Department of Internal Medicine, Division of Nephrology, Korea University, Ansan, Republic of Korea.
Department of Internal Medicine, Inje University, Ilsan-Paik Hospital, Goyang, Republic of Korea.
Gerontology. 2023;69(7):852-865. doi: 10.1159/000529392. Epub 2023 Jan 28.
Aging of the kidney is associated with complex molecular, histological, and functional changes. Although the aging process itself does not induce renal damage, underlying disease such as diabetes mellitus can aggravate kidney injury during aging. Although oxidative stress is considered an important mediator in age-related renal fibrosis, it is unclear how oxidative stress increases during normal and diabetic aging.
In this study, we investigated molecular changes in the kidney in normal and diabetic aging mice. C57BL/6 mice were studied at 2, 12, and 24 months of age, and leptin receptor-deficient db/db mice were studied at 8, 12, 16, 20, 24, and 38 weeks of age. We measured renal functional parameters, fibrotic and inflammatory markers, and oxidative stress markers at all the above time points.
Both nondiabetic and diabetic mice exhibited progressive microalbuminuria during their lifespan. Interestingly, both diabetic aging and normal aging mice showed progressive increases in oxidative stress markers such as plasma and urinary 8-isoprostane, as well as renal lipid hydroperoxide content. In renal tissues, proinflammatory and profibrotic molecules were significantly upregulated in an age-dependent manner. Expression of three NADPH oxidase (Nox) isoforms, namely, Nox1, Nox2, and Nox4, was significantly increased during aging. Compared with normal aging mice, diabetic db/db mice demonstrated more dramatic changes during aging process.
Our findings suggest that NADPH oxidases play an important role in the aging kidney under both normal and diabetic conditions. Targeting of these oxidases might be a new promising therapy to treat issues associated with aging kidneys.
肾脏的衰老与复杂的分子、组织学和功能变化有关。尽管衰老过程本身不会引起肾脏损伤，但糖尿病等潜在疾病会在衰老过程中加重肾脏损伤。虽然氧化应激被认为是与年龄相关的肾纤维化的重要介质，但目前尚不清楚在正常和糖尿病衰老过程中氧化应激是如何增加的。
在这项研究中，我们研究了正常和糖尿病衰老小鼠肾脏中的分子变化。C57BL/6 小鼠分别在 2、12 和 24 个月时进行研究，瘦素受体缺失型 db/db 小鼠分别在 8、12、16、20、24 和 38 周龄时进行研究。我们在所有上述时间点测量了肾脏功能参数、纤维化和炎症标志物以及氧化应激标志物。
非糖尿病和糖尿病小鼠在其整个生命周期中均表现出微量白蛋白尿的进行性增加。有趣的是，糖尿病衰老和正常衰老的小鼠均表现出氧化应激标志物（如血浆和尿液 8-异前列腺素）以及肾脂质过氧化物含量的进行性增加。在肾脏组织中，促炎和促纤维化分子也呈年龄依赖性显著上调。三种 NADPH 氧化酶（Nox）同工型（即 Nox1、Nox2 和 Nox4）的表达在衰老过程中显著增加。与正常衰老的小鼠相比，糖尿病 db/db 小鼠在衰老过程中表现出更显著的变化。
我们的研究结果表明，NADPH 氧化酶在正常和糖尿病条件下的衰老肾脏中都起着重要作用。针对这些氧化酶可能是治疗与衰老肾脏相关问题的一种新的有前途的治疗方法。
