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RAGE-Aptamer Blocks the Development and Progression of Experimental Diabetic Nephropathy

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RAGE-Aptamer Blocks the Development and Progression of Experimental Diabetic Nephropathy Diabetes Volume 66, June 2017 1683 RAGE-Aptamer Blocks the Development and Progression of Experimental Diabetic Nephropathy Takanori Matsui,1 Yuichiro Higashimoto,2 Yuri Nishino,1 Nobutaka Nakamura,1 Kei Fukami,3 and Sho-ichi Yamagishi1 Diabetes 2017;66:1683–1695 | https://doi.org/10.2337/db16-1281 The interaction of advanced glycation end products both of which could account for the high mortality rate in (AGEs) and their receptor (RAGE) plays a central role patients with diabetes (2). in diabetic nephropathy. We screened DNA aptamers Over a course of days to weeks, reducing sugars can react directed against RAGE (RAGE-aptamers) in vitro and nonenzymatically with the amino groups of proteins and examined the effects on the development and progres- lipids to initiate a complex series of rearrangement, de- sion of diabetic nephropathy in streptozotocin-induced hydration, and condensation and then to form a class of K diabetic rats. RAGE-aptamer bound to RAGE with a d of irreversibly cross-linked adducts called advanced glycation 5.68 nmol/L and resultantly blocked the binding of AGEs end products (AGEs) (3,4). The formation and accumulation COMPLICATIONS to RAGE. When diabetic rats received continuous intra- of AGEs in various tissues progress under diabetic condi- peritoneal injection of RAGE-aptamer from week 7 to tions (3,4). Interaction of AGEs with the receptor for AGEs 11 of diabetes, the increases in renal NADPH oxidase ac- (RAGE) generates oxidative stress and stimulates inflamma- tivity, oxidative stress generation, AGE, RAGE, inflamma- tory and fibrotic reactions, which could contribute to progres- tory and fibrotic gene and protein levels, macrophage and sive alteration in renal architecture and impairment of renal extracellular matrix accumulation, and albuminuria were – significantly suppressed, which were associated with im- function in diabetes (5 8). Moreover, RAGE-overexpressing provement of podocyte damage. Two-week infusion of diabetic mice exhibit progressive glomerulosclerosis with RAGE-aptamer just after the induction of diabetes also renal dysfunction, whereas homozygous RAGE knockout inhibited the AGE-RAGE-oxidative stress system and diabetic mice show reduced mesangial matrix expansion MCP-1 levels in the kidneys of 8-week-old diabetic rats and glomerular basement membrane thickening and sclero- and simultaneously ameliorated podocyte injury and albu- sis with preserved renal function (9–11). These findings minuria. Moreover, RAGE-aptamer significantly suppressed suggest that suppression of the AGE-RAGE axis in the kid- the AGE-induced oxidative stress generation and inflam- ney may be a therapeutic target for diabetic nephropathy. matory and fibrotic reactions in human cultured mesangial Indeed, inhibitors of AGE formation, as well as blockade of cells. The findings suggest that continuous infusion of the interaction of AGEs with RAGE by an exogenously ad- RAGE-aptamer could attenuate the development and pro- ministered soluble form of RAGE, attenuate the development gression of experimental diabetic nephropathy by blocking and progression of experimental diabetic nephropathy the AGE-RAGE axis. (11–14). Long-term treatment with neutralizing RAGE antibodies reduces urinary albumin excretion (UAE) and increases creatinine clearance in both type 1 and type Diabetes has been an increasing global health challenge (1). 2 diabetic mice (15,16). However, randomized, double- Among various complications, diabetic nephropathy is the blind, placebo-controlled trials have revealed that AGE for- most common cause of end-stage renal disease and often is mation inhibitors, such as aminoguanidine and vitamin B6, associated with an increased risk for cardiovascular disease, do not significantly prevent the progression of diabetic 1Department of Pathophysiology and Therapeutics of Diabetic Vascular Compli- Received 21 October 2016 and accepted 24 March 2017. cations, Kurume University School of Medicine, Kurume, Japan © 2017 by the American Diabetes Association. Readers may use this article as 2 Department of Chemistry, Kurume University School of Medicine, Kurume, long as the work is properly cited, the use is educational and not for profit, and the Japan work is not altered. More information is available at http://www.diabetesjournals 3 Division of Nephrology, Department of Medicine, Kurume University School of .org/content/license. Medicine, Kurume, Japan Corresponding author: Sho-ichi Yamagishi, [email protected]. 