemistry 1988; 89:151–161.
25. Hartel-Schenk S, Gossrau R, Reutter W. Comparative immunohistochemistry
and histochemistry of dipeptidyl peptidase IV in rat organs during development. Histochem J 1990; 22:567–578.
26. Stefanovic V, Ardaillou N, Vlahovic P, et al. Interferon-gamma induces dipeptidyl peptidase IV expression in human glomerular epithelial cells. Immunology
1993; 80:465–470.
27. Yang J, Campitelli J, Hu G, et al. Increase in DPP-IV in the intestine, liver and
kidney of the rat treated with high fat diet and streptozotocin. Life Sci 2007;
81:272–279.
28. Kanwar YS, Wada J, Sun L, et al. Diabetic nephropathy: mechanisms of renal
disease progression. Exp Biol Med Maywood NJ 2008; 233:4–11.
29. Mitic B, Lazarevic G, Vlahovic P, et al. Diagnostic value of the aminopeptidase
N, N-acetyl-beta-D-glucosaminidase and dipeptidyl peptidase IV in evaluating
tubular dysfunction in patients with glomerulopathies. Ren Fail 2008;
30:896–903.
30. Hutchings CJ, Koglin M, Marshall FH. Therapeutic antibodies directed at G
protein-coupled receptors. MAbs 2010; 2:594–606.
31. Panjwani N, Mulvihill EE, Longuet C, et al. GLP-1 receptor activation indirectly
reduces hepatic lipid accumulation but does not attenuate development of
atherosclerosis in diabetic male ApoE(-/-) mice. Endocrinology 2013;
154:127–139.
32. Sirinek KR, O’Dorisio TM, Gaskill HV, Levine BA. Chronic renal failure: effect
of hemodialysis on gastrointestinal hormones. Am J Surg 1984; 148:732–
735.
33. Orskov C, Andreasen J, Holst JJ. All products of proglucagon are elevated in
plasma from uremic patients. J Clin Endocrinol Metab 1992; 74:379–384.
34. Hegbrant J, Thysell H, Ekman R. Plasma levels of gastrointestinal regulatory
peptides in patients receiving maintenance hemodialysis. Scand J Gastroenterol 1991; 26:599–604.
35. Meier JJ, Nauck MA, Kranz D, et al. Secretion, degradation, and elimination of
glucagon-like peptide 1 and gastric inhibitory polypeptide in patients with
chronic renal insufficiency and healthy control subjects. Diabetes 2004;
53:654–662.
36. Ban K, Noyan-Ashraf MH, Hoefer J, et al. Cardioprotective and vasodilatory
actions of glucagon-like peptide 1 receptor are mediated through both
glucagon-like peptide 1 receptor-dependent and -independent pathways.
Circulation 2008; 117:2340–2350.
37. Vahl TP, Paty BW, Fuller BD, et al. Effects of GLP-1-(7-36)NH2, GLP-1(7-37), and GLP-1- (9-36)NH2 on intravenous glucose tolerance and
glucose-induced insulin secretion in healthy humans. J Clin Endocrinol Metab
2003; 88:1772–1779.
38. Simonsen L, Holst JJ, Deacon CF. Exendin-4, but not glucagon-like peptide-1,
is cleared exclusively by glomerular filtration in anaesthetised pigs. Diabetologia 2006; 49:706–712.
39. Linnebjerg H, Kothare PA, Park S, et al. Effect of renal impairment on the
pharmacokinetics of exenatide. Br J Clin Pharmacol 2007; 64:317–327.
40. Brown DX, Evans M. Choosing between GLP-1 receptor agonists and DPP-4
inhibitors: a pharmacological perspective. J Nutr Metab 2012; 2012:
381713.
41. Malm-Erjefält M, Bjørnsdottir I, Vanggaard J, et al. Metabolism and excretion of
the once-daily human glucagon-like peptide-1 analog liraglutide in healthy
male subjects and its in vitro degradation by dipeptidyl peptidase IV and
neutral endopeptidase. Drug Metab Dispos Biol Fate Chem 2010; 38:1944–
1953.
42. Jacobsen LV, Hindsberger C, Robson R, Zdravkovic M. Effect of renal
impairment on the pharmacokinetics of the GLP-1 analogue liraglutide. Br
J Clin Pharmacol 2009; 68:898–905.
