Prevention of salt-induced renal injury by activation of NAD(P)H:quinone oxidoreductase 1, associated with NADPH oxidase.
NADPH oxidase (NOX) is a predominant source of reactive oxygen species (ROS), and the activity of NOX, which uses NADPH as a common rate-limiting substrate, is upregulated by prolonged dietary salt intake. β-Lapachone (βL), a well-known substrate of NAD(P)H:quinone oxidoreductase 1 (NQO1), decreases the cellular NAD(P)H/NAD(P)(+) ratio via activation of NQO1. In this study, we evaluated whether NQO1 activation by βL modulates salt-induced renal injury associated with NOX-derived ROS regulation in an animal model. Dahl salt-sensitive (DS) rats fed a high-salt (HS) diet were used to investigate the renoprotective effect of NQO1 activation. βL treatment significantly lowered the cellular NAD(P)H:NAD(P)(+) ratio and dramatically reduced NOX activity in the kidneys of HS diet-fed DS rats. In accordance with this, total ROS production and expression of oxidative adducts also decreased in the βL-treated group. Furthermore, HS diet-induced proteinuria and glomerular damage were markedly suppressed, and inflammation, fibrosis, and apoptotic cell death were significantly diminished by βL treatment. This study is the first to demonstrate that activation of NQO1 has a renoprotective effect that is mediated by NOX activity via modulation of the cellular NAD(P)H:NAD(P)(+) ratio. These results provide strong evidence that NQO1 might be a new therapeutic target for the prevention of salt-induced renal injury.
Laboratory Animal Center, Korea Research Institute of Bioscience and Biotechnology, University of Science and Technology, Daejeon, South Korea.
Yong-Hoon
YH
Kim
Jung Hwan
JH
Hwang
Jung-Ran
JR
Noh
Gil-Tae
GT
Gang
Surendar
S
Tadi
Yong-Hyeon
YH
Yim
Nam Ho
NH
Jeoung
Tae Hwan
TH
Kwak
Sang-Hee
SH
Lee
Gi Ryang
GR
Kweon
Jin-Man
JM
Kim
Minho
M
Shong
In-Kyu
IK
Lee
Chul-Ho
CH
Lee
D058186:Acute Kidney Injury / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D004789:Enzyme Activation; D020536:Enzyme Activators / Q000494:pharmacology* / Q000627:therapeutic use; D005355:Fibrosis; D007249:Inflammation / Q000378:metabolism / Q000517:prevention & control; D007678:Kidney Glomerulus / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D008297:Male; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000378:metabolism*; D009249:NADP / Q000378:metabolism; D019255:NADPH Oxidases / Q000378:metabolism*; D009285:Naphthoquinones / Q000494:pharmacology* / Q000627:therapeutic use; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D051381:Rats; D020303:Rats, Inbred Dahl; D017382:Reactive Oxygen Species / Q000378:metabolism; D012965:Sodium Chloride
D020536:Enzyme Activators; D009285:Naphthoquinones; D017382:Reactive Oxygen Species; D012965:Sodium Chloride; D009249:NADP; C014638:beta-lapachone; D019255:NADPH Oxidases; D016660:NAD(P)H Dehydrogenase (Quinone); C507703:NQO1 protein, rat