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Vaccination Against Receptor for Advanced Glycation End Products Attenuates the Progression of Diabetic Kidney Disease

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posted on 21.06.2021, 18:24 by Tatsuhiko Azegami, Takashin Nakayama, Kaori Hayashi, Akihito Hishikawa, Norifumi Yoshimoto, Ran Nakamichi, Hiroshi Itoh
Effective treatment of diabetic kidney disease (DKD) remains a large unmet medical need. Within the disease’s complicated pathogenic mechanism, activation of the advanced glycation end-products (AGEs)–receptor for AGEs (RAGE) axis plays a pivotal role in the development and progression of DKD. To provide a new therapeutic strategy against DKD progression, we developed a vaccine against RAGE. Three rounds of immunization of mice with the RAGE vaccine successfully induced antigen-specific serum IgG antibody titers, and elevated antibody titers were sustained for at least 38 weeks. In addition, RAGE vaccination significantly attenuated the increase in urinary albumin excretion in streptozotocin-induced diabetic mice (type 1 diabetes model) and leptin-receptor–deficient db/db mice (type 2 diabetes model). In microscopic analyses, RAGE vaccination suppressed glomerular hypertrophy and mesangial expansion in both diabetic models and significantly reduced glomerular basement membrane thickness in streptozotocin-induced diabetic mice. Results of an in vitro study indicated that the serum IgG antibody elicited by RAGE vaccination suppressed the expression of AGE-induced vascular cell adhesion molecule 1 and intracellular adhesion molecule 1 in endothelial cells. Thus, our newly developed RAGE vaccine attenuated the progression of DKD in mice and is a promising potential therapeutic strategy for patients with DKD.

Funding

This work was supported by JSPS KAKENHI grant number JP18K16006, Takeda Science Foundation, Novartis Research Grants, and the Japan Foundation for Applied Enzymes (to T.A.).

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