PMID- 29020797
OWN - NLM
STAT- MEDLINE
DCOM- 20190529
LR  - 20220113
IS  - 1557-7716 (Electronic)
IS  - 1523-0864 (Print)
IS  - 1523-0864 (Linking)
VI  - 28
IP  - 17
DP  - 2018 Jun 10
TI  - Extracellular Superoxide Dismutase Attenuates Renal Oxidative Stress Through the 
      Activation of Adenosine Monophosphate-Activated Protein Kinase in Diabetic 
      Nephropathy.
PG  - 1543-1561
LID - 10.1089/ars.2017.7207 [doi]
AB  - AIMS: Oxidative stress plays a crucial role in the pathogenesis of diabetic 
      nephropathy (DN). We evaluated whether extracellular superoxide dismutase 
      (EC-SOD) has a renoprotective effect through activation of adenosine 
      monophosphate-activated protein kinase (AMPK) in diabetic kidneys. RESULTS: Human 
      recombinant EC-SOD (hEC-SOD) was administered to 8-week-old male C57BLKS/J db/db 
      mice through intraperitoneal injection once a week for 8 weeks. Renal SOD3 
      expression was suppressed in db/db mice, which was significantly enhanced by 
      hEC-SOD treatment. hEC-SOD improved albuminuria, mesangial expansion, and 
      interstitial fibrosis in db/db mice. At the molecular level, hEC-SOD increased 
      phosphorylation of AMPK, activation of peroxisome proliferative-activated 
      receptor gamma coactivator 1alpha (PGC-1alpha), and dephosphorylation of forkhead box O 
      transcription factor (FoxO)1 and FoxO3a. The protective effects of hEC-SOD were 
      attributed to enhanced nuclear translocation of nuclear factor E2-related factor 
      2 (Nrf2) and subsequently increased expression of NAD(P)H dehydrogenase 1 and 
      heme oxygenase-1. Consequently, hEC-SOD recovered from systemic and renal 
      inflammation and apoptosis, as reflected by the decreases of serum and renal 
      monocyte chemoattractant protein-1 and tumor necrosis factor-alpha levels and 
      increases of BCL-2/BAX ratio in diabetic kidney. hEC-SOD also improved oxidative 
      stress and resulted in increased renal and urinary 8-hydroxy-2'-deoxyguanosine 
      and 8-isoprostane levels in db/db mice. In cultured human glomerular endothelial 
      cells, hEC-SOD ameliorated apoptosis and oxidative stress caused by high glucose 
      exposure through activation of AMPK and PGC-1alpha and dephosphorylation of FoxOs. 
      INNOVATION: These findings demonstrated for the first time that EC-SOD can 
      potentially ameliorate hyperglycemia-induced oxidative stress, apoptosis, and 
      inflammation through activation of AMPK and its downstream pathways in diabetic 
      kidneys. CONCLUSIONS: EC-SOD is a potential therapeutic target for treatment of 
      type 2 DN through intrarenal AMPK-PGC-1alpha-Nrf2 and AMPK-FoxOs signaling. Antioxid. 
      Redox Signal. 28, 1543-1561.
FAU - Hong, Yu Ah
AU  - Hong YA
AD  - 1 Division of Nephrology, Department of Internal Medicine, The Catholic 
      University of Korea , Seoul, Republic of Korea.
FAU - Lim, Ji Hee
AU  - Lim JH
AD  - 1 Division of Nephrology, Department of Internal Medicine, The Catholic 
      University of Korea , Seoul, Republic of Korea.
FAU - Kim, Min Young
AU  - Kim MY
AD  - 1 Division of Nephrology, Department of Internal Medicine, The Catholic 
      University of Korea , Seoul, Republic of Korea.
FAU - Kim, Yaeni
AU  - Kim Y
AD  - 1 Division of Nephrology, Department of Internal Medicine, The Catholic 
      University of Korea , Seoul, Republic of Korea.
FAU - Park, Hoon Suk
AU  - Park HS
AD  - 1 Division of Nephrology, Department of Internal Medicine, The Catholic 
      University of Korea , Seoul, Republic of Korea.
FAU - Kim, Hyung Wook
AU  - Kim HW
AD  - 1 Division of Nephrology, Department of Internal Medicine, The Catholic 
      University of Korea , Seoul, Republic of Korea.
FAU - Choi, Bum Soon
AU  - Choi BS
AD  - 1 Division of Nephrology, Department of Internal Medicine, The Catholic 
      University of Korea , Seoul, Republic of Korea.
FAU - Chang, Yoon Sik
AU  - Chang YS
AD  - 1 Division of Nephrology, Department of Internal Medicine, The Catholic 
      University of Korea , Seoul, Republic of Korea.
FAU - Kim, Hye Won
AU  - Kim HW
AD  - 2 Department of Rehabilitation, The Catholic University of Korea , Seoul, 
      Republic of Korea.
FAU - Kim, Tae-Yoon
AU  - Kim TY
AD  - 3 Department of Dermatology, The Catholic University of Korea , Seoul, Republic 
      of Korea.
FAU - Park, Cheol Whee
AU  - Park CW
AD  - 1 Division of Nephrology, Department of Internal Medicine, The Catholic 
      University of Korea , Seoul, Republic of Korea.
LA  - eng
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20171114
PL  - United States
TA  - Antioxid Redox Signal
JT  - Antioxidants & redox signaling
JID - 100888899
RN  - EC 1.15.1.1 (Superoxide Dismutase)
RN  - EC 2.7.11.31 (AMP-Activated Protein Kinases)
SB  - IM
MH  - AMP-Activated Protein Kinases/*metabolism
MH  - Animals
MH  - Diabetes Mellitus, Experimental/*metabolism
MH  - Diabetic Nephropathies/*metabolism
MH  - HEK293 Cells
MH  - Humans
MH  - Kidney/*metabolism
MH  - Male
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - *Oxidative Stress
MH  - Superoxide Dismutase/*metabolism
PMC - PMC6909782
OTO - NOTNLM
OT  - adenosine monophosphate-activated protein kinase
OT  - apoptosis
OT  - diabetic nephropathy
OT  - extracellular superoxide dismutase
OT  - inflammation
OT  - oxidative stress
COIS- No competing financial interests exist for any author. All authors declare that 
      there is no duality of interest associated with this article.
EDAT- 2017/10/13 06:00
MHDA- 2019/05/30 06:00
PMCR- 2019/06/10
CRDT- 2017/10/13 06:00
PHST- 2017/10/13 06:00 [pubmed]
PHST- 2019/05/30 06:00 [medline]
PHST- 2017/10/13 06:00 [entrez]
PHST- 2019/06/10 00:00 [pmc-release]
AID - 10.1089/ars.2017.7207 [pii]
AID - 10.1089/ars.2017.7207 [doi]
PST - ppublish
SO  - Antioxid Redox Signal. 2018 Jun 10;28(17):1543-1561. doi: 10.1089/ars.2017.7207. 
      Epub 2017 Nov 14.