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• W2000258452 abstract "Advanced glycation end products (AGEs) and their receptor (RAGE) play a role in diabetic nephropathy. Asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide synthase, contributes to diabetic nephropathy. We have found that glucagon-like peptide-1 (GLP-1) inhibits the AGE-induced inflammatory reactions in endothelial cells. However, effects of GLP-1 on the AGE-RAGE-ADMA axis are unknown. This study examined the effects of GLP-1 on reactive oxygen species (ROS) generation, gene expression of protein arginine methyltransfetase-1 (PRMT-1), an enzyme that mainly generates ADMA, and ADMA levels in human proximal tubular cells. Streptozotocin-induced diabetic rats received continuous i.p. infusion of 0.3 μg of vehicle or 1.5 μg of the GLP-1 analog exendin-4 per kilogram of body weight for 2 weeks. We further investigated whether and how exendin-4 treatment reduced ADMA levels and renal damage in streptozotocin-induced diabetic rats. GLP-1 inhibited the AGE-induced RAGE and PRMT-1 gene expression, ROS, and ADMA generation in tubular cells, which were blocked by small-interfering RNAs raised against GLP-1 receptor. Exendin-4 treatment decreased gene expression of Rage, Prmt-1, Icam-1, and Mcp-1 and ADMA level; reduced urinary excretions of 8-hydroxy-2′-deoxyguanosine and albumin; and improved histopathologic changes of the kidney in diabetic rats. Our present study suggests that GLP-1 receptor agonist may inhibit the AGE-RAGE–mediated ADMA generation by suppressing PRMT-1 expression via inhibition of ROS generation, thereby protecting against the development and progression of diabetic nephropathy. Advanced glycation end products (AGEs) and their receptor (RAGE) play a role in diabetic nephropathy. Asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide synthase, contributes to diabetic nephropathy. We have found that glucagon-like peptide-1 (GLP-1) inhibits the AGE-induced inflammatory reactions in endothelial cells. However, effects of GLP-1 on the AGE-RAGE-ADMA axis are unknown. This study examined the effects of GLP-1 on reactive oxygen species (ROS) generation, gene expression of protein arginine methyltransfetase-1 (PRMT-1), an enzyme that mainly generates ADMA, and ADMA levels in human proximal tubular cells. Streptozotocin-induced diabetic rats received continuous i.p. infusion of 0.3 μg of vehicle or 1.5 μg of the GLP-1 analog exendin-4 per kilogram of body weight for 2 weeks. We further investigated whether and how exendin-4 treatment reduced ADMA levels and renal damage in streptozotocin-induced diabetic rats. GLP-1 inhibited the AGE-induced RAGE and PRMT-1 gene expression, ROS, and ADMA generation in tubular cells, which were blocked by small-interfering RNAs raised against GLP-1 receptor. Exendin-4 treatment decreased gene expression of Rage, Prmt-1, Icam-1, and Mcp-1 and ADMA level; reduced urinary excretions of 8-hydroxy-2′-deoxyguanosine and albumin; and improved histopathologic changes of the kidney in diabetic rats. Our present study suggests that GLP-1 receptor agonist may inhibit the AGE-RAGE–mediated ADMA generation by suppressing PRMT-1 expression via inhibition of ROS generation, thereby protecting against the development and progression of diabetic nephropathy. The pathologic role of the nonenzymatic modification of proteins by reducing sugars, a process that is known as glycation (also called the Maillard reaction), has become increasingly evident in various types of diseases.1Vlassara H. Bucala R. Recent progress in advanced glycation and diabetic vascular disease: role of advanced glycation end product receptors.Diabetes Suppl. 