title: RAGE-Aptamer Blocks the Development and Progression of Experimental Diabetic Nephropathy.
abstract: The interaction of advanced glycation end products (AGEs) and their receptor (RAGE) plays a central role in diabetic nephropathy. We screened DNA aptamers directed against RAGE (RAGE-aptamers) in vitro and examined the effects on the development and progression of diabetic nephropathy in streptozotocin-induced diabetic rats. RAGE-aptamer bound to RAGE with aKdof 5.68 nmol/L and resultantly blocked the binding of AGEs to RAGE. When diabetic rats received continuous intraperitoneal injection of RAGE-aptamer from week 7 to 11 of diabetes, the increases in renal NADPH oxidase activity, oxidative stress generation, AGE, RAGE, inflammatory and fibrotic gene and protein levels, macrophage and extracellular matrix accumulation, and albuminuria were significantly suppressed, which were associated with improvement of podocyte damage. Two-week infusion of RAGE-aptamer just after the induction of diabetes also inhibited the AGE-RAGE-oxidative stress system and MCP-1 levels in the kidneys of 8-week-old diabetic rats and simultaneously ameliorated podocyte injury and albuminuria. Moreover, RAGE-aptamer significantly suppressed the AGE-induced oxidative stress generation and inflammatory and fibrotic reactions in human cultured mesangial cells. The findings suggest that continuous infusion of RAGE-aptamer could attenuate the development and progression of experimental diabetic nephropathy by blocking the AGE-RAGE axis.
authors.affiliation: Department of Pathophysiology and Therapeutics of Diabetic Vascular Complications, Kurume University School of Medicine, Kurume, Japan.
authors.forename: Takanori
authors.initials: T
authors.lastname: Matsui
authors.affiliation: Department of Chemistry, Kurume University School of Medicine, Kurume, Japan.
authors.forename: Yuichiro
authors.initials: Y
authors.lastname: Higashimoto
authors.affiliation: Department of Pathophysiology and Therapeutics of Diabetic Vascular Complications, Kurume University School of Medicine, Kurume, Japan.
authors.forename: Yuri
authors.initials: Y
authors.lastname: Nishino
authors.affiliation: Department of Pathophysiology and Therapeutics of Diabetic Vascular Complications, Kurume University School of Medicine, Kurume, Japan.
authors.forename: Nobutaka
authors.initials: N
authors.lastname: Nakamura
authors.affiliation: Division of Nephrology, Department of Medicine, Kurume University School of Medicine, Kurume, Japan.
authors.forename: Kei
authors.initials: K
authors.lastname: Fukami
authors.affiliation: Department of Pathophysiology and Therapeutics of Diabetic Vascular Complications, Kurume University School of Medicine, Kurume, Japan shoichi@med.kurume-u.ac.jp.
authors.forename: Sho-Ichi
authors.initials: SI
authors.lastname: Yamagishi
mesh_terms: D000419:Albuminuria; D000818:Animals; D052157:Aptamers, Nucleotide / Q000494:pharmacology*; D018932:Chemokine CCL2 / Q000187:drug effects / Q000235:genetics; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism*; D003928:Diabetic Nephropathies / Q000378:metabolism*; D004797:Enzyme-Linked Immunosorbent Assay; D005355:Fibrosis / Q000235:genetics; D005786:Gene Expression Regulation / Q000187:drug effects; D017127:Glycation End Products, Advanced / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000235:genetics; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D050527:Mesangial Cells / Q000187:drug effects* / Q000473:pathology; D019255:NADPH Oxidases / Q000187:drug effects / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D050199:Podocytes / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D060888:Real-Time Polymerase Chain Reaction; D000067759:Receptor for Advanced Glycation End Products / Q000037:antagonists & inhibitors* / Q000187:drug effects / Q000235:genetics / Q000378:metabolism
chemical_list: D052157:Aptamers, Nucleotide; C491766:Ccl2 protein, rat; D018932:Chemokine CCL2; D017127:Glycation End Products, Advanced; D000067759:Receptor for Advanced Glycation End Products; D019255:NADPH Oxidases