Endocrine Research
717
Authors
S. Nakashima1, T. Matsui1, M. Takeuchi2, S.-I. Yamagishi1
Affiliations
1
Department of Pathophysiology and Therapeutics of Diabetic Vascular Complications, Kurume University School of Medicine, Kurume, Japan 2 Department of Advanced Medicine, Medical Research Institute, Kanazawa Medical University, Kanazawa, Japan
Key words ▶ AGEs ● ▶ RAGE ● ▶ oxidative stress ● ▶ DPP-4 ● ▶ linagliptin ● ▶ diabetic nephropathy ●
Abstract
received 20.12.2013 accepted 11.03.2014 Bibliography DOI http://dx.doi.org/ 10.1055/s-0034-1371892 Published online: April 7, 2014 Horm Metab Res 2014; 46: 717–721 © Georg Thieme Verlag KG Stuttgart · New York ISSN 0018-5043 Correspondence S.-i. Yamagishi, MD, PhD Department of Pathophysiology and Therapeutics of Diabetic Vascular Complications Kurume University School of Medicine 67 Asahi-machi Kurume 830-0011 Japan Tel.: + 81/942/31 7873 Fax: + 81/942/31 7895 [email protected]
▼
Advanced glycation end products (AGEs) and their receptor (RAGE) play a role in diabetic nephropathy. We have recently found that linagliptin, an inhibitor of dipeptidyl peptidase-4 (DPP-4) suppresses the AGE-induced oxidative stress generation and intercellular adhesion molecule-1 (ICAM-1) gene expression in endothelial cells. However, whether linagliptin could have beneficial effects on experimental diabetic nephropathy in a glucose-lowering independent manner remains unknown. To address the issue, this study examined the effects of linagliptin on renal damage in streptozotocin-induced diabetic rats. Serum levels of DPP-4 were significantly elevated in diabetic rats compared with
Introduction
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Nonenzymatic modification of proteins by reducing sugars, a process that is also known as Maillard reaction, progresses at an extremely accelerated rate under diabetes [1–3]. The early glycation products undergo further complex reaction, such as rearrangement, dehydration, and condensation to become irreversibly crosslinked heterogeneous fluorescent derivatives, termed advanced glycation end products (AGEs) [1–3]. Recent understandings of this process have revealed that AGEs and their receptor (RAGE) interaction evokes oxidative stress generation and inflammatory reactions, thereby causing progressive alteration in renal architecture and loss of renal function in diabetes [4–10]. Given that diabetic nephropathy is the most common cause of end-stage renal disease (ESRD) in the world, which could account for the disability and high mortality rates in patients with diabetes [11, 12], blockade of the AGE-RAGE axis in the kidney might be a novel therapeutic strategy to
control rats. Although linagliptin treatment for 2 weeks did not improve hyperglycemia in diabetic rats, linagliptin significantly reduced AGEs levels, RAGE gene expression, and 8-hydroxy-2′deoxyguanosine, a marker of oxidative stress in the kidney of diabetic rats. Furthermore, linagliptin significantly reduced albuminuria, renal ICAM-1 mRNA levels, and lymphocyte infiltration into the glomeruli of diabetic rats. Our present study suggests that linagliptin could exert beneficial effects on diabetic nephropathy partly by blocking the AGE-RAGE-evoked oxidative stress generation in the kidney of streptozotocin-induced diabetic rats. Inhibition of DPP-4 by linagliptin might be a promising strategy for the treatment of diabetic nephropathy.
block the progression of diabetic nephropathy and resultantly reduce the risk for ESRD in these subjects. Incretins such as glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptides (GIP) are gut hormones secreted from L and K cells in the intestine in response to food intake, respectively [13, 14], both of which are target proteins of dipeptidyl peptidase-4 (DPP-4) and rapidly degraded and inactivated by this proteolytic enzyme [15, 16]. Since GLP-1 and GIP augment glucose-induced insulin release from pancreatic β-cells, suppress glucagon secretion, and slow gastric emptying [13, 14], inhibition of DPP-4 has been proposed as a potential therapeutic target for the treatment of patients with type 2 diabetes. Furthermore, we have recently found that linagliptin, an inhibitor of DPP-4 suppresses the AGE-induced oxidative stress generation and intercellular adhesion molecule-1 (ICAM-1) gene expression in endothelial cells (ECs) [17]. These observations suggest the pleiotropic actions of linagliptin on vascular injury in
Nakashima S et al. Linagliptin and Diabetic Nephropathy … Horm Metab Res 2014; 46: 717–721
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Linagliptin Blocks Renal Damage in Type 1 Diabetic Rats by Suppressing Advanced Glycation End Products-Receptor Axis
718 Endocrine Research Immunohistochemical analysis
An inhibitor of DPP-4, linagliptin, was a generous gift from Boehringer Ingelheim (Ingelheim, Germany).
The kidneys were fixed in 4 % paraformaldehyde and embedded in paraffin, sectioned at 4 μm intervals and mounted on glass slides. After blocking endogenous peroxidase activity, the sections were incubated overnight at 4 °C with anti-8-hydroxy-2′deoxyguanosine (8-OHdG) Abs (Japan Institute for the Control of Aging NIKKEN SEIL Co., Ltd., Shizuoka, Japan) or CCR7 Abs directed specially against lymphocytes (Epitomics, Burlingame, CA, USA). Then the reactions were visualized with a Histofine Simple Stain Rat MAX-POMULTI kit (Nichirei Co., Tokyo, Japan) as described previously [18]. Immunoreactivity of each sample was measured by microcomputer-assisted image J.
