Matsui Takanori, Sotokawauchi Ami, Nishino Yuri, Koga Yoshinori, Yamagishi Sho-Ichi
Department of Bioscience and Biotechnology, Fukui Prefectural University, Eiheiji, 910-1195, Japan.
Department of Pediatric Surgery, Kurume University School of Medicine, Kurume, 830-0011, Japan.
Mol Med. 2025 Mar 6;31(1):88. doi: 10.1186/s10020-025-01138-0.
Although randomized clinical trials revealed that inhibitors of sodium-glucose cotransporter 2 (SGLT2) reduced the risk of cardiovascular and renal events in patients with type 2 diabetes, the underlying molecular mechanisms remain to be elucidated. Since there is accumulating evidence that AGEs and their receptor (RAGE) play a crucial role in diabetes-related complications, we examined here whether empagliflozin ameliorates renal and metabolic derangements in db/db mice, an obese type 2 diabetes animal by blocking the AGE-RAGE axis.
Eight-week-old db/db mice were fed a 0.045% empagliflozin diet (db/db + Empa) or normal diet (db/db) for 13 weeks. The same week-old db/ + m mice were maintained on normal diet (db/ + m) used as a control. At baseline and 13 weeks after intervention, biochemical analyses in the serum and urine were performed, and kidneys and adipose tissues were obtained for morphological, immunohistochemical, and reverse transcription-polymerase chain reaction analyses.
Empagliflozin treatment for 13 weeks significantly reduced AGEs, N-(5-hydro-5-methyl-4-imidazolon-2-yl)-ornithine (MG-H1), RAGE, NADPH oxidase-derived oxidative stress, inflammatory and fibrotic reactions in the kidneys of db/db mice of 21-week-old in association with attenuation of glomerular extracellular matrix accumulation, podocyte loss, proteinuria, and tubulointerstitial damage. Empagliflozin also reduced the AGE-RAGE-oxidative stress-induced inflammatory reactions in the adipose tissues of db/db mice, which was associated with restoration of adiponectin levels and decreased insulin resistance. Serum MG-H1 levels of control and db/db mice at 21 weeks of age were significantly associated with proteinuria, tubulointerstitial damage, tissue AGEs levels, and serum monocyte chemoattractant protein-1 and adiponectin (inversely) values.
Our present findings suggest that empagliflozin could ameliorate renal and metabolic derangements in type 2 diabetes animals by attenuating the AGE-RAGE axis.
尽管随机临床试验表明，钠-葡萄糖协同转运蛋白2（SGLT2）抑制剂可降低2型糖尿病患者发生心血管和肾脏事件的风险，但其潜在分子机制仍有待阐明。鉴于越来越多的证据表明晚期糖基化终末产物（AGEs）及其受体（RAGE）在糖尿病相关并发症中起关键作用，我们在此研究了恩格列净是否通过阻断AGE-RAGE轴来改善db/db小鼠（一种肥胖的2型糖尿病动物模型）的肾脏和代谢紊乱。
8周龄的db/db小鼠分别给予0.045%恩格列净饮食（db/db + Empa）或正常饮食（db/db），持续13周。同周龄的db/+m小鼠维持正常饮食（db/+m）作为对照。在基线和干预13周后，进行血清和尿液的生化分析，并获取肾脏和脂肪组织进行形态学、免疫组织化学及逆转录-聚合酶链反应分析。
恩格列净治疗13周可显著降低21周龄db/db小鼠肾脏中的AGEs、N-（5-羟-5-甲基-4-咪唑啉-2-基）-鸟氨酸（MG-H1）、RAGE、烟酰胺腺嘌呤二核苷酸磷酸（NADPH）氧化酶衍生的氧化应激、炎症和纤维化反应，同时减轻肾小球细胞外基质积聚、足细胞丢失、蛋白尿和肾小管间质损伤。恩格列净还可减轻db/db小鼠脂肪组织中AGE-RAGE-氧化应激诱导的炎症反应，这与脂联素水平的恢复及胰岛素抵抗的降低有关。21周龄对照小鼠和db/db小鼠的血清MG-H1水平与蛋白尿、肾小管间质损伤、组织AGEs水平以及血清单核细胞趋化蛋白-1和脂联素（呈负相关）值显著相关。
我们目前的研究结果表明，恩格列净可通过减弱AGE-RAGE轴来改善2型糖尿病动物模型的肾脏和代谢紊乱。
