Knockout of receptor for advanced glycation end‐products attenuates age‐related renal lesions

Abstract

Pro-aging effects of endogenous advanced glycation end-products (AGEs) have been reported, and there is increasing interest in the pro-inflammatory and -fibrotic effects of their binding to RAGE (the main AGE receptor). The role of dietary AGEs in aging remains ill-defined, but the predominantly renal accumulation of dietary carboxymethyllysine (CML) suggests the kidneys may be particularly affected. We studied the impact of RAGE invalidation and a CML-enriched diet on renal aging. Two-month-old male, wild-type (WT) and RAGE^-/- C57Bl/6 mice were fed a control or a CML-enriched diet (200 μg CML/g_food ) for 18 months. Compared to controls, we observed higher CML levels in the kidneys of both CML WT and CML RAGE^-/- mice, with a predominantly tubular localization. The CML-rich diet had no significant impact on the studied renal parameters, whereby only a trend to worsening glomerular sclerosis was detected. Irrespective of diet, RAGE^-/- mice were significantly protected against nephrosclerosis lesions (hyalinosis, tubular atrophy, fibrosis and glomerular sclerosis) and renal senile apolipoprotein A-II (ApoA-II) amyloidosis (p < 0.001). A positive linear correlation between sclerosis score and ApoA-II amyloidosis score (r = 0.92) was observed. Compared with old WT mice, old RAGE^-/- mice exhibited lower expression of inflammation markers and activation of AKT, and greater expression of Sod2 and SIRT1. Overall, nephrosclerosis lesions and senile amyloidosis were significantly reduced in RAGE^-/- mice, indicating a protective effect of RAGE deletion with respect to renal aging. This could be due to reduced inflammation and oxidative stress in RAGE^-/- mice, suggesting RAGE is an important receptor in so-called inflamm-aging.