Animal experiments
Statistical analysis
Nine week-old male Spraque-Dawley (SD) rats received single 60 mg/kg intraperitoneal injection of streptozotocin (Sigma, St. Louis, MO, USA) in 10 mM citrate buffer (pH 4.5). Nondiabetic control rats (Control) received citrate buffer alone. Animals with blood glucose levels greater than 250 mg/dl 48 h later were considered diabetic. STZ rats received 3 mg/kg linagliptin by oral gavage. At baseline and after 2 weeks of treatment, animals were housed in metabolic cages to collect urine for measurement of urinary excretion levels of albumin and then body weight, heart rate (HR), blood pressure (BP), blood glucose (BG), and blood biochemistries, including serum levels of DPP-4 were measured. BP was monitored by a tail-cuff sphygmomanometer (BP-98 A; Softron, Tokyo, Japan). Albuminuria was determined with a commercially available enzyme-linked immunosorbent assay (ELISA) kit (Shibayagi Co., Ltd., Gunma, Japan). Serum DPP-4 values were measured with ELISA kit for DPP-4 (Uscn, Life Science Inc., Houston, TX, USA). Other biochemistries were determined as described previously [18]. Then the rats were killed and the kidneys were excised for real-time reverse transcriptionpolymerase chain reactions (RT-PCR), Western blotting, and immunohistochemical analyses. All experimental procedures were conducted in accordance with the National Institutes Health Guide for Care and Use of Laboratory Animals and were approved by the ethical committee of Kurume University School of Medicine.
All values were presented as mean ± standard error. Student’s t-test was performed for statistical comparisons; p < 0.05 was considered significant.
Materials and Methods
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Materials
Real-time RT-PCR Total RNAs were extracted from the kidneys of Control, STZ, and STZ + linagliptin rats with RNAqueous-4PCR kit (Ambion Inc., Austin, TX, USA) according to the manufacturer’s instructions. Quantitative real-time RT-PCR was performed using Assay-onDemand and TaqMan 5 fluorogenic nuclease chemistry (Applied Biosystems, Foster city, CA, USA) according to the supplier’s recommendation. IDs of primers for rat RAGE, ICAM-1, β-actin, and 18 S gene were Rn00584249_m1, Rn00564227_m1, Rn00667869_ m1, and Hs99999901_s1, respectively.
Western blot analysis Ten micrograms of proteins were extracted from the kidneys of Control, STZ, and STZ + linagliptin rats with lysis buffer, and then separated by SDS-PAGE and transferred to nitrocellulose membranes as described previously [18]. Membranes were probed with antibodies (Abs) raised against AGEs, and then immune complexes were visualized with an enhanced chemiluminescence detection system (Amersham Bioscience, Buckinghamshire, UK) as described previously [18].
Results
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▶ Table 1, compared with control rats at 11 weeks As shown in ● old, body weight, heart rate (HR), total cholesterol (T-Chol), and high-density lipoprotein-cholesterol (HDL-C) levels were significantly lower, while systolic BP, BG, and blood urea nitrogen were higher in diabetic rats (STZ rats). Although linagliptin treatment for 2 weeks did not affect BG levels in diabetic rats, it significantly decreased body weight, HR, and diastolic BP, and increased T-Chol and HDL-C values in STZ rats. We examined whether serum DPP-4 levels were elevated under ▶ Fig. 1, serum DPP-4 levels diabetic conditions. As shown in ● were significantly elevated in streptozotocin-induced type 1 diabetic rats; DPP-4 levels in diabetic rats were increased to about 2.5-fold of those of control rats. We next investigated the effects of linagliptin, an inhibitor of DPP-4 on AGE-RAGE-oxidative stress axis in the kidney of dia▶ Fig. 2, AGE-modified protein levels, betic rats. As shown in ● RAGE gene expression, and a marker of oxidative stress, 8-OHdG levels, were significantly increased in the kidneys of type 1 diabetic rats compared with nondiabetic control rats, all of which were completely blocked by the treatment with linagliptin. Furthermore, linagliptin treatment for 2 weeks completely inhibited the increase in albuminuria, renal ICAM-1 gene levels, and lymphocyte infiltration into the glomeruli of streptozotocin▶ Fig. 3). induced type 1 diabetic rats (●
Discussion
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We have recently found that (1) DPP-4 induces oxidative stress generation, RAGE and ICAM-1 gene expression in ECs, (2) AGEs stimulate DPP-4 production from ECs, and (3) linagliptin inhibits the AGE-induced reactive oxygen species generation and upregulation of RAGE and ICAM-1 mRNA levels in ECs [17]. These observations suggest that linagliptin could inhibit the AGERAGE-induced EC damage partly by blocking the pathological crosstalk between DPP-4 and AGE-RAGE axis. However, it remains unclear whether linagliptin could have pleiotropic beneficial effects on renal injury in diabetic rats by suppressing the AGE-RAGE-evoked oxidative stress production. To address the issue, in this study, we evaluated the effects of linagliptin on diabetic nephropathy using a 2-week streptozotocin-induced type
Nakashima S et al. Linagliptin and Diabetic Nephropathy … Horm Metab Res 2014; 46: 717–721
This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.
diabetes. However, whether linagliptin could have beneficial effects on experimental diabetic nephropathy in a glucose-lowering independent manner remains unknown. To address the issue, this study examined the effects of linagliptin on renal damage in streptozotocin-induced diabetic rats (STZ rats).