1996; 3: S65-S66Crossref Google Scholar, 2Brownlee M. Cerami A. Vlassara A. Advanced glycosylation end products in tissue and the biochemical basis of diabetic complications.N Engl J Med. 1998; 318: 1315-1321Google Scholar, 3Rahbar S. Novel inhibitors of glycation and AGE formation.Cell Biochem Biophys. 2007; 48: 147-157Crossref PubMed Scopus (70) Google Scholar It is now well established that early glycation products undergo progressive modification over time in vivo to the formation of irreversible cross-links, after which these molecules are termed “advanced glycation end products” (AGEs).1Vlassara H. Bucala R. Recent progress in advanced glycation and diabetic vascular disease: role of advanced glycation end product receptors.Diabetes Suppl. 1996; 3: S65-S66Crossref Google Scholar, 2Brownlee M. Cerami A. Vlassara A. Advanced glycosylation end products in tissue and the biochemical basis of diabetic complications.N Engl J Med. 1998; 318: 1315-1321Google Scholar, 3Rahbar S. Novel inhibitors of glycation and AGE formation.Cell Biochem Biophys. 2007; 48: 147-157Crossref PubMed Scopus (70) Google Scholar The formation and accumulation of AGEs in various tissues have been reported to progress at an accelerated rate under hyperglycemic conditions.1Vlassara H. Bucala R. Recent progress in advanced glycation and diabetic vascular disease: role of advanced glycation end product receptors.Diabetes Suppl. 1996; 3: S65-S66Crossref Google Scholar, 2Brownlee M. Cerami A. Vlassara A. Advanced glycosylation end products in tissue and the biochemical basis of diabetic complications.N Engl J Med. 1998; 318: 1315-1321Google Scholar, 3Rahbar S. Novel inhibitors of glycation and AGE formation.Cell Biochem Biophys. 2007; 48: 147-157Crossref PubMed Scopus (70) Google Scholar There is a growing body of evidence that AGE and receptor for AGE (RAGE) interaction stimulates oxidative stress generation and subsequently evokes inflammatory reactions, thereby causing progressive alteration in renal architecture and loss of renal function in diabetes.4Yamamoto Y. Kato I. Doi T. Yonekura H. Ohashi S. Takeuchi M. Watanabe T. Yamagishi S. Sakurai S. Takasawa S. Okamoto H. Yamamoto H. Development and prevention of advanced diabetic nephropathy in RAGE-overexpressing mice.J Clin Invest. 2001; 108: 261-268Crossref PubMed Scopus (446) Google Scholar, 5Wendt T.M. Tanji N. Guo J. Kislinger T.R. Qu W. Lu Y. Bucciarelli L.G. Rong L.L. Moser B. Markowitz G.S. Stein G. Bierhaus A. Liliensiek B. Arnold B. Nawroth P.P. Stern D.M. D'Agati V.D. Schmidt A.M. RAGE drives the development of glomerulosclerosis and implicates podocyte activation in the pathogenesis of diabetic nephropathy.Am J Pathol. 2003; 162: 1123-1137Abstract Full Text Full Text PDF PubMed Scopus (512) Google Scholar, 6Reiniger N. Lau K. McCalla D. Eby B. Cheng B. Lu Y. Qu W. Quadri N. Ananthakrishnan R. Furmansky M. Rosario R. Song F. Rai V. Weinberg A. Friedman R. Ramasamy R. D'Agati V. Schmidt A.M. Deletion of the receptor for advanced glycation end products reduces glomerulosclerosis and preserves renal function in the diabetic OVE26 mouse.Diabetes. 2010; 59: 2043-2054Crossref PubMed Scopus (144) Google Scholar, 7Yamagishi S. Imaizumi T. Diabetic vascular complications: pathophysiology, biochemical basis and potential therapeutic strategy.Curr Pharm Des. 2005; 11: 2279-2299Crossref PubMed Scopus (435) Google Scholar, 8Yamagishi S. Matsui T. Advanced glycation end products, oxidative stress and diabetic nephropathy.Oxid Med Cell Longev. 