CML通过RAGE/AMPK介导脂自噬损伤加重糖尿病小鼠肾脏脂毒性机制

Abstract

Dietary advanced glycation end products (AGEs) accumulate in the kidney and have been implicated in the progression of diabetic kidney disease (DKD), yet their direct renal toxicity remains unclear. This study aimed to investigate the renal toxic effects of Nε-(carboxymethyl)-L-lysine (CML), a representative dietary AGEs, and the potential protective effect of cyanidin-3-O-glucoside (C3G). CML administration (0.5, 1, and 2 mg/kg/day for 12 weeks) dose-dependently aggravated renal injury in diabetic mice, as evidenced by increased urinary protein excretion and histopathological damage. Moreover, dose-dependent tubular lipid accumulation was observed in CML-treated diabetic mice, and similar changes were observed in vitro in human renal tubular epithelial (HK-2) cells exposed to high glucose and palmitic acid. Mechanistically, CML increased RAGE expression and suppressed AMPK phosphorylation, accompanied by impaired lipophagy-related changes, as indicated by a decreased LC3-II/LC3-I ratio and increased p62 accumulation. Inhibition of RAGE or activation of AMPK improved lipophagy-related markers and reduced lipid accumulation, supporting the involvement of the RAGE/AMPK axis. Additionally, C3G partially attenuated these changes. Collectively, these findings suggest that dietary-derived CML aggravates diabetic kidney injury through RAGE/AMPK-mediated lipophagy impairment.