Endocrine Research
Characteristics
Body weight (g) HR (beats/min) SBP (mm Hg) DBP (mm Hg) BG (mg/dl) BUN (mg/dl) Cr (mg/dl) T-Chol (mg/dl) HDL-C (mg/dl) TG (mg/dl)
9 Weeks
11 Weeks
Control rats
Control rats
STZ rats
STZ rats + linagliptin
(n = 4)
(n = 5)
(n = 4)
(n = 4)
288 ± 1 420 ± 3 139 ± 2 89 ± 2 98 ± 1 17.2 ± 0.7 0.20 ± 0.00 72.2 ± 2.9 54.5 ± 2.7 54.0 ± 12.0
368 ± 2 352 ± 6 117 ± 2 87 ± 1 98 ± 2 18.3 ± 0.7 0.26 ± 0.04 69.6 ± 2.3 49.6 ± 2.7 59.7 ± 11.1
266 ± 6 ** 297 ± 3 ** 140 ± 1 ** 87 ± 2 604 ± 39 ** 38.2 ± 2.0 ** 0.23 ± 0.02 47.1 ± 2.8 ** 35.1 ± 2.7 ** 46.0 ± 15.0
223 ± 10 ## 275 ± 3 ## 137 ± 1 80 ± 3 # 669 ± 23 32.7 ± 1.9 0.20 ± 0.00 75.8 ± 3.4 ## 57.4 ± 2.3 ## 91.5 ± 18.7
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Table 1 Characteristics of animals.
Data are presented as mean ± SE #
and ## p < 0.05 and p < 0.01 compared with STZ rats at 11 weeks old, respectively
HR: Heart rate; SBP: Systolic blood pressure; DBP: Diastolic blood pressure BG: Blood glucose; BUN: Blood urea nitrogen; Cr: creatinine; T-Chol: Total cholesterol HDL-C: High-density lipoprotein-cholesterol; TG: Triglycerides
Fig. 1 Serum DPP-4 levels in Control and streptozotocin-induced diabetic rats (STZ rats). Nine week-old male SD rats received single 60 mg/kg intraperitoneal injection of streptozotocin (STZ rats). Nondiabetic control rats received citrate buffer alone. After 2 weeks, serum levels of DPP-4 were measured. n = 5 for control rats; n = 4 for STZ rats. Assay was duplicated.
1 diabetic rat model, because (1) DPP-4 inhibitors such as linagliptin could not improve hyperglycemia in type 1 diabetic rats [19] and (2) albuminuria, enhanced accumulation of AGEs, and inflammatory reactions are observed in the kidneys of this diabetic model [18]. In the present study, we found that (1) serum DPP-4 levels were significantly increased in streptozotocininduced diabetic rats, (2) AGEs, RAGE gene expression, an oxidative stress marker, 8-OHdG levels in the kidneys of diabetic rats were significantly increased, all of which were completely prevented by linagliptin, and (3) linagliptin treatment for 2 weeks also significantly reduced albuminuria, renal ICAM-1 mRNA levels, and lymphocyte infiltration into the glomeruli of diabetic rats. Therefore, the findings have extended our previous observations showing that linagliptin blocked the crosstalk between DPP-4 and AGE-RAGE axis in ECs [17]. We have very recently found that DPP-4 inhibitor suppresses the AGE-RAGE axis and resultantly reduces albuminuria in type 2 diabetes patients [20], further supporting the concept that linagliptin could inhibit the activation of AGE-RAGE axis in the diabetic kidneys as well. In this study, we could not clarify the underlying mechanism for renoprotective actions of linagliptin. However, we have previously found that GLP-1 or GIP limits endothelial and mesangial cells’ susceptibility toward pro-oxidative and pro-inflammatory effects of AGEs by suppressing RAGE gene expression through
the elevation of cyclic AMP, whose effect could be augmented by the addition of DPP-4 inhibitor [21–24]. Since AGE-RAGE axis evokes oxidative stress generation in various cell types via NADPH oxidase activity, which is blocked by cAMP-elevating agents [11, 25–27], linagliptin might enhance the inhibitory effects of incretins on RAGE gene expression and oxidative stress generation, which could lead to suppress the inflammatory reactions in the diabetic kidneys and subsequently reduce albuminuria in type 1 diabetic rats. In addition, the AGE-RAGEinduced oxidative stress generation could further potentiate the harmful effects of AGEs via RAGE overexpression [11, 28, 29]. Since linagliptin contains xanthine scaffold structure, which could inhibit xanthine oxidase activity in vitro [30], the anti-oxidative unique properties of this drug might also be involved in the blockade of crosstalk between oxidative stress generation and RAGE gene induction. In the present study, although linagliptin treatment increased rather than decreased total cholesterol levels and did not improve hyperglycemia in diabetic rats, AGEs accumulation levels in the kidneys were significantly suppressed by the treatment with linagliptin. It is unlikely that linagliptin decreased renal AGEs levels by improving glycemic or lipid parameters. Aortic AGEs and oxidative stress levels have been shown to decrease in diabetic RAGE and apolipoprotein E double knockout mice [31]. Hence, it is conceivable that AGEs-RAGE-induced oxidative stress generation might participate in AGEs formation themselves. Therefore, reduction of renal AGEs accumulation by linagliptin treatment could be mainly ascribed to its RAGE-suppressing properties. Given the harmful effects of the AGE-RAGEoxidative stress axis in renal damage in diabetes [4–10], our present findings suggest that inhibition of DPP-4 by linagliptin might be a promising strategy for the treatment of diabetic nephropathy.