2010; 3: 101-108Crossref PubMed Scopus (282) Google Scholar RAGE-overexpressing diabetic mice have been found to have progressive glomerulosclerosis with renal dysfunction, compared with diabetic littermates lacking the RAGE transgene.4Yamamoto Y. Kato I. Doi T. Yonekura H. Ohashi S. Takeuchi M. Watanabe T. Yamagishi S. Sakurai S. Takasawa S. Okamoto H. Yamamoto H. Development and prevention of advanced diabetic nephropathy in RAGE-overexpressing mice.J Clin Invest. 2001; 108: 261-268Crossref PubMed Scopus (446) Google Scholar Diabetic homozygous RAGE null mice failed to develop significantly increased mesangial matrix expansion or thickening of the glomerular basement membrane.5Wendt T.M. Tanji N. Guo J. Kislinger T.R. Qu W. Lu Y. Bucciarelli L.G. Rong L.L. Moser B. Markowitz G.S. Stein G. Bierhaus A. Liliensiek B. Arnold B. Nawroth P.P. Stern D.M. D'Agati V.D. Schmidt A.M. RAGE drives the development of glomerulosclerosis and implicates podocyte activation in the pathogenesis of diabetic nephropathy.Am J Pathol. 2003; 162: 1123-1137Abstract Full Text Full Text PDF PubMed Scopus (512) Google Scholar Furthermore, deletion of RAGE is also reported to prevent diabetic nephropathy in the OVE26 type 1 mouse, a model of progressive glomerulosclerosis, and decline of renal function.6Reiniger N. Lau K. McCalla D. Eby B. Cheng B. Lu Y. Qu W. Quadri N. Ananthakrishnan R. Furmansky M. Rosario R. Song F. Rai V. Weinberg A. Friedman R. Ramasamy R. D'Agati V. Schmidt A.M. Deletion of the receptor for advanced glycation end products reduces glomerulosclerosis and preserves renal function in the diabetic OVE26 mouse.Diabetes. 2010; 59: 2043-2054Crossref PubMed Scopus (144) Google Scholar Glucagon-like peptide-1 (GLP-1) is one of the incretins, a gut hormone secreted from L cells in the intestine in response to food intake.9Kim W. Egan J.M. The role of incretins in glucose homeostasis and diabetes treatment.Pharmacol Rev. 2008; 60: 470-512Crossref PubMed Scopus (586) Google Scholar GLP-1 augments glucose-induced insulin release from pancreatic β-cells, suppresses glucagon secretion, and slows gastric emptying.9Kim W. Egan J.M. The role of incretins in glucose homeostasis and diabetes treatment.Pharmacol Rev. 2008; 60: 470-512Crossref PubMed Scopus (586) Google Scholar Therefore, GLP-1 has been proposed as a potential therapeutic target for the treatment of patients with type 2 diabetes. The biological actions of GLP-1 on pancreatic cells are mainly mediated by the high-affinity GLP-1 receptor (GLP-1R).10Winzell M.S. Ahrén B. G-protein-coupled receptors and islet function-implications for treatment of type 2 diabetes.Pharmacol Rev. 2007; 116: 437-448Google Scholar GLP-1R exists in extrapancreatic tissues, including brain, peripheral nervous system, kidney, heart, and vasculature.11Chilton R. Wyatt J. Nandish S. Oliveros R. Lujan M. Cardiovascular comorbidities of type 2 diabetes mellitus: defining the potential of glucagonlike peptide-1-based therapies.Am J Med. 2011; 124: S35-S53Abstract Full Text Full Text PDF PubMed Scopus (60) Google Scholar, 12Anagnostis P. Athyros V.G. Adamidou F. Panagiotou A. Kita M. Karagiannis A. Mikhailidis D.P. Glucagon-like peptide-1-based therapies and cardiovascular disease: looking beyond glycaemic control.Diabetes Obes Metab. 2011; 13: 302-312Crossref PubMed Scopus (118) Google Scholar These observations suggest that GLP-1 could exert pleiotropic actions, that is, glucose-lowering independent beneficial effects on vascular complications in diabetes via GLP-1R–mediated activation of cAMP pathway. Nitric oxide (NO) is a multifunctional molecule critical to a number of physiologic and pathologic processes in humans.13Baylis C. Nitric oxide deficiency in chronic kidney disease.Am J Physiol Renal Physiol. 