43. Byetta (exenatide injection). Prescribing information. http://pi.lilly.com/us/
byetta-pi.pdf. [Accessed 2 November 2008]
44. Chan JCN, Scott R, Arjona Ferreira JC, et al. Safety and efficacy of sitagliptin
in patients with type 2 diabetes and chronic renal insufficiency. Diabetes
Obes Metab 2008; 10:545–555.
45. Nowicki M, Rychlik I, Haller H, et al. Long-term treatment with the dipeptidyl
peptidase-4 inhibitor saxagliptin in patients with type 2 diabetes mellitus and
renal impairment: a randomised controlled 52-week efficacy and safety study.
Int J Clin Pract 2011; 65:1230–1239.
46. Deacon CF. Dipeptidyl peptidase-4 inhibitors in the treatment of type 2
diabetes: a comparative review. Diabetes Obes Metab 2011; 13:7–18.
47. Blech S, Ludwig-Schwellinger E, Gräfe-Mody EU, et al. The metabolism and
disposition of the oral dipeptidyl peptidase-4 inhibitor, linagliptin, in humans.
Drug Metab Dispos Biol Fate Chem 2010; 38:667–678.
48. Friedrich C, Emser A, Woerle H-J, Graefe-Mody U. Renal impairment has no
clinically relevant effect on the long-term exposure of linagliptin in patients with
type 2 diabetes. Am J Ther 2013. [Epub ahead of print]
49. Mima A, Hiraoka-Yamomoto J, Li Q, et al. Protective effects of GLP-1 on
&
glomerular endothelium and its inhibition by PKCb activation in diabetes.
Diabetes 2012; 61:2967–2979.
The authors found that renal protective effects of GLP-1 might be mediated via
the inhibition of Ang II actions and diminished by diabetes because of PKCb
activation and the increased degradation of GLP-1R in the glomerular endothelial
cells.
50. Park CW, Kim HW, Ko SH, et al. Long-term treatment of glucagon-like
peptide-1 analog exendin-4 ameliorates diabetic nephropathy through
improving metabolic anomalies in db/db mice. J Am Soc Nephrol 2007;
18:1227–1238.
51. Kodera R, Shikata K, Kataoka HU, et al. Glucagon-like peptide-1 receptor
agonist ameliorates renal injury through its anti-inflammatory action without
lowering blood glucose level in a rat model of type 1 diabetes. Diabetologia
2011; 54:965–978.
52. Hendarto H, Inoguchi T, Maeda Y, et al. GLP-1 analog liraglutide protects
against oxidative stress and albuminuria in streptozotocin-induced diabetic
rats via protein kinase A-mediated inhibition of renal NAD(P)H oxidases.
Metabolism 2012; 61:1422–1434.
53. Ojima A, Ishibashi Y, Matsui T, et al. Glucagon-like peptide-1 receptor agonist
&
inhibits asymmetric dimethylarginine generation in the kidney of streptozotocin-induced diabetic rats by blocking advanced glycation end productinduced protein arginine methyltranferase-1 expression. Am J Pathol 2013;
182:132–141.
This study describes one possible mechanistic explanation for the known protective effects of GLP-1 receptor agonist against the development and progression of
diabetic nephropathy.
1062-4821 ß 2013 Wolters Kluwer Health | Lippincott Williams & Wilkins
www.co-nephrolhypertens.com
59
Hormones, autacoids, neurotransmitters and growth factors
54. Yang H, Li H, Wang Z, et al. Exendin-4 ameliorates renal ischemia-reperfusion
injury in the rat. J Surg Res 2013. [Epub ahead of print]
55. Li W, Cui M, Wei Y, et al. Inhibition of the expression of TGF-b1 and CTGF in
human mesangial cells by exendin-4, a glucagon-like peptide-1 receptor
agonist. Cell Physiol Biochem Int J Exp Cell Physiol Biochem Pharmacol
2012; 30:749–757.
56. Ishibashi Y, Matsui T, Ojima A, et al. Glucagon-like peptide-1 inhibits angiotensin II-induced mesangial cell damage via protein kinase A. Microvasc Res
2012; 84:395–398.
57. Hirata K, Kume S, Araki S, et al. Exendin-4 has an antihypertensive effect in
salt-sensitive mice model. Biochem Biophys Res Commun 2009; 380:44–
49.