Limitations
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Although an oral dose of linagliptin of 3–10 mg/kg body weight daily was shown not to affect blood glucose levels in nondiabetic animals [32], lack of control rats + linagliptin group is one of the limitations in the present study. Moreover, since experimental animal model does not completely mimic human diabetic neph-
Nakashima S et al. Linagliptin and Diabetic Nephropathy … Horm Metab Res 2014; 46: 717–721
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** p < 0.01 compared with Control rats at 11 weeks old
Fig. 2 Effects of linagliptin on AGE-modified protein levels a, RAGE gene expression b, and 8-OHdG levels c in the kidneys of streptozotocininduced diabetic rats (STZ rats). a Ten micrograms of proteins were extracted from the kidneys of Control, STZ, and STZ + linagliptin rats with lysis buffer, and then separated by SDS-PAGE and transferred to nitrocellulose membranes. Membranes were probed with Abs raised against AGEs, and then immune complexes were visualized with an enhanced chemiluminescence detection system. b Total RNAs were extracted from the kidneys of Control, STZ and STZ + linagliptin rats with RNAqueous4PCR kit. Quantitative real-time RT-PCR was performed. Data were normalized by the intensity of β-actin mRNA-derived signals. c The kidneys
were fixed in 4 % paraformaldehyde and embedded in paraffin, sectioned at 4-μm intervals and mounted on glass slides. Then the sections were incubated overnight at 4 °C with anti-8-OHdG Abs, and the reactions were visualized with a Histofine Simple Stain Rat MAX-POMULTI kit. Immunoreactivity of each sample was measured by microcomputer-assisted image J. Upper panel shows the representative microphotograph. Lower panel shows the quantitative data. a–c Data were shown as the related value obtained with the control rats. ** p < 0.01 compared to the value with STZ rats. n = 5 for control rats; n = 4 for STZ rats; n = 4 for STZ + linagliptin rats. b Assay was quadruplicated. c Twenty different fields in each sample were evaluated.
Fig. 3 Effects of linagliptin on albuminuria a, renal ICAM-1 gene expression b, and lymphocyte infiltration into the glomeruli c in streptozotocininduced diabetic rats (STZ rats). a Albuminuria was determined with an ELISA kit. b Total RNAs were extracted from the kidneys of Control, STZ and STZ + linagliptin rats with RNAqueous-4PCR kit. Quantitative real-time RT-PCR was performed. Data were normalized by the intensity of 18S mRNA-derived signals. c The kidneys were fixed in 4 % paraformaldehyde and embedded in paraffin, sectioned at 4-μm intervals and mounted on glass slides. Then the sections were incubated overnight at 4 °C with antiCCR7 Abs, and the reactions were visualized with a Histofine Simple Stain
Rat MAX-POMULTI kit. Immunoreactivity of each sample was measured by microcomputer-assisted image J. Upper panel shows the representative microphotograph. Lower panel shows the quantitative data. a–c Data were shown as the related value obtained with the control rats. * and ** p < 0.05 and p < 0.01 compared to the value with STZ rats, respectively. a n = 4 for control rats; n = 4 for STZ rats; n = 4 for STZ + linagliptin rats. b and c n = 5 for control rats; n = 4 for STZ rats; n = 4 for STZ + linagliptin rats. b Assay was quadruplicated. c Twenty different fields in each sample were evaluated.
Nakashima S et al. Linagliptin and Diabetic Nephropathy … Horm Metab Res 2014; 46: 717–721
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720 Endocrine Research
ropathy, further prospective study is needed to clarify whether linagliptin treatment could inhibit the AGE-RAGE axis and be superior to other oral hypoglycemic agents in protecting against diabetic nephropathy in humans.
Acknowledgements
▼
This study was supported in part by Grants-in-Aid for Scientific Research (B) from the Ministry of Education, Culture, Sports, Science and Technology, Japan (to S.Y.), and by MEXT-Supported Program for the Strategic Research Foundation at Private Universities, the Ministry of Education, Culture, Sports, Science and Technology (MEXT) (to S.Y.).
Conflict of Interest
▼
Dr. S-i. Yamagishi has received honoraria such as lecture fees from Boehringer Ingelheim and Eli Lilly.
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17 Ishibashi Y, Matsui T, Maeda S, Higashimoto Y, Yamagishi S. Advanced glycation end products evoke endothelial cell damage by stimulating soluble dipeptidyl peptidase-4 production and its interaction with mannose 6-phosphate/insulin-like growth factor II receptor. Cardiovasc Diabetol 2013; 12: 125 18 Ojima A, Ishibashi Y, Matsui T, Maeda S, Nishino Y, Takeuchi M, Fukami K, Yamagishi S. Glucagon-like peptide-1 receptor agonist inhibits asymmetric dimethylarginine generation in the kidney of streptozotocin-induced diabetic rats by blocking advanced glycation end product-induced protein arginine methyltranferase-1 expression. Am J Pathol 2013; 182: 132–141 19 Maeda S, Matsui T, Yamagishi S. Vildagliptin inhibits oxidative stress and vascular damage in streptozotocin-induced diabetic rats. Int J Cardiol 2012; 158: 171–173 20 Sakata K, Hayakawa M, Yano Y, Tamaki N, Yokota N, Eto T, Watanabe R, Hirayama N, Matsuo T, Kuroki K, Sagara S, Mishima O, Koga M, Nagata N, Nishino Y, Kitamura K, Kario K, Takeuchi M, Yamagishi SI. Efficacy of alogliptin, a dipeptidyl peptidase-4 inhibitor, on glucose parameters, the activity of the advanced glycation end product – receptor for advanced glycation end product axis, and albuminuria in Japanese type 2 diabetes. Diabetes Metab Res Rev 2013; 29: 624–630 21 Ishibashi Y, Matsui T, Takeuchi M, Yamagishi S. Glucagon-like peptide-1 (GLP-1) inhibits advanced glycation end product (AGE)-induced upregulation of VCAM-1 mRNA levels in endothelial cells by suppressing AGE receptor (RAGE) expression. Biochem Biophys Res Commun 2010; 391: 1405–1408 22 Ishibashi Y, Nishino Y, Matsui T, Takeuchi M, Yamagishi S. Glucagonlike peptide-1 suppresses advanced glycation end product-induced monocyte chemoattractant protein-1 expression in mesangial cells