NRF2 pathway activation attenuates ageing-related renal phenotypes due to α-klotho deficiency

Mingyue Zhao, Shohei Murakami, Daisuke Matsumaru, Takeshi Kawauchi, Yo Ichi Nabeshima, Hozumi Motohashi

Research output: Contribution to journalArticlepeer-review

4 Citations (Scopus)


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 a Keap1-knockdown background, in which the NRF2 pathway is constitutively activated in the whole body. NRF2 pathway activation in Kl-/- 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 of Kl-/- mice. Thus, NRF2 is expected to exert an antiageing function by partly compensating for the functional decline of α-Klotho during physiological ageing.

Original languageEnglish
Pages (from-to)579-589
Number of pages11
JournalJournal of biochemistry
Issue number5
Publication statusPublished - 2022 May 1


  • KEAP1-NRF2 system
  • ageing
  • kidney
  • oxidative stress
  • α-klotho

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology


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