2008; 294: F1-F9Crossref PubMed Scopus (314) Google Scholar, 14Yamagishi S. Matsui T. Nitric oxide, a janus-faced therapeutic target for diabetic microangiopathy: friend or foe?.Pharmacol Res. 2011; 64: 187-194Crossref PubMed Scopus (97) Google Scholar NO not only inhibits inflammatory-proliferative reactions in vascular wall cells but also exerts antithrombogenic and endothelial cell protective properties in vivo.13Baylis C. Nitric oxide deficiency in chronic kidney disease.Am J Physiol Renal Physiol. 2008; 294: F1-F9Crossref PubMed Scopus (314) Google Scholar, 14Yamagishi S. Matsui T. Nitric oxide, a janus-faced therapeutic target for diabetic microangiopathy: friend or foe?.Pharmacol Res. 2011; 64: 187-194Crossref PubMed Scopus (97) Google Scholar Therefore, impaired production and/or bioavailability of NO are considered to play a role in vascular complications in diabetes, such as diabetic nephropathy and cardiovascular disease.15Yamagishi S. Ueda S. Nakamura K. Matsui T. Okuda S. Role of asymmetric dimethylarginine (ADMA) in diabetic vascular complications.Curr Pharm Des. 2008; 14: 2613-2618Crossref PubMed Scopus (32) Google Scholar, 16Böger R.H. Bode-Böger S.M. Frölich J.C. The L-arginine-nitric oxide pathway: role in atherosclerosis and therapeutic implications.Atherosclerosis. 1996; 127: 1-11Abstract Full Text PDF PubMed Scopus (160) Google Scholar Indeed, circulating level of asymmetric dimethylarginine (ADMA), an endogenous NO synthase inhibitor, is increased in early diabetic nephropathy in type 1 diabetes and associated with future cardiovascular events in these individuals.17Tarnow L. Hovind P. Teerlink T. Stehouwer C.D. Parving H.H. Elevated plasma asymmetric dimethylarginine as a marker of cardiovascular morbidity in early diabetic nephropathy in type 1 diabetes.Diabetes Care. 2004; 27: 765-769Crossref PubMed Scopus (174) Google Scholar Furthermore, we have previously found that serum levels of AGEs are positively associated with soluble form of RAGE and ADMA in patients with chronic kidney disease, thus suggesting the active involvement of the AGE-RAGE system in the elevated levels of ADMA.18Nakamura T. Sato E. Fujiwara N. Kawagoe Y. Ueda Y. Suzuki T. Yamada S. Takeuchi M. Fukami K. Ueda S. Adachi H. Matsui T. Okuda S. Yamagishi S. Positive association of serum levels of advanced glycation end products and high mobility group box-1 with asymmetric dimethylarginine in nondiabetic chronic kidney disease patients.Metabolism. 2009; 58: 1624-1628Abstract Full Text Full Text PDF PubMed Scopus (43) Google Scholar However, it remains unknown how the AGE-RAGE interaction increases ADMA levels in diabetic kidney and whether GLP-1 could reduce the ADMA levels by suppressing the AGE-RAGE axis. To address these issues, we examined the effects of GLP-1 on RAGE mRNA levels, reactive oxygen species (ROS) generation, gene expression of protein arginine methyltransfetase-1 (PRMT-1), and dimethylarginine dimethylaminohydrolase-1 (DDAH-1), responsible enzymes that mainly generate and metabolize ADMA,15Yamagishi S. Ueda S. Nakamura K. Matsui T. Okuda S. Role of asymmetric dimethylarginine (ADMA) in diabetic vascular complications.Curr Pharm Des. 2008; 14: 2613-2618Crossref PubMed Scopus (32) Google Scholar and ADMA levels in human proximal tubular epithelial cells. Then we investigated whether continuous intraperitoneal infusion of the GLP-1 analog exendin-4 could decrease ADMA levels in the kidney of streptozotocin-induced diabetic rats and inhibit renal damage in these animals. Bovine serum albumin (BSA) (essentially fatty acid free and essentially globulin-free, lyophilized powder), GLP-1 (7 to 36) amide, 8-bromo-cAMP (8-Br-cAMP; an analog of cAMP), N-acetylcysteine (NAC), monoclonal antibody (Ab) raised against α-tubulin, and exendin-4 (GLP-1 analog) were purchased from Sigma Chemical