by reducing advanced glycation end product receptor level. Metabolism 2011; 60: 1271–1277 23 Ojima A, Matsui T, Maeda S, Takeuchi M, Yamagishi S. Glucose-dependent insulinotropic polypeptide (GIP) inhibits signaling pathways of advanced glycation end products (AGEs) in endothelial cells via its antioxidative properties. Horm Metab Res 2012; 44: 501–505 24 Ishibashi Y, Matsui T, Takeuchi M, Yamagishi S. Sitagliptin augments protective effects of GLP-1 against advanced glycation end product receptor axis in endothelial cells. Horm Metab Res 2011; 43: 731–734 25 Yamagishi S, Nakamura K, Matsui T, Inagaki Y, Takenaka K, Jinnouchi Y, Yoshida Y, Matsuura T, Narama I, Motomiya Y, Takeuchi M, Inoue H, Yoshimura A, Bucala R, Imaizumi T. Pigment epithelium-derived factor inhibits advanced glycation end product-induced retinal vascular hyperpermeability by blocking reactive oxygen species-mediated vascular endothelial growth factor expression. J Biol Chem 2006; 281: 20213–20220 26 Yamagishi S, Fujimori H, Yonekura H, Yamamoto Y, Yamamoto H. Advanced glycation endproducts inhibit prostacyclin production and induce plasminogen activator inhibitor-1 in human microvascular endothelial cells. Diabetologia 1998; 41: 1435–1441 27 Yamagishi S, Amano S, Inagaki Y, Okamoto T, Takeuchi M, Makita Z. Beraprost sodium, a prostaglandin I2 analogue, protects against advanced gycation end products-induced injury in cultured retinal pericytes. Mol Med 2002; 8: 546–550 28 Yamagishi S, Nakamura K, Matsui T, Noda Y, Imaizumi T. Receptor for advanced glycation end products (RAGE): a novel therapeutic target for diabetic vascular complication. Curr Pharm Des 2008; 14: 487–495 29 Ide Y, Matsui T, Ishibashi Y, Takeuchi M, Yamagishi S. Pigment epithelium-derived factor inhibits advanced glycation end product-elicited mesangial cell damage by blocking NF-kappaB activation. Microvasc Res 2010; 80: 227–232 30 Morishita R, Yamagishi S. A diabetes treatment strategy to reduce the risk of cardiovascular events; Clinical benefits and potential of linagliptin. Immun Endoc Metab Agents Med Chem 2013; 13: 81–88 31 Soro-Paavonen A, Watson AM, Li J, Paavonen K, Koitka A, Calkin AC, Barit D, Coughlan MT, Drew BG, Lancaster GI, Thomas M, Forbes JM, Nawroth PP, Bierhaus A, Cooper ME, Jandeleit-Dahm KA. Receptor for advanced glycation end products (RAGE) deficiency attenuates the development of atherosclerosis in diabetes. Diabetes 2008; 57: 2461–2469 32 Jelsing J, Vrang N, van Witteloostuijn SB, Mark M, Klein T. The DPP4 inhibitor linagliptin delays the onset of diabetes and preserves β-cell mass in non-obese diabetic mice. J Endocrinol 2012; 214: 381–387
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Endocrine Research
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717
Authors
S. Nakashima1, T. Matsui1, M. Takeuchi2, S.-I. Yamagishi1
Affiliations
1
Department of Pathophysiology and Therapeutics of Diabetic Vascular Complications, Kurume University School of Medicine, Kurume, Japan 2 Department of Advanced Medicine, Medical Research Institute, Kanazawa Medical University, Kanazawa, Japan
Key words ▶ AGEs ● ▶ RAGE ● ▶ oxidative stress ● ▶ DPP-4 ● ▶ linagliptin ● ▶ diabetic nephropathy ●
Abstract
received 20.12.2013 accepted 11.03.2014 Bibliography DOI http://dx.doi.org/ 10.1055/s-0034-1371892 Published online: April 7, 2014 Horm Metab Res 2014; 46: 717–721 © Georg Thieme Verlag KG Stuttgart · New York ISSN 0018-5043 Correspondence S.-i. Yamagishi, MD, PhD Department of Pathophysiology and Therapeutics of Diabetic Vascular Complications Kurume University School of Medicine 67 Asahi-machi Kurume 830-0011 Japan Tel.: + 81/942/31 7873 Fax: + 81/942/31 7895 [email protected]
▼
Advanced glycation end products (AGEs) and their receptor (RAGE) play a role in diabetic nephropathy. We have recently found that linagliptin, an inhibitor of dipeptidyl peptidase-4 (DPP-4) suppresses the AGE-induced oxidative stress generation and intercellular adhesion molecule-1 (ICAM-1) gene expression in endothelial cells. However, whether linagliptin could have beneficial effects on experimental diabetic nephropathy in a glucose-lowering independent manner remains unknown. To address the issue, this study examined the effects of linagliptin on renal damage in streptozotocin-induced diabetic rats. Serum levels of DPP-4 were significantly elevated in diabetic rats compared with
Introduction
▼
Nonenzymatic modification of proteins by reducing sugars, a process that is also known as Maillard reaction, progresses at an extremely accelerated rate under diabetes [1–3]. The early glycation products undergo further complex reaction, such as rearrangement, dehydration, and condensation to become irreversibly crosslinked heterogeneous fluorescent derivatives, termed advanced glycation end products (AGEs) [1–3]. Recent understandings of this process have revealed that AGEs and their receptor (RAGE) interaction evokes oxidative stress generation and inflammatory reactions, thereby causing progressive alteration in renal architecture and loss of renal function in diabetes [4–10]. Given that diabetic nephropathy is the most common cause of end-stage renal disease (ESRD) in the world, which could account for the disability and high mortality rates in patients with diabetes [11, 12], blockade of the AGE-RAGE axis in the kidney might be a novel therapeutic strategy to
control rats. Although linagliptin treatment for 2 weeks did not improve hyperglycemia in diabetic rats, linagliptin significantly reduced AGEs levels, RAGE gene expression, and 8-hydroxy-2′deoxyguanosine, a marker of oxidative stress in the kidney of diabetic rats. Furthermore, linagliptin significantly reduced albuminuria, renal ICAM-1 mRNA levels, and lymphocyte infiltration into the glomeruli of diabetic rats. Our present study suggests that linagliptin could exert beneficial effects on diabetic nephropathy partly by blocking the AGE-RAGE-evoked oxidative stress generation in the kidney of streptozotocin-induced diabetic rats. Inhibition of DPP-4 by linagliptin might be a promising strategy for the treatment of diabetic nephropathy.
