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

Matsui, Takanori; Higashimoto, Yuichiro; Nishino, Yoshinori; Nakamura, Nobutaka; Fukami, Kei; Yamagishi, Sho‐ichi

doi:10.2337/db16-1281

Cited by 100 publications

(95 citation statements)

References 51 publications

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“…Recently, we reported that a DNA aptamer, a short and single-stranded DNA, directed against RAGE (RAGE aptamer) inhibited the binding of AGE to RAGE and attenuated the development and progression of streptozotocin-induced diabetic nephropathy in rats and deoxycorticosterone acetate/salt-induced renal injury in mice [17, 18]. We examined the inhibitory effects of the RAGE aptamer on PDGF-induced proliferation of PASMCs.…”

Section: Resultsmentioning

confidence: 99%

Crucial role of RAGE in inappropriate increase of smooth muscle cells from patients with pulmonary arterial hypertension

et al. 2018

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BackgroundPulmonary vascular remodeling of pulmonary arterial hypertension (PAH) is characterized by an inappropriate increase of vascular cells. The receptor for advanced glycation end products (RAGE) is a type I single-pass transmembrane protein belonging to the immunoglobulin superfamily and is involved in a broad range of hyperproliferative diseases. RAGE is also implicated in the etiology of PAH and is overexpressed in pulmonary artery smooth muscle cells (PASMCs) in patients with PAH. We examined the role of RAGE in the inappropriate increase of PASMCs in patients with PAH.Methods and resultsPASMCs were obtained from 12 patients with PAH including 9 patients with idiopathic PAH (IPAH) and 3 patients with heritable PAH (HPAH) (2 patients with BMPR2 mutation and one patient with SMAD9 mutation) who underwent lung transplantation. Western blot analysis and immunofluorescence staining revealed that RAGE and S100A8 and A9, ligands of RAGE, were overexpressed in IPAH and HPAH-PASMCs in the absence of any external growth stimulus. PDGF-BB (10 ng/mL) up-regulated the expression of RAGE in IPAH and HPAH-PASMCs. PAH-PASMCs are hyperplastic in the absence of any external growth stimulus as assessed by 3H-thymidine incorporation. This result indicates overgrowth characterized by continued growth under a condition of no growth stimulation in PAH-PASMCs. PDGF-BB stimulation caused a higher growth rate of PAH-PASMCs than that of non-PAH-PASMCs. AS-1, an inhibitor of TIR domain-mediated RAGE signaling, significantly inhibited overgrowth characterized by continued growth under a condition of no growth stimulation in IPAH and HPAH-PASMCs (P<0.0001). Furthermore, AS-1 significantly inhibited PDGF-stimulated proliferation of IPAH and HPAH-PASMCs (P<0.0001).ConclusionsRAGE plays a crucial role in the inappropriate increase of PAH-PASMCs. Inhibition of RAGE signaling may be a new therapeutic strategy for PAH.

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Section: Resultsmentioning

confidence: 99%

Crucial role of RAGE in inappropriate increase of smooth muscle cells from patients with pulmonary arterial hypertension

et al. 2018

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“…104-107 Furthermore, RAGE-aptamers promoted regression of experimental diabetic nephropathy in type 1 diabetic animals, attenuated melanoma growth and metastasis in nude mice, and ameliorated renal injury in hypertensive mice. [108][109][110] These findings suggest that blockade of the AGE-RAGE axis by AGE-or RAGE-aptamers may be a therapeutic target for CVD.…”

Section: Circulating Levels Of Ages and Cvdmentioning

confidence: 90%

Role of Advanced Glycation Endproduct (AGE)-Receptor for Advanced Glycation Endproduct (RAGE) Axis in Cardiovascular Disease and Its Therapeutic Intervention

Yamagishi

2019

Circ J

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Despite the early loss of glycemic differences between the original intensive therapy group and conventional treatment in the DCCT/ EDIC and UKPDS 80 trials, a continued reduction in microvascular risk and risk reductions for emergency myocardial infarction and all-cause death were observed 10-30 years after the end of these trials. These observations demonstrated that so-called "metabolic memory" could cause chronic abnormalities in diabetic vessels that are not easily reversed, even by subsequent improvement in blood glucose levels, thus suggesting a long-term beneficial influence of early metabolic control; that is, legacy effects on the risk of vascular complications and death in patients with both type 1 and type 2 diabetes. Formation and accumulation of advanced glycation endproducts (AGEs) are known to progress at an accelerated rate under diabetes. Furthermore, AGEs are hardly degraded and remain for a long time in diabetic vessels even after glycemic control is improved. Therefore, AGEs could explain why former cumulative diabetic exposure could contribute to current progression of vascular complications in diabetes. Here, the clinical utility of measurement of serum and tissue accumulation levels of AGEs for evaluating the prevalence and severity of numerous types of cardiovascular disease is reviewed and novel therapeutic strategies that could target the AGE-RAGE axis in CVD are discussed.

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“…Moreover, these phenotypes were prevented by the administration of an AGE inhibitor, indicating that the AGE-RAGE signal is an effective target for overcoming DKD. Other studies have evaluated the effects of the specific inhibition of RAGE with DNA aptamer and demonstrated that RAGE-aptamer attenuates the development of experimental DKD by inhibiting oxidative stress [33,34].…”

Section: The Age-rage Pathwaymentioning

confidence: 99%

Targeting Redox Imbalance as an Approach for Diabetic Kidney Disease

et al. 2020

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Diabetic kidney disease (DKD) is a worldwide public health problem. It is the leading cause of end-stage renal disease and is associated with increased mortality from cardiovascular complications. The tight interactions between redox imbalance and the development of DKD are becoming increasingly evident. Numerous cascades, including the polyol and hexosamine pathways have been implicated in the oxidative stress of diabetes patients. However, the precise molecular mechanism by which oxidative stress affects the progression of DKD remains to be elucidated. Given the limited therapeutic options for DKD, it is essential to understand how oxidants and antioxidants are controlled in diabetes and how oxidative stress impacts the progression of renal damage. This review aims to provide an overview of the current status of knowledge regarding the pathological roles of oxidative stress in DKD. Finally, we summarize recent therapeutic approaches to preventing DKD with a focus on the anti-oxidative effects of newly developed anti-hyperglycemic agents.

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

Cited by 100 publications

References 51 publications

Crucial role of RAGE in inappropriate increase of smooth muscle cells from patients with pulmonary arterial hypertension

Crucial role of RAGE in inappropriate increase of smooth muscle cells from patients with pulmonary arterial hypertension

Role of Advanced Glycation Endproduct (AGE)-Receptor for Advanced Glycation Endproduct (RAGE) Axis in Cardiovascular Disease and Its Therapeutic Intervention

Targeting Redox Imbalance as an Approach for Diabetic Kidney Disease

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