Co. (St. Louis, MO). d-glyceraldehyde was purchased from Nakalai Tesque (Kyoto, Japan). Abs directed against human GLP-1R and ADMA were purchased from Santa Cruz Biotechnology Inc. (Delaware, CA) and Active Motif Inc. (Carlsbad, CA), respectively. AGE-BSA was prepared as described previously.19Takeuchi M. Makita Z. Bucala R. Suzuki T. Koike T. Kameda Y. Immunological evidence that non-carboxymethyllysine advanced glycation end-products are produced from short chain sugars and dicarbonyl compounds in vivo.Mol Med. 2000; 6: 114-125Crossref PubMed Google Scholar, 20Yamagishi 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: 20213-20220Crossref PubMed Scopus (224) Google Scholar In brief, BSA (25 mg/mL) was incubated under sterile conditions with 0.1 mol/L glyceraldehyde in 0.2 mol/L NaPO4 buffer (pH 7.4) for 7 days. Then unincorporated sugars were removed by PD-10 column chromatography and dialysis against PBS. Control nonglycated BSA was incubated in the same conditions except for the absence of reducing sugars. Preparations were tested for endotoxin using Endospecy ES-20S system (Seikagaku Co., Tokyo, Japan); no endotoxin was detectable. The extent of chemical modification was determined as described with 2,4,6-trinitrobenzenesulfonic acid as a difference in lysine residues of modified and unmodified protein preparations.13Baylis C. Nitric oxide deficiency in chronic kidney disease.Am J Physiol Renal Physiol. 2008; 294: F1-F9Crossref PubMed Scopus (314) Google Scholar, 14Yamagishi S. Matsui T. Nitric oxide, a janus-faced therapeutic target for diabetic microangiopathy: friend or foe?.Pharmacol Res. 2011; 64: 187-194Crossref PubMed Scopus (97) Google Scholar The extent of lysine modification of modified BSA preparations was 65% for AGE-BSA.21Yamagishi S. Yonekura H. Yamamoto Y. Katsuno K. Sato F. Mita I. Ooka H. Satozawa N. Kawakami T. Nomura M. Yamamoto H. Advanced glycation end products-driven angiogenesis in vitro. Induction of the growth and tube formation of human microvascular endothelial cells through autocrine vascular endothelial growth factor.J Biol Chem. 1997; 272: 8723-8730Crossref PubMed Scopus (299) Google Scholar Polyclonal Ab raised against AGE-BSA was prepared as previously described.19Takeuchi M. Makita Z. Bucala R. Suzuki T. Koike T. Kameda Y. Immunological evidence that non-carboxymethyllysine advanced glycation end-products are produced from short chain sugars and dicarbonyl compounds in vivo.Mol Med. 2000; 6: 114-125Crossref PubMed Google Scholar Ab directed against human RAGE (RAGE-Ab) for neutralizing assays, which recognized the amino acid residues 167 to 180 of human RAGE protein, was prepared as described previously.22Sasaki N. Takeuchi M. Chowei H. Kikuchi S. Hayashi Y. Nakano N. Ikeda H. Yamagishi S. Kitamoto T. Saito T. Makita Z. Advanced glycation end products (AGE) and their receptor (RAGE) in the brain of patients with Creutzfeldt-Jakob disease with prion plaques.Neurosci Lett. 2002; 326: 117-120Crossref PubMed Scopus (97) Google Scholar Proximal tubular epithelial cells from human kidney were maintained in basal medium supplemented with 5% fetal bovine serum, 0.5 μg/mL of hydrocortisone, 10 ng/mL of human epidermal growth factor, 0.5 μg/mL of epinephrine, 6.5 ng/mL of triiodo-l-thyronine, 10 μg/mL of transferrin, 5 μg/mL of insulin, and GA-1000 according to the supplier instructions (Clonetics Corp., San Diego, CA).23Yamagishi S. Inagaki Y. Okamoto T. Amano S. Koga K. Takeuchi M. Advanced glycation end products inhibit de novo protein synthesis and induce TGF-beta overexpression in proximal tubular cells.Kidney Int. 2003; 63: 464-473Crossref PubMed Scopus (158) Google Scholar Cells at three to five passages were used for the