block the progression of diabetic nephropathy and resultantly reduce the risk for ESRD in these subjects. Incretins such as glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptides (GIP) are gut hormones secreted from L and K cells in the intestine in response to food intake, respectively [13, 14], both of which are target proteins of dipeptidyl peptidase-4 (DPP-4) and rapidly degraded and inactivated by this proteolytic enzyme [15, 16]. Since GLP-1 and GIP augment glucose-induced insulin release from pancreatic β-cells, suppress glucagon secretion, and slow gastric emptying [13, 14], inhibition of DPP-4 has been proposed as a potential therapeutic target for the treatment of patients with type 2 diabetes. Furthermore, we have recently found that linagliptin, an inhibitor of DPP-4 suppresses the AGE-induced oxidative stress generation and intercellular adhesion molecule-1 (ICAM-1) gene expression in endothelial cells (ECs) [17]. These observations suggest the pleiotropic actions of linagliptin on vascular injury in
Nakashima S et al. Linagliptin and Diabetic Nephropathy … Horm Metab Res 2014; 46: 717–721
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Linagliptin Blocks Renal Damage in Type 1 Diabetic Rats by Suppressing Advanced Glycation End Products-Receptor Axis
718 Endocrine Research Immunohistochemical analysis
An inhibitor of DPP-4, linagliptin, was a generous gift from Boehringer Ingelheim (Ingelheim, Germany).
The kidneys were fixed in 4 % paraformaldehyde and embedded in paraffin, sectioned at 4 μm intervals and mounted on glass slides. After blocking endogenous peroxidase activity, the sections were incubated overnight at 4 °C with anti-8-hydroxy-2′deoxyguanosine (8-OHdG) Abs (Japan Institute for the Control of Aging NIKKEN SEIL Co., Ltd., Shizuoka, Japan) or CCR7 Abs directed specially against lymphocytes (Epitomics, Burlingame, CA, USA). Then the reactions were visualized with a Histofine Simple Stain Rat MAX-POMULTI kit (Nichirei Co., Tokyo, Japan) as described previously [18]. Immunoreactivity of each sample was measured by microcomputer-assisted image J.
Animal experiments
Statistical analysis
Nine week-old male Spraque-Dawley (SD) rats received single 60 mg/kg intraperitoneal injection of streptozotocin (Sigma, St. Louis, MO, USA) in 10 mM citrate buffer (pH 4.5). Nondiabetic control rats (Control) received citrate buffer alone. Animals with blood glucose levels greater than 250 mg/dl 48 h later were considered diabetic. STZ rats received 3 mg/kg linagliptin by oral gavage. At baseline and after 2 weeks of treatment, animals were housed in metabolic cages to collect urine for measurement of urinary excretion levels of albumin and then body weight, heart rate (HR), blood pressure (BP), blood glucose (BG), and blood biochemistries, including serum levels of DPP-4 were measured. BP was monitored by a tail-cuff sphygmomanometer (BP-98 A; Softron, Tokyo, Japan). Albuminuria was determined with a commercially available enzyme-linked immunosorbent assay (ELISA) kit (Shibayagi Co., Ltd., Gunma, Japan). Serum DPP-4 values were measured with ELISA kit for DPP-4 (Uscn, Life Science Inc., Houston, TX, USA). Other biochemistries were determined as described previously [18]. Then the rats were killed and the kidneys were excised for real-time reverse transcriptionpolymerase chain reactions (RT-PCR), Western blotting, and immunohistochemical analyses. All experimental procedures were conducted in accordance with the National Institutes Health Guide for Care and Use of Laboratory Animals and were approved by the ethical committee of Kurume University School of Medicine.
All values were presented as mean ± standard error. Student’s t-test was performed for statistical comparisons; p < 0.05 was considered significant.
Materials and Methods
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Materials
Real-time RT-PCR Total RNAs were extracted from the kidneys of Control, STZ, and STZ + linagliptin rats with RNAqueous-4PCR kit (Ambion Inc., Austin, TX, USA) according to the manufacturer’s instructions. Quantitative real-time RT-PCR was performed using Assay-onDemand and TaqMan 5 fluorogenic nuclease chemistry (Applied Biosystems, Foster city, CA, USA) according to the supplier’s recommendation. IDs of primers for rat RAGE, ICAM-1, β-actin, and 18 S gene were Rn00584249_m1, Rn00564227_m1, Rn00667869_ m1, and Hs99999901_s1, respectively.
Western blot analysis Ten micrograms of proteins were extracted from the kidneys of Control, STZ, and STZ + linagliptin rats with lysis buffer, and then separated by SDS-PAGE and transferred to nitrocellulose membranes as described previously [18]. Membranes were probed with antibodies (Abs) raised against AGEs, and then immune complexes were visualized with an enhanced chemiluminescence detection system (Amersham Bioscience, Buckinghamshire, UK) as described previously [18].
