Date Published: February 22, 2019
Publisher: John Wiley and Sons Inc.
Author(s): Thibault Teissier, Valentine Quersin, Viviane Gnemmi, Maité Daroux, Mike Howsam, Florian Delguste, Cécile Lemoine, Chantal Fradin, Ann‐Marie Schmidt, Christelle Cauffiez, Thierry Brousseau, François Glowacki, Frédéric J. Tessier, Eric Boulanger, Marie Frimat.
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/gfood) 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.
Kidney function declines with age (Bolignano, Mattace‐Raso, Sijbrands, & Zoccali, 2014; Glassock, Warnock, & Delanaye, 2017), resulting in elderly people being particularly susceptible to developing chronic kidney disease (CKD). The prevalence of CKD—defined as a glomerular filtration rate (GFR) inferior to 60 ml/min/1.73 m2—was thus more than 30% in a European cohort of patients over 70 years old (Ebert et al., 2016; Glassock et al., 2017). Nonspecific morphologic changes are associated with aging kidneys and designated by the generic term “nephrosclerosis.” Histologically, this is characterized by nephron loss, global glomerulosclerosis (GS > 10%), arteriosclerosis, tubular atrophy, and interstitial fibrosis (>5%) (Denic, Glassock, & Rule, 2016; O’Sullivan, Hughes, & Ferenbach, 2017).
Although the small sample sizes necessitate caution in interpreting our results, we here report that RAGE knockout mice developed significantly less nephrosclerosis and senile amyloid lesions than WT mice, suggesting a key role for this receptor in the renal aging process. Prolonged exposure to a CML‐enriched diet was associated with CML accumulation in kidneys, but there was no evident relationship between these deposits and renal injuries; CML accumulation was RAGE‐independent and thus could not explain the differences between WT and RAGE−/− mice in kidney function/structure. We found lower levels of inflammation and oxidative stress in RAGE−/− mice, which may contribute to our proposed protective effect of RAGE invalidation through modulation of SIRT1 expression and the AKT/mTOR pathway.
The authors declare no conflict of interest.
Study design: MF and EB. Provided RAGE‐KO mice: AMS. Performed research: TT, VQ, MD, MH, FD, CL and TB. Histological data analyses: VQ, VG and MF. Statistical analyses: TT and FG. MH provided English proofreading assistance. All authors discussed the data and approved the submission.