experiments. AGE and/or GLP-1 treatments were performed in a serum-free basal medium containing 10 μg/mL of transferrin and GA-1000. Sense and antisense human GLP-1R small-interfering RNAs (siRNAs) (GLP-1R siRNA) used in this experiment (5′-UCAUCAAGCUGUUUACAGATT-3′ and 5′-UCUGUAAACAGCUUGAUGAAG-3′, respectively) were synthesized by Applied Biosystems (Foster, CA). Control nonsilencing siRNAs (control siRNA) were also obtained from Applied Biosystems (Silencer Negative Control 1 siRNA). Then the siRNA duplexes were transfected to tubular cells using Lipofectamine2000 (Invitrogen, Carlsbad, CA) as described previously.24Ishibashi Y. Matsui T. Takeuchi M. Yamagishi S. Glucagon-like peptide-1 (GLP-1) inhibits advanced glycation end product (AGE)-induced up-regulation of VCAM-1 mRNA levels in endothelial cells by suppressing AGE receptor (RAGE) expression.Biochem Biophys Res Commun. 2010; 391: 1405-1408Crossref PubMed Scopus (130) Google Scholar After 2 days of transfection, GLP-1R protein levels were analyzed. Transfected or nontransfected tubular cells were treated with 100 μg/mL, AGE-BSA, or nonglycated BSA in the presence or absence of 0.3 nmol/L GLP-1, 5 μmol/L 8-Br-cAMP, 5 μg/mL of RAGE-Ab, or 1 mmol/L NAC for 4 hours. Then total RNA was extracted with the RNAqueous-4PCR kit (Ambion Inc., Austin, TX) according to the manufacturer instructions. Quantitative real-time RT-PCR (RT-qPCR) was performed using Assay-on-Demand and TaqMan 5 fluorogenic nuclease chemistry (Applied Biosystems) according to the supplier recommendation. The identification numbers of primers for human RAGE, PRMT-1, and β-actin (ACTB) genes were Hs00153957_m1, Hs01587651_g1, and Hs99999903_m1, respectively. Proteins were extracted from transfected or nontransfected tubular cells with lysis buffer and then separated by SDS-PAGE and transferred to nitrocellulose membranes as described previously.25Yoshida T. Yamagishi S. Nakamura K. Matsui T. Imaizumi T. Takeuchi M. Koga H. Ueno T. Sata M. Telmisartan inhibits AGE-induced C-reactive protein production through downregulation of the receptor for AGE via peroxisome proliferator-activated receptor-gamma activation.Diabetologia. 2006; 49: 3094-3099Crossref PubMed Scopus (114) Google Scholar Membranes were probed with Abs against GLP-1R, ADMA, or α-tubulin, and then immune complexes were visualized with an enhanced chemiluminescence detection system (Amersham Bioscience, Buckinghamshire, United Kingdom). Transfected or nontransfected tubular cells were treated with 100 μg/mL of AGE-BSA or nonglycated BSA in the presence or absence of 0.3 nmol/L GLP-1 for 4 hours, and then the cells were incubated with phenol red free Dulbecco's modified Eagle medium containing 3 μmol/L dihydroethidium (DHE; Molecular Probes Inc., Eugene, OR). After 15 minutes, the cells were imaged under a laser scanning confocal microscope. Intensity of DHE staining in five different fields of each sample was analyzed by microcomputer-assisted ImageJ software version 1.46 (NIH, Bethesda, MD). Transfected or nontransfected tubular cells were treated with 100 μg/mL of AGE-BSA or nonglycated BSA in the presence or absence of 0.3 nmol/L GLP-1 for 4 hours; the cells were then fixed with 4% paraformaldehyde and washed with PBS. The cells were stained with rabbit Ab raised against human ADMA. ADMA was visualized with Alexa Fluor 488 goat anti-rabbit IgG (Molecular Probes). Intensity of ADMA staining in five different fields of each sample was analyzed by microcomputer-assisted ImageJ. Six-week-old male Wistar rats received a single 60-mg/kg i.p. injection of streptozotocin (Sigma) in 10 mmol/L citrate buffer (pH 4.5). Nondiabetic control rats received citrate buffer alone. Animals