Results
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▶ Table 1, compared with control rats at 11 weeks As shown in ● old, body weight, heart rate (HR), total cholesterol (T-Chol), and high-density lipoprotein-cholesterol (HDL-C) levels were significantly lower, while systolic BP, BG, and blood urea nitrogen were higher in diabetic rats (STZ rats). Although linagliptin treatment for 2 weeks did not affect BG levels in diabetic rats, it significantly decreased body weight, HR, and diastolic BP, and increased T-Chol and HDL-C values in STZ rats. We examined whether serum DPP-4 levels were elevated under ▶ Fig. 1, serum DPP-4 levels diabetic conditions. As shown in ● were significantly elevated in streptozotocin-induced type 1 diabetic rats; DPP-4 levels in diabetic rats were increased to about 2.5-fold of those of control rats. We next investigated the effects of linagliptin, an inhibitor of DPP-4 on AGE-RAGE-oxidative stress axis in the kidney of dia▶ Fig. 2, AGE-modified protein levels, betic rats. As shown in ● RAGE gene expression, and a marker of oxidative stress, 8-OHdG levels, were significantly increased in the kidneys of type 1 diabetic rats compared with nondiabetic control rats, all of which were completely blocked by the treatment with linagliptin. Furthermore, linagliptin treatment for 2 weeks completely inhibited the increase in albuminuria, renal ICAM-1 gene levels, and lymphocyte infiltration into the glomeruli of streptozotocin▶ Fig. 3). induced type 1 diabetic rats (●
Discussion
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We have recently found that (1) DPP-4 induces oxidative stress generation, RAGE and ICAM-1 gene expression in ECs, (2) AGEs stimulate DPP-4 production from ECs, and (3) linagliptin inhibits the AGE-induced reactive oxygen species generation and upregulation of RAGE and ICAM-1 mRNA levels in ECs [17]. These observations suggest that linagliptin could inhibit the AGERAGE-induced EC damage partly by blocking the pathological crosstalk between DPP-4 and AGE-RAGE axis. However, it remains unclear whether linagliptin could have pleiotropic beneficial effects on renal injury in diabetic rats by suppressing the AGE-RAGE-evoked oxidative stress production. To address the issue, in this study, we evaluated the effects of linagliptin on diabetic nephropathy using a 2-week streptozotocin-induced type
Nakashima S et al. Linagliptin and Diabetic Nephropathy … Horm Metab Res 2014; 46: 717–721
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diabetes. However, whether linagliptin could have beneficial effects on experimental diabetic nephropathy in a glucose-lowering independent manner remains unknown. To address the issue, this study examined the effects of linagliptin on renal damage in streptozotocin-induced diabetic rats (STZ rats).
Endocrine Research
Characteristics
Body weight (g) HR (beats/min) SBP (mm Hg) DBP (mm Hg) BG (mg/dl) BUN (mg/dl) Cr (mg/dl) T-Chol (mg/dl) HDL-C (mg/dl) TG (mg/dl)
9 Weeks
11 Weeks
Control rats
Control rats
STZ rats
STZ rats + linagliptin
(n = 4)
(n = 5)
(n = 4)
(n = 4)
288 ± 1 420 ± 3 139 ± 2 89 ± 2 98 ± 1 17.2 ± 0.7 0.20 ± 0.00 72.2 ± 2.9 54.5 ± 2.7 54.0 ± 12.0
368 ± 2 352 ± 6 117 ± 2 87 ± 1 98 ± 2 18.3 ± 0.7 0.26 ± 0.04 69.6 ± 2.3 49.6 ± 2.7 59.7 ± 11.1
266 ± 6 ** 297 ± 3 ** 140 ± 1 ** 87 ± 2 604 ± 39 ** 38.2 ± 2.0 ** 0.23 ± 0.02 47.1 ± 2.8 ** 35.1 ± 2.7 ** 46.0 ± 15.0
223 ± 10 ## 275 ± 3 ## 137 ± 1 80 ± 3 # 669 ± 23 32.7 ± 1.9 0.20 ± 0.00 75.8 ± 3.4 ## 57.4 ± 2.3 ## 91.5 ± 18.7
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Table 1 Characteristics of animals.
Data are presented as mean ± SE #
and ## p < 0.05 and p < 0.01 compared with STZ rats at 11 weeks old, respectively
HR: Heart rate; SBP: Systolic blood pressure; DBP: Diastolic blood pressure BG: Blood glucose; BUN: Blood urea nitrogen; Cr: creatinine; T-Chol: Total cholesterol HDL-C: High-density lipoprotein-cholesterol; TG: Triglycerides
Fig. 1 Serum DPP-4 levels in Control and streptozotocin-induced diabetic rats (STZ rats). Nine week-old male SD rats received single 60 mg/kg intraperitoneal injection of streptozotocin (STZ rats). Nondiabetic control rats received citrate buffer alone. After 2 weeks, serum levels of DPP-4 were measured. n = 5 for control rats; n = 4 for STZ rats. Assay was duplicated.
