目的:晚期糖基化终产物(AGEs)与年龄相关的肾功能下降有关,条件加剧,如高血糖和氧化应激。AGEs在肾脏中的积累有助于随着衰老观察到的肾功能的进行性下降。然而,AGEs在年龄相关性肾功能下降中的确切作用和机制尚不清楚.在这项研究中,我们研究了AGEs对自然衰老小鼠肾脏衰老的影响和潜在机制.
方法:雄性C57BL/6小鼠分为三组:6-,57-,107周龄.首先,对6周龄和107周龄的小鼠实施安乐死。将剩余的小鼠分成年轻(6周)和年老(57周)组。57周龄小鼠口服氨基胍(100mg/kg/天),AGEs抑制剂,或车辆13周,最终年龄为70周。收集血清和肾组织进行生化测定,组织学检查,免疫组织化学染色,和免疫印迹分析。
结果:我们的发现揭示了血清和肾脏组织标本中AGEs的显著积累和自然衰老小鼠的肾功能障碍。氨基胍不仅可以逆转AGEs的积累,而且可以改善肾功能障碍。此外,氨基胍减弱纤维化标志物的上调(磷酸化p38/α-SMA和C/EBP同源蛋白,CHOP),衰老标记(p53和p21),和衰老肾脏中的氧化应激标志物(4-HNE)。
结论:这些发现强调了AGEs在年龄相关性肾功能不全中的关键作用,并强调了氨基胍在减轻纤维化和衰老方面的治疗潜力。为对抗与年龄相关的肾脏疾病提供了潜在的途径。
OBJECTIVE: Advanced glycation end-products (AGEs) are implicated in the age-related decline of renal function, exacerbated by conditions, such as hyperglycemia and oxidative stress. The accumulation of AGEs in the kidneys contributes to the progressive decline in renal function observed with aging. However, the precise role and mechanisms of AGEs in the age-related decline of renal function remain unclear. In this study, we investigated the impact and potential mechanisms of AGEs on aging kidneys in naturally aging mice.
METHODS: Male C57BL/6 mice were divided into three groups: 6-, 57-, and 107-week-old. First, the 6- and 107-week-old mice were euthanized. The remaining mice were divided into young (6 weeks) and old (57 weeks) groups. The 57-week-old mice were orally administered aminoguanidine (100 mg/kg/day), an AGEs inhibitor, or vehicle for 13 weeks, resulting in a final age of 70 weeks. The serum and kidney tissues were collected for biochemical measurement, histological examination, immunohistochemistry staining, and immunoblotting analysis.
RESULTS: Our findings revealed a notable accumulation of AGEs in both serum and kidney tissue specimens and renal dysfunction in naturally aging mice. Aminoguanidine not only reversed AGEs accumulation but also ameliorated renal dysfunction. Additionally, aminoguanidine attenuated the upregulation of fibrosis markers (phosphorylated p38/α-SMA and C/EBP homologous protein, CHOP), senescence markers (p53 and p21), and oxidative stress marker (4-HNE) in the aging kidneys.
CONCLUSIONS: These findings underscore the critical role of AGEs in age-related renal dysfunction and highlight the therapeutic potential of aminoguanidine in mitigating fibrosis and senescence, offering prospective avenues for combating age-associated renal ailments.