with blood glucose levels >250 mg/dL 48 hours later were considered diabetic. Streptozotocin-induced diabetic rats received continuous i.p. infusion of vehicle, 0.3 μg/kg/h of exendin-4, or 1.5 μg/kg/h of exendin-4 using an osmotic mini pump (ALZET micro-osmotic pump model 1002; Durect Corporation, Cupertino, CA). After 2 weeks, animals were housed in metabolic cages to collect urine for measurement of urinary excretion levels of albumin and 8-hydroxy-2′-deoxyguanosine (8-OHdG), and then body weight, heart rate, and blood pressure were measured. Albuminuria and urinary excretion level of 8-OHdG were determined with commercially available enzyme-linked immunosorbent assay (ELISA) kits (Exocell, Philadelphia, PA, and NIKKEN SEIL Co. Ltd., Shizuoka, Japan). Then the rats were euthanized and the kidneys were excised for real-time RT-PCR, Western blotting, and morphologic analyses. Blood chemical analyses were performed with standard enzymatic methods as described previously.26Fujimura T. Yamagishi S. Ueda S. Fukami K. Shibata R. Matsumoto Y. Kaida Y. Hayashida A. Koike K. Matsui T. Nakamura K. Okuda S. Administration of pigment epithelium-derived factor (PEDF) reduces proteinuria by suppressing decreased nephrin and increased VEGF expression in the glomeruli of adriamycin-injected rats.Nephrol Dial Transplant. 2009; 24: 1397-1406Crossref PubMed Scopus (35) Google Scholar Identifications of TaqMan primers for rat Rage, intercellular adhesion molecule 1 (Icam-1), monocyte chemoattractant protein 1 (Mcp-1), β-actin, glyceraldehyde-3-phosphate dehydrogenase (GAPDH), and 18S gene were Rn00584249_m1, Rn00564227_m1, Rn00580555_m1, Rn00667869_m1, Rn99999916_s1, and Hs99999901_s1, respectively. RT-qPCR analysis for rat Prmt-1 was performed using SYBR Green reagent (Applied Biosystems) according to the manufacturer recommendation. The forward and reverse primers for rat Prmt-1 were 5′-AACTGAAGCTCGCACTCTCG-3′ and 5′-TCAGCACAGATCTCCTTGGC-3′. ADMA and AGE levels in the kidney were measured with Western blotting analysis using polyclonal Abs raised against ADMA (Active Motif Inc.) and AGEs as described previously.19Takeuchi M. Makita Z. Bucala R. Suzuki T. Koike T. Kameda Y. Immunological evidence that non-carboxymethyllysine advanced glycation end-products are produced from short chain sugars and dicarbonyl compounds in vivo.Mol Med. 2000; 6: 114-125Crossref PubMed Google Scholar, 25Yoshida T. Yamagishi S. Nakamura K. Matsui T. Imaizumi T. Takeuchi M. Koga H. Ueno T. Sata M. Telmisartan inhibits AGE-induced C-reactive protein production through downregulation of the receptor for AGE via peroxisome proliferator-activated receptor-gamma activation.Diabetologia. 2006; 49: 3094-3099Crossref PubMed Scopus (114) Google Scholar All animal procedures were conducted according to the guidelines provided by the Kurume University Institutional Animal Care and Use Committee under an approved protocol. The kidneys were fixed in 4% paraformaldehyde and embedded in paraffin, sectioned at 4-μm intervals, and mounted on glass slides. The sections were stained with H&E and Masson's trichrome for light microscopic analysis. Glomerular area delimited by the internal edge of the Bowman's capsule was measured using ImageJ software. The intensity of Masson's trichrome staining in the glomeruli and tubulointerstitium were quantitatively analyzed by Optimas image analysis software version 6.57 (Media Cybernetics, Silver Spring, MD). The kidney sections were incubated in 0.3% hydrogen peroxide methanol for 30 minutes to block endogenous peroxidase activity and incubated overnight at 4°C with F4/80 Ab directed specially against macrophages (Santa Cruz Biotechnology Inc.). Then the reactions