PMID- 36601735
OWN - NLM
STAT- MEDLINE
DCOM- 20230817
LR  - 20231213
IS  - 1557-7716 (Electronic)
IS  - 1523-0864 (Linking)
VI  - 39
IP  - 4-6
DP  - 2023 Aug
TI  - Connexin32 Promotes the Activation of Foxo3a to Ameliorate Diabetic Nephropathy 
      via Inhibiting the Polyubiquitination and Degradation of Sirt1.
PG  - 241-261
LID - 10.1089/ars.2022.0108 [doi]
AB  - Aims: Renal oxidative stress (OSS) is the leading cause of diabetic nephropathy 
      (DN). The silent information regulator 1/forkhead boxo3a (Sirt1/Foxo3a) pathway 
      plays an essential role in regulating the antioxidant enzyme system. In this 
      study, we aimed to investigate the mechanism of connexin32 (Cx32) on the 
      antioxidant enzyme system in DN. Results: In this study, Cx32 overexpression 
      significantly reduced reactive oxygen species generation and effectively 
      inhibited the excessive production of extracellular matrix such as fibronectin 
      (FN) and intercellular adhesion molecule-1 (ICAM-1) in high-glucose (HG)-induced 
      glomerular mesangial cells. In addition, Cx32 overexpression reversed the 
      downregulation of Sirt1, and promoted the nuclear transcription of Foxo3a, 
      subsequently activating the antioxidant enzymes including catalase and manganese 
      superoxide dismutase (MnSOD), however, Cx32 knockdown showed the opposite 
      effects. A further mechanism study showed that Cx32 promoted the 
      autoubiquitination and degradation of Smad ubiquitylation regulatory factor-1 
      (Smurf1), thereby reducing the ubiquitination of Sirt1 at Lys(335) and the 
      degradation of Sirt1. Moreover, the in vivo results showed that 
      adenovirus-mediated Cx32 overexpression activated the Sirt1/Foxo3a pathway, and 
      inhibited OSS in the kidney tissues, eventually improving the renal function and 
      glomerulosclerosis in diabetic mice. Innovation: This study highlighted the 
      antioxidant role of Cx32-Sirt1-Foxo3a axis to alleviate DN, which is a new 
      mechanism of Cx32 alleviating DN. Conclusion: Cx32 alleviated DN via activating 
      the Sirt1/Foxo3a antioxidant pathway. The specific mechanism was that Cx32 
      upregulated the Sirt1 expression through reducing the ubiquitination of Lys(335) 
      of Sirt1 by inhibiting Smurf1. Antioxid. Redox Signal. 39, 241-261.
FAU - Li, Shanshan
AU  - Li S
AD  - Laboratory of Pharmacology & Toxicology, School of Pharmaceutical Sciences, Sun 
      Yat-sen University, Guangzhou, China.
FAU - Xiao, Haiming
AU  - Xiao H
AD  - Laboratory of Pharmacology & Toxicology, School of Pharmaceutical Sciences, Sun 
      Yat-sen University, Guangzhou, China.
FAU - Sun, Xiaohong
AU  - Sun X
AD  - Department of Pharmacy, Shenzhen Children's Hospital, Shenzhen, China.
FAU - Chen, Zhiquan
AU  - Chen Z
AD  - Department of Pharmacology, School of Pharmacy, Guangxi Medical University, 
      Nanning, China.
FAU - Lin, Zeyuan
AU  - Lin Z
AD  - Laboratory of Pharmacology & Toxicology, School of Pharmaceutical Sciences, Sun 
      Yat-sen University, Guangzhou, China.
FAU - Li, Chuting
AU  - Li C
AD  - Laboratory of Pharmacology & Toxicology, School of Pharmaceutical Sciences, Sun 
      Yat-sen University, Guangzhou, China.
FAU - Zeng, Jingran
AU  - Zeng J
AD  - Laboratory of Pharmacology & Toxicology, School of Pharmaceutical Sciences, Sun 
      Yat-sen University, Guangzhou, China.
FAU - Xu, Zhanchi
AU  - Xu Z
AD  - Laboratory of Pharmacology & Toxicology, School of Pharmaceutical Sciences, Sun 
      Yat-sen University, Guangzhou, China.
FAU - Cheng, Yuanyuan
AU  - Cheng Y
AD  - School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, 
      Guangzhou, China.
FAU - Huang, Heqing
AU  - Huang H
AD  - Laboratory of Pharmacology & Toxicology, School of Pharmaceutical Sciences, Sun 
      Yat-sen University, Guangzhou, China.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20230403
PL  - United States
TA  - Antioxid Redox Signal
JT  - Antioxidants & redox signaling
JID - 100888899
RN  - EC 3.5.1.- (Sirt1 protein, mouse)
RN  - EC 3.5.1.- (Sirtuin 1)
RN  - 0 (FoxO3 protein, mouse)
SB  - IM
MH  - Animals
MH  - Mice
MH  - *Diabetes Mellitus, Experimental/metabolism
MH  - *Diabetic Nephropathies/metabolism
MH  - Oxidative Stress
MH  - Sirtuin 1/genetics/metabolism
MH  - Ubiquitination
MH  - Gap Junction beta-1 Protein
OTO - NOTNLM
OT  - Cx32
OT  - Sirt1/Foxo3a
OT  - Smurf1
OT  - diabetic nephropathy
OT  - oxidative stress
OT  - ubiquitination
EDAT- 2023/01/06 06:00
MHDA- 2023/08/16 06:43
CRDT- 2023/01/05 03:34
PHST- 2023/08/16 06:43 [medline]
PHST- 2023/01/06 06:00 [pubmed]
PHST- 2023/01/05 03:34 [entrez]
AID - 10.1089/ars.2022.0108 [doi]
PST - ppublish
SO  - Antioxid Redox Signal. 2023 Aug;39(4-6):241-261. doi: 10.1089/ars.2022.0108. Epub 
      2023 Apr 3.