DNA aptamer raised against receptor for advanced glycation end products suppresses renal tubular damage and improves insulin resistance in diabetic mice

Abstract

Objective: Interaction of advanced glycation end products (AGEs) with the receptor RAGE plays a role in diabetic nephropathy. However, effects of RAGE-aptamer on tubular damage remain unknown. We examined whether RAGE-aptamer inhibited tubular damage in KKAy/Ta mice, obese type 2 diabetic mice with insulin resistance. Materials and Methods: Male 8-week-old KKAy/Ta mice received continuous intraperitoneal infusion of either control-aptamer or RAGE-aptamer for 8 weeks. Blood biochemistry and blood pressure, and urinary N-acetyl-β-D-glucosaminidase (NAG) activity and albumin excretion levels were monitored. Kidney and adipose tissue samples were obtained for immunohistochemical analyses. Results: Although RAGE-aptamer did not affect blood glucose, blood pressure, body weight, or serum creatinine values, it significantly inhibited the increase in urinary NAG activity and HOMA-IR in diabetic mice at 12 and 16 and at 16 weeks old, respectively. Furthermore, compared with control-aptamer-treated mice, renal carboxymethyllysine, RAGE, and NADPH oxidase-driven superoxide generation were significantly decreased in RAGE-aptamer-treated mice at 12 weeks old with subsequent amelioration of histological alterations in glomerular and interstitial area, while adipose tissue adiponectin expression was increased. Conclusion: Our present results suggest that RAGE-aptamer could inhibit tubular injury in obese type 2 diabetic mice partly by suppressing the AGE-RAGE-oxidative stress axis and improving insulin resistance.

Structures of Toxic Advanced Glycation End-Products Derived from Glyceraldehyde, A Sugar Metabolite

“…Yamagishi's group recently reported that RAGE-aptamer significantly inhibited the binding of AGEs, senescent macroprotein derivatives formed at an accelerated rate under DM, to RAGE, and, as a result, the onset/progression of diabetic nephropathy, melanoma growth and metastasis, and renal injury were attenuated in animal models of chronic kidney disease [99][100][101][102][103].…”

The RAGE/DIAPH1 Signaling Axis & Implications for the Pathogenesis of Diabetic Complications

“…In that work, although RAGE expression was largely pinpointed in podocytes, expression of the receptor was noted in non-podocytes as well, such as in endothelial cells [66]. For the past two decades, multiple studies using gain-of-function genetic approaches [67], loss-of-function genetic approaches [68][69][70] and pharmacological approaches, such as sRAGE, anti-RAGE antibodies, DNA aptamers against AGEs or RAGE, and low-molecular weight heparin [68,69,[71][72][73][74] were employed to illustrate roles for RAGE in murine models of type 1 and type 2 diabetic kidney disease (DKD). Interestingly, in a murine model of type 1 DKD using streptozotocin, roles for bone marrow-derived RAGE in the recruitment of immune cells and tubulointerstitial disease were illustrated [75].…”