PMID- 37237889
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20230530
IS  - 2076-3921 (Print)
IS  - 2076-3921 (Electronic)
IS  - 2076-3921 (Linking)
VI  - 12
IP  - 5
DP  - 2023 Apr 28
TI  - Activation of NRF2 Signaling Pathway Delays the Progression of Hyperuricemic 
      Nephropathy by Reducing Oxidative Stress.
LID - 10.3390/antiox12051022 [doi]
LID - 1022
AB  - Hyperuricemia (HUA)-induced oxidative stress is a crucial contributor to 
      hyperuricemic nephropathy (HN), but the molecular mechanisms underlying the 
      disturbed redox homeostasis in kidneys remain elusive. Using RNA sequencing, 
      together with biochemical analyses, we found that nuclear factor erythroid 
      2-related factor 2 (NRF2) expression and nuclear localization levels were 
      increased in early HN progression and then gradually declined below the baseline 
      level. We identified the impaired activity of the NRF2-activated antioxidant 
      pathway as a driver of oxidative damage in HN progression. Through nrf2 deletion, 
      we further confirmed aggravated kidney damage in nrf2 knockout HN mice compared 
      with HN mice. In contrast, the pharmacological agonist of NRF2 improved kidney 
      function and alleviated renal fibrosis in mice. Mechanistically, the activation 
      of NRF2 signaling reduced oxidative stress by restoring mitochondrial homeostasis 
      and reducing NADPH oxidase 4 (NOX4) expression in vivo or in vitro. Moreover, the 
      activation of NRF2 promoted the expression levels of heme oxygenase 1 (HO-1) and 
      quinone oxidoreductase 1 (NQO1) and enhanced the antioxidant capacity of cells. 
      Furthermore, the activation of NRF2 ameliorated renal fibrosis in HN mice through 
      the downregulation of the transforming growth factor-beta 1 (TGF-beta1) signaling 
      pathway and ultimately delayed the progression of HN. Collectively, these results 
      suggested NRF2 as a key regulator in improving mitochondrial homeostasis and 
      fibrosis in renal tubular cells by reducing oxidative stress, upregulating the 
      antioxidant signaling pathway, and downregulating the TGF-beta1 signaling pathway. 
      The activation of NRF2 represents a promising strategy to restore redox 
      homeostasis and combat HN.
FAU - Qiao, Panshuang
AU  - Qiao P
AD  - State Key Laboratory of Natural and Biomimetic Drugs, Department of Pharmacology, 
      School of Basic Medical Sciences, Peking University, Beijing 100191, China.
FAU - Sun, Yi
AU  - Sun Y
AD  - Department of Pharmacology, School of Pharmacy, China Pharmaceutical University, 
      Nanjing 210009, China.
FAU - Wang, Yiming
AU  - Wang Y
AD  - State Key Laboratory of Natural and Biomimetic Drugs, Department of Pharmacology, 
      School of Basic Medical Sciences, Peking University, Beijing 100191, China.
FAU - Lin, Simei
AU  - Lin S
AD  - State Key Laboratory of Natural and Biomimetic Drugs, Department of Pharmacology, 
      School of Basic Medical Sciences, Peking University, Beijing 100191, China.
FAU - An, Yongpan
AU  - An Y
AD  - State Key Laboratory of Natural and Biomimetic Drugs, Department of Pharmacology, 
      School of Basic Medical Sciences, Peking University, Beijing 100191, China.
FAU - Wang, Liang
AU  - Wang L
AD  - State Key Laboratory of Natural and Biomimetic Drugs, Department of Pharmacology, 
      School of Basic Medical Sciences, Peking University, Beijing 100191, China.
FAU - Liu, Jihan
AU  - Liu J
AD  - State Key Laboratory of Natural and Biomimetic Drugs, Department of Pharmacology, 
      School of Basic Medical Sciences, Peking University, Beijing 100191, China.
FAU - Huang, Yajun
AU  - Huang Y
AD  - State Key Laboratory of Natural and Biomimetic Drugs, Department of Pharmacology, 
      School of Basic Medical Sciences, Peking University, Beijing 100191, China.
FAU - Yang, Baoxue
AU  - Yang B
AUID- ORCID: 0000-0002-7966-2095
AD  - State Key Laboratory of Natural and Biomimetic Drugs, Department of Pharmacology, 
      School of Basic Medical Sciences, Peking University, Beijing 100191, China.
FAU - Zhou, Hong
AU  - Zhou H
AD  - State Key Laboratory of Natural and Biomimetic Drugs, Department of Pharmacology, 
      School of Basic Medical Sciences, Peking University, Beijing 100191, China.
AD  - Department of the Integration of Chinese and Western Medicine, School of Basic 
      Medical Sciences, Peking University, Beijing 100191, China.
LA  - eng
GR  - 81873597/National Natural Science Foundation of China/
GR  - 81703520/National Natural Science Foundation of China/
GR  - 2019BFG02017/Key Research and Development Program of Ningxia/
PT  - Journal Article
DEP - 20230428
PL  - Switzerland
TA  - Antioxidants (Basel)
JT  - Antioxidants (Basel, Switzerland)
JID - 101668981
PMC - PMC10215166
OTO - NOTNLM
OT  - NRF2
OT  - chronic kidney disease
OT  - hyperuricemic nephropathy
OT  - mitochondria
OT  - oxidative stress
OT  - tubulointerstitial fibrosis
COIS- The authors declare no conflict of interest.
EDAT- 2023/05/27 09:42
MHDA- 2023/05/27 09:43
PMCR- 2023/04/28
CRDT- 2023/05/27 01:02
PHST- 2023/03/29 00:00 [received]
PHST- 2023/04/25 00:00 [revised]
PHST- 2023/04/26 00:00 [accepted]
PHST- 2023/05/27 09:43 [medline]
PHST- 2023/05/27 09:42 [pubmed]
PHST- 2023/05/27 01:02 [entrez]
PHST- 2023/04/28 00:00 [pmc-release]
AID - antiox12051022 [pii]
AID - antioxidants-12-01022 [pii]
AID - 10.3390/antiox12051022 [doi]
PST - epublish
SO  - Antioxidants (Basel). 2023 Apr 28;12(5):1022. doi: 10.3390/antiox12051022.