were visualized with an avidin-biotin-alkaline phosphatase kit (Vectastain ABC-AP; Vector Laboratories, Inc., Burlingame, CA). Ten different fields in each sample were chosen, and the number of F4/80+ cells per glomerulus was counted. Unless otherwise indicated, all values were presented as mean ± SE. One-way analysis of variance followed by the Scheffé F test was performed for statistical comparisons; P < 0.05 was considered significant. Engagement of RAGE with AGEs activates its downstream signaling via ROS generation in various types of cells.4Yamamoto Y. Kato I. Doi T. Yonekura H. Ohashi S. Takeuchi M. Watanabe T. Yamagishi S. Sakurai S. Takasawa S. Okamoto H. Yamamoto H. Development and prevention of advanced diabetic nephropathy in RAGE-overexpressing mice.J Clin Invest. 2001; 108: 261-268Crossref PubMed Scopus (446) Google Scholar, 5Wendt T.M. Tanji N. Guo J. Kislinger T.R. Qu W. Lu Y. Bucciarelli L.G. Rong L.L. Moser B. Markowitz G.S. Stein G. Bierhaus A. Liliensiek B. Arnold B. Nawroth P.P. Stern D.M. D'Agati V.D. Schmidt A.M. RAGE drives the development of glomerulosclerosis and implicates podocyte activation in the pathogenesis of diabetic nephropathy.Am J Pathol. 2003; 162: 1123-1137Abstract Full Text Full Text PDF PubMed Scopus (512) Google Scholar, 6Reiniger N. Lau K. McCalla D. Eby B. Cheng B. Lu Y. Qu W. Quadri N. Ananthakrishnan R. Furmansky M. Rosario R. Song F. Rai V. Weinberg A. Friedman R. Ramasamy R. D'Agati V. Schmidt A.M. Deletion of the receptor for advanced glycation end products reduces glomerulosclerosis and preserves renal function in the diabetic OVE26 mouse.Diabetes. 2010; 59: 2043-2054Crossref PubMed Scopus (144) Google Scholar, 7Yamagishi S. Imaizumi T. Diabetic vascular complications: pathophysiology, biochemical basis and potential therapeutic strategy.Curr Pharm Des. 2005; 11: 2279-2299Crossref PubMed Scopus (435) Google Scholar, 8Yamagishi S. Matsui T. Advanced glycation end products, oxidative stress and diabetic nephropathy.Oxid Med Cell Longev. 2010; 3: 101-108Crossref PubMed Scopus (282) Google Scholar Therefore, we first examined the effect of GLP-1 on RAGE gene expression and ROS generation in tubular cells. As shown in Figure 1, A and B, 0.3 nmol/L GLP-1 significantly inhibited the AGE-induced increase in RAGE mRNA levels and superoxide generation in tubular cells. Furthermore, AGEs up-regulated PRMT-1 mRNA levels in tubular cells, which were blocked by the treatment with 0.3 nmol/L GLP-1, neutralizing RAGE-Ab, or an anti-oxidant NAC (Figure 1, C and D). Because of the ambiguity as to the location of GLP-1R in human kidney, we examined whether proximal tubular cells expressed GLP-1R. As shown in Figure 2A, Western blotting analysis revealed a single band with a molecular mass of 56 kDa, corresponding to the GLP-1R seen in tubular cells. We also confirmed that GLP-1R was barely detectable in tubular cells exposed to siRNA molecules specific for human GLP-1R (Figure 2A). We next examined the involvement of GLP-1R in GLP-1 actions on tubular cells. For this, we investigated the effects of siRNAs raised against GLP-1R on RAGE gene expression, superoxide generation, and PRMT-1 mRNA level in tubular cells. Control siRNA did not affect the effects of AGEs on tubular cells; AGEs significantly increased RAGE and PRMT-1 mRNA levels and ROS generation in control siRNA-treated cells (Figure 2, B–D). GLP-1 decreased RAGE gene expression, ROS generation, and PRMT-1 mRNA level in AGEs plus control siRNA-exposed tubular cells, all of which were significantly blocked by the treatment with GLP-1R siRNA transfection (Figure 2, B–D). Because the actions of the GLP-" @default.
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