NRF2 pathway activation attenuates ageing-related renal phenotypes due to α-klotho deficiency
NRF2 pathway activation attenuates ageing-related renal phenotypes due to α-klotho deficiency
复制标题
NRF2 通路激活可减弱 α-klotho 缺乏导致的与衰老相关的肾脏表型
DOI：
10.1093/jb/mvac014
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发表时间：
2022
期刊：
影响因子：
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通讯作者：
Motohashi Hozumi
中科院分区：
文献类型：
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作者：
Zhao Mingyue;Murakami Shohei;Matsumaru Daisuke;Kawauchi Takeshi;Nabeshima Yo-ichi;Motohashi Hozumi
氧化应激是细胞和组织中与年龄相关的功能衰退的主要原因之一。KEAP 1-NRF 2系统在氧化还原平衡的调节中起着核心作用，NRF 2激活通过控制衰老组织中的氧化应激发挥抗衰老作用。α-Klotho被鉴定为一种衰老抑制蛋白，基于其突变小鼠的过早衰老表型，已知其表达在衰老过程中逐渐减少。由于α-klotho已被证明具有抗氧化功能，α-klotho突变小鼠的衰老相关表型似乎至少部分归因于氧化应激增加。为了检测NRF 2激活是否拮抗α-klotho缺陷引起的衰老相关表型，我们将α-klotho缺陷（Kl−/−）小鼠与aKeap 1敲低背景杂交，其中NRF 2通路在全身组成性激活。Kl −/−小鼠的NRF 2通路激活延长了寿命，并显着改善了与衰老相关的肾脏表型。随着抗氧化基因表达的增加伴随着氧化应激的减少，NRF 2的抗氧化作用似乎对Kl −/−小鼠衰老相关的肾脏表型的衰减做出了重要贡献。因此，NRF 2有望通过部分补偿生理衰老过程中α-Klotho的功能下降而发挥抗衰老功能。
Oxidative stress is one of the major causes of the age-related functional decline in cells and tissues. The KEAP1–NRF2 system plays a central role in the regulation of redox balance, and NRF2 activation exerts antiageing effects by controlling oxidative stress in aged tissues. α-Klotho was identified as an ageing suppressor protein based on the premature ageing phenotypes of its mutant mice, and its expression is known to gradually decrease during ageing. Because α-klotho has been shown to possess antioxidant function, ageing-related phenotypes of α-klotho mutant mice seem to be attributable to increased oxidative stress at least in part. To examine whether NRF2 activation antagonizes ageing-related phenotypes caused by α-klotho deficiency, we crossed α-klotho–deficient (Kl−/−) mice with aKeap1-knockdown background, in which the NRF2 pathway is constitutively activated in the whole body. NRF2 pathway activation inKl−/−mice extended the lifespan and dramatically improved ageing-related renal phenotypes. With elevated expression of antioxidant genes accompanied by an oxidative stress decrease, the antioxidant effects of NRF2 seem to make a major contribution to the attenuation of ageing-related renal phenotypes ofKl−/−mice. Thus, NRF2 is expected to exert an antiageing function by partly compensating for the functional decline of α-Klotho during physiological ageing.