Department of Pediatrics, College of Medicine, National Taiwan University & Hospital, Taipei 100, Taiwan.
Graduate Institute of Toxicology, College of Medicine, National Taiwan University, Taipei, Taiwan.
Life Sci. 2024 Oct 1;354:122984. doi: 10.1016/j.lfs.2024.122984. Epub 2024 Aug 14.
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.
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.
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.
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.
晚期糖基化终产物（AGEs）与肾功能的年龄相关性下降有关，高血糖和氧化应激等情况会使其恶化。AGEs 在肾脏中的积累导致随着年龄的增长观察到肾功能逐渐下降。然而，AGEs 在肾功能与年龄相关的下降中的确切作用和机制仍不清楚。在这项研究中，我们研究了 AGEs 对自然衰老小鼠肾脏的影响及其潜在机制。
雄性 C57BL/6 小鼠分为三组：6 周、57 周和 107 周龄。首先，处死 6 周和 107 周龄的小鼠。其余的小鼠分为年轻（6 周）和年老（57 周）组。57 周龄的小鼠每天口服氨基胍（100mg/kg），一种 AGEs 抑制剂，或给予载体 13 周，最终年龄为 70 周。收集血清和肾脏组织进行生化测定、组织学检查、免疫组化染色和免疫印迹分析。
我们的研究结果显示，自然衰老小鼠的血清和肾脏组织标本中 AGEs 明显积累，且存在肾功能障碍。氨基胍不仅逆转了 AGEs 的积累，还改善了肾功能障碍。此外，氨基胍还减弱了衰老肾脏中纤维化标志物（磷酸化 p38/α-SMA 和 C/EBP 同源蛋白，CHOP）、衰老标志物（p53 和 p21）和氧化应激标志物（4-HNE）的上调。
这些发现强调了 AGEs 在与年龄相关的肾功能障碍中的关键作用，并突出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有前景的途径。