58. Crowley SD, Gurley SB, Herrera MJ, et al. Angiotensin II causes hypertension
and cardiac hypertrophy through its receptors in the kidney. Proc Natl Acad
Sci U S A 2006; 103:17985–17990.
59. Liu Q, Adams L, Broyde A, et al. The exenatide analogue AC3174 attenuates
hypertension, insulin resistance, and renal dysfunction in Dahl salt-sensitive
rats. Cardiovasc Diabetol 2010; 9:32.
60. Thomson SC, Kashkouli A, Singh P. Glucagon-like peptide-1 receptor stimulation increases GFR and suppresses proximal reabsorption in the rat. Am J
Physiol Renal Physiol 2013; 304:F137–F144.
61. Kirino Y, Sato Y, Kamimoto T, et al. Interrelationship of dipeptidyl peptidase IV
(DPP4) with the development of diabetes, dyslipidaemia and nephropathy: a
streptozotocin-induced model using wild-type and DPP4-deficient rats.
J Endocrinol 2009; 200:53–61.
62. Liu WJ, Xie SH, Liu YN, et al. Dipeptidyl peptidase IV inhibitor attenuates
kidney injury in streptozotocin-induced diabetic rats. J Pharmacol Exp Ther
2012; 340:248–255.
63. Mega C, de Lemos ET, Vala H, et al. Diabetic nephropathy amelioration by a
low-dose sitagliptin in an animal model of type 2 diabetes (Zucker diabetic
fatty rat). Exp Diabetes Res 2011; 2011: 162092.
60
www.co-nephrolhypertens.com
64. Alter ML, Ott IM, von Websky K, et al. DPP-4 inhibition on top of angiotensin
receptor blockade offers a new therapeutic approach for diabetic nephropathy. Kidney Blood Press Res 2012; 36:119–130.
This experiment is important, as it indicates that linagliptin on top of an Ang II receptor
blocker may offer a new therapeutic approach for patients with diabetic nephropathy
who do not adequately respond to angiotensin 2 receptor blocker treatment.
65. Groop P-H, Cooper ME, Perkovic V, et al. Linagliptin lowers albuminuria on
top of recommended standard treatment in patients with type 2 diabetes and
renal dysfunction. Diabetes Care 2013; 36:3460–3468.
66. Boehringer Ingelheim Pharmaceuticals. MARLINA: efficacy, safety and modification of albuminuria in type 2 diabetes subjects with renal disease with
linagliptin. In ClinicalTrials.gov [website on the Internet]. Bethesda, MD: US
National Library of Medicine; 2011 [updated May 15 2013]. http://www.
clinicaltrials.gov/ct2/show/NCT01792518. NLM identifier: NCT01792518.
[Accessed 29 May 2013]
67. Hocher B, Reichetzeder C, Alter ML. Renal and cardiac effects of DPP4
inhibitors: from preclinical development to clinical research. Kidney Blood
Press Res 2012; 36:65–84.
68. Chaykovska L, Alter ML, von Websky K, et al. Effects of telmisartan and
linagliptin when used in combination on blood pressure and oxidative stress in
rats with 2-kidney-1-clip hypertension. J Hypertens 2013; 31:2290–2299.
69. Pacheco BP, Crajoinas RO, Couto GK, et al. Dipeptidyl peptidase IV inhibition
attenuates blood pressure rising in young spontaneously hypertensive rats.
J Hypertens 2011; 29:520–528.
70. Gomez N, Touihri K, Matheeussen V, et al. Dipeptidyl peptidase IV inhibition
improves cardiorenal function in overpacing-induced heart failure. Eur J Heart
Fail 2012; 14:14–21.
71. Girardi AC, Degray BC, Nagy T, et al. Association of Na(þ)-H(þ) exchanger
isoform NHE3 and dipeptidyl peptidase IV in the renal proximal tubule. J Biol
Chem 2001; 276:46671–46677.
72. Girardi ACC, Knauf F, Demuth H-U, Aronson PS. Role of dipeptidyl peptidase
IV in regulating activity of Naþ/Hþ exchanger isoform NHE3 in proximal
tubule cells. Am J Physiol Cell Physiol 2004; 287:C1238–C1245.
&
Volume 23 Number 1 January 2014