1684 RAGE-Aptamer Against Diabetic Nephropathy Diabetes Volume 66, June 2017 nephropathy (17,18). Therefore, to develop a novel thera- with 1 mg AGEs overnight were incubated with the re- peutic strategy that specifically targets RAGE rather than action mixtures for 1 h and then with anti-RAGE poly- AGEs is desired. clonal antibody (Santa Cruz Biotechnology, Dallas, TX). Aptamers are short, single-stranded DNA or RNA oligo- After 1 h, horseradish peroxidase–conjugated anti-rabbit nucleotides that are selected against various kinds of target IgG and 3,39,5,59-tetramethylbenzidine were added to the proteins by systematic evolution of ligands by exponential wells, and absorbance at 450 nm was measured. enrichment (SELEX) (19,20). Aptamers can take a three- dimensional structure in which conformation recognizes their Quartz Crystal Microbalance Binding Assay cognate targets with high affinity and specificity (19,20). The binding affinities of control-aptamer, RAGE-aptamer, The wide range of sequences and three-dimensional folding or AGE-BSA to vRAGE were measured by using a sensitive patterns of oligonucleotides allow aptamers to function like 27-MHz quartz crystal microbalance (QCM) binding assay antibodies; therefore, aptamers are termed chemical anti- (Initium Inc., Kanagawa, Japan) as described previously (26). bodies (19,20). Pegaptanib (Macugen) was the first U.S. Food Animals and Drug Administration–approved RNA aptamer directed against the vascular endothelial growth factor 165 isoform Male 6-week-old Wistar rats (Charles River Laboratories for the treatment of wet-type age-related macular degener- Japan) were used. Rats received single intraperitoneal ation (21). ARC1779 and NU172, DNA-aptamers raised injection of streptozotocin (60 mg/kg body weight) in 10 mmol/L citrate buffer (pH 4.5). Animals with blood against the A1 domain of von Willebrand factor and exosite . Iofa-thrombin, currently are undergoing phase II clinical glucose levels 200 mg/dL 48 h later were considered di- trials (22,23). Because aptamers are potentially used as an- abetic. One unit bovine insulin (two times per week) was tagonists and agonists of target proteins (20), we screened subcutaneously injected into diabetic rats to maintain life, high-affinity DNA aptamers directed against RAGE (RAGE- butitwasnotenoughtoconsistentlyreducebloodglucose aptamers) by using SELEX in vitro, characterized the bind- levels. Nondiabetic control rats received citrate buffer alone. ing affinity to and antagonistic activity for RAGE, and Experiment 1 investigated whether continuous infusion of RAGE-aptamer At 7 weeks after the injection of streptozotocin or vehicle, could reverse as well as prevent the development of diabetic from 9 control and 12 diabetic rats, 4 each were transferred nephropathy in streptozotocin-induced diabetic rats. More- to metabolic cages for urinalysis. After 24 h, the rats were over, we examined the effects ofRAGE-aptameronreactive killed, and blood and kidneys were obtained for NADPH fl fi oxygen species (ROS) generation and in ammatory and - oxidase activity assay, real-time RT-PCR, and biochemical, brotic reactions in AGE-exposed mesangial cells. immunohistochemical, and morphological analyses. The remaining five control and eight diabetic rats received RESEARCH DESIGN AND METHODS continuous intraperitoneal infusion (2 pmol/day/g body Materials weight) of either control-aptamer or RAGE-aptamer by an BSA, D-glyceraldehyde, streptozotocin, and bovine insulin osmotic minipump (Durect Co., Cupertino, CA). After were purchased from Sigma-Aldrich (St. Louis, MO). another 4 weeks, blood and kidneys were obtained for the above-mentioned analyses. At 7 and 11 weeks after the Preparation of AGEs injection of streptozotocin or vehicle, blood pressures were BSA (25 mg/mL) was incubated under sterile conditions measured by a tail-cuff sphygmomanometer by using an with 0.1 mol/L D-glyceraldehyde at 37°C for 7 days (24). automated system with a photoelectric sensor. Control nonglycated BSA was incubated in the same condi- tions except for the absence of D-glyceraldehyde. Experiment 2 Immobilizing AGE-Binding V-Domain of RAGE Two days after the injection of streptozotocin or vehicle, on Agarose Beads four control and four diabetic rats were killed. The HumanV-domainofRAGE(vRAGE)(residues23–121) car- remaining 8 control and 12 diabetic rats received contin- rying a C-terminal hexahistidine tag sequence (Novagen, uous intraperitoneal infusion (0.5 pmol/day/g body weight) Darmstadt, Germany) was amplified by PCR. vRAGE was of either control-aptamer or RAGE-aptamer by an osmotic coupled to a Ni Sepharose 6 Fast Flow bead matrix (GE minipump. After 2 weeks, rats were killed, and blood and Healthcare, Buckinghamshire, U.K.). kidneys were obtained for analyses. Albuminuria was measured with a commercially available Preparation and Selection of RAGE-Aptamer ELISA kit (Shibayagi, Shibukawa, Japan). Serum and urinary A random combinatorial single-stranded DNA library with 8-hydroxy-29-deoxyguanosine (8-OHdG) levels were mea- normal phosphate ester backbone
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