1 diabetic rat model, because (1) DPP-4 inhibitors such as linagliptin could not improve hyperglycemia in type 1 diabetic rats [19] and (2) albuminuria, enhanced accumulation of AGEs, and inflammatory reactions are observed in the kidneys of this diabetic model [18]. In the present study, we found that (1) serum DPP-4 levels were significantly increased in streptozotocininduced diabetic rats, (2) AGEs, RAGE gene expression, an oxidative stress marker, 8-OHdG levels in the kidneys of diabetic rats were significantly increased, all of which were completely prevented by linagliptin, and (3) linagliptin treatment for 2 weeks also significantly reduced albuminuria, renal ICAM-1 mRNA levels, and lymphocyte infiltration into the glomeruli of diabetic rats. Therefore, the findings have extended our previous observations showing that linagliptin blocked the crosstalk between DPP-4 and AGE-RAGE axis in ECs [17]. We have very recently found that DPP-4 inhibitor suppresses the AGE-RAGE axis and resultantly reduces albuminuria in type 2 diabetes patients [20], further supporting the concept that linagliptin could inhibit the activation of AGE-RAGE axis in the diabetic kidneys as well. In this study, we could not clarify the underlying mechanism for renoprotective actions of linagliptin. However, we have previously found that GLP-1 or GIP limits endothelial and mesangial cells’ susceptibility toward pro-oxidative and pro-inflammatory effects of AGEs by suppressing RAGE gene expression through
the elevation of cyclic AMP, whose effect could be augmented by the addition of DPP-4 inhibitor [21–24]. Since AGE-RAGE axis evokes oxidative stress generation in various cell types via NADPH oxidase activity, which is blocked by cAMP-elevating agents [11, 25–27], linagliptin might enhance the inhibitory effects of incretins on RAGE gene expression and oxidative stress generation, which could lead to suppress the inflammatory reactions in the diabetic kidneys and subsequently reduce albuminuria in type 1 diabetic rats. In addition, the AGE-RAGEinduced oxidative stress generation could further potentiate the harmful effects of AGEs via RAGE overexpression [11, 28, 29]. Since linagliptin contains xanthine scaffold structure, which could inhibit xanthine oxidase activity in vitro [30], the anti-oxidative unique properties of this drug might also be involved in the blockade of crosstalk between oxidative stress generation and RAGE gene induction. In the present study, although linagliptin treatment increased rather than decreased total cholesterol levels and did not improve hyperglycemia in diabetic rats, AGEs accumulation levels in the kidneys were significantly suppressed by the treatment with linagliptin. It is unlikely that linagliptin decreased renal AGEs levels by improving glycemic or lipid parameters. Aortic AGEs and oxidative stress levels have been shown to decrease in diabetic RAGE and apolipoprotein E double knockout mice [31]. Hence, it is conceivable that AGEs-RAGE-induced oxidative stress generation might participate in AGEs formation themselves. Therefore, reduction of renal AGEs accumulation by linagliptin treatment could be mainly ascribed to its RAGE-suppressing properties. Given the harmful effects of the AGE-RAGEoxidative stress axis in renal damage in diabetes [4–10], our present findings suggest that inhibition of DPP-4 by linagliptin might be a promising strategy for the treatment of diabetic nephropathy.
Limitations
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Although an oral dose of linagliptin of 3–10 mg/kg body weight daily was shown not to affect blood glucose levels in nondiabetic animals [32], lack of control rats + linagliptin group is one of the limitations in the present study. Moreover, since experimental animal model does not completely mimic human diabetic neph-
Nakashima S et al. Linagliptin and Diabetic Nephropathy … Horm Metab Res 2014; 46: 717–721
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** p < 0.01 compared with Control rats at 11 weeks old
Fig. 2 Effects of linagliptin on AGE-modified protein levels a, RAGE gene expression b, and 8-OHdG levels c in the kidneys of streptozotocininduced diabetic rats (STZ rats). a Ten micrograms of proteins were extracted from the kidneys of Control, STZ, and STZ + linagliptin rats with lysis buffer, and then separated by SDS-PAGE and transferred to nitrocellulose membranes. Membranes were probed with Abs raised against AGEs, and then immune complexes were visualized with an enhanced chemiluminescence detection system. b Total RNAs were extracted from the kidneys of Control, STZ and STZ + linagliptin rats with RNAqueous4PCR kit. Quantitative real-time RT-PCR was performed. Data were normalized by the intensity of β-actin mRNA-derived signals. c The kidneys
were fixed in 4 % paraformaldehyde and embedded in paraffin, sectioned at 4-μm intervals and mounted on glass slides. Then the sections were incubated overnight at 4 °C with anti-8-OHdG Abs, and the reactions were visualized with a Histofine Simple Stain Rat MAX-POMULTI kit. Immunoreactivity of each sample was measured by microcomputer-assisted image J. Upper panel shows the representative microphotograph. Lower panel shows the quantitative data. a–c Data were shown as the related value obtained with the control rats. ** p < 0.01 compared to the value with STZ rats. n = 5 for control rats; n = 4 for STZ rats; n = 4 for STZ + linagliptin rats. b Assay was quadruplicated. c Twenty different fields in each sample were evaluated.
Fig. 3 Effects of linagliptin on albuminuria a, renal ICAM-1 gene expression b, and lymphocyte infiltration into the glomeruli c in streptozotocininduced diabetic rats (STZ rats). a Albuminuria was determined with an ELISA kit. b Total RNAs were extracted from the kidneys of Control, STZ and STZ + linagliptin rats with RNAqueous-4PCR kit. Quantitative real-time RT-PCR was performed. Data were normalized by the intensity of 18S mRNA-derived signals. c The kidneys were fixed in 4 % paraformaldehyde and embedded in paraffin, sectioned at 4-μm intervals and mounted on glass slides. Then the sections were incubated overnight at 4 °C with antiCCR7 Abs, and the reactions were visualized with a Histofine Simple Stain
Rat MAX-POMULTI kit. Immunoreactivity of each sample was measured by microcomputer-assisted image J. Upper panel shows the representative microphotograph. Lower panel shows the quantitative data. a–c Data were shown as the related value obtained with the control rats. * and ** p < 0.05 and p < 0.01 compared to the value with STZ rats, respectively. a n = 4 for control rats; n = 4 for STZ rats; n = 4 for STZ + linagliptin rats. b and c n = 5 for control rats; n = 4 for STZ rats; n = 4 for STZ + linagliptin rats. b Assay was quadruplicated. c Twenty different fields in each sample were evaluated.
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720 Endocrine Research
ropathy, further prospective study is needed to clarify whether linagliptin treatment could inhibit the AGE-RAGE axis and be superior to other oral hypoglycemic agents in protecting against diabetic nephropathy in humans.
Acknowledgements
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This study was supported in part by Grants-in-Aid for Scientific Research (B) from the Ministry of Education, Culture, Sports, Science and Technology, Japan (to S.Y.), and by MEXT-Supported Program for the Strategic Research Foundation at Private Universities, the Ministry of Education, Culture, Sports, Science and Technology (MEXT) (to S.Y.).
Conflict of Interest
▼
Dr. S-i. Yamagishi has received honoraria such as lecture fees from Boehringer Ingelheim and Eli Lilly.
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Endocrine Research
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