Interactions of NADPH oxidase, renin-angiotensin-aldosterone system and reactive oxygen species in mequindox-mediated aldosterone secretion in Wistar rats.
High doses of mequindox (MEQ) are associated with oxidative stress and pathological toxicity in the kidney. In this study, we demonstrated long term effects of MEQ on intra- or extra-adrenal renin-angiotensin-aldosterone system (RAAS) in vivo. RAAS plays a major role in aldosterone secretion. High doses of MEQ in the diet for 180 days in male rats led to inhibition of intra- and extra-adrenal RAAS, concident with down-regulation of Na(+)/K(+)-ATPase (NAKA) and mineralocorticoid receptor (MR), the downstream of aldosterone action. Significant changes of malondialdehyde (MDA), reduced glutathione (GSH), and superoxide dismutase (SOD) in kidney were also observed in the high doses (110, 275mg/kg) groups. The mRNA levels of most subunits of NADPH oxidase were significantly upregulated at low doses (25-110mg/kg) but the upregulation was diminished at higher doses in both kidney and adrenal gland, indicating a complicated and contradictory effect of MEQ on NADPH. These results highlight the complex interactions of drug metabolism, RAAS, NADPH oxidase and oxidative stress in response to MEQ-induced tissue toxicity and aldosterone secretion.
Huang
Xian-Ju
XJ
MOA Key Laboratory of Food Safety Evaluation/National Reference Laboratory of Veterinary Drug Residues (HZAU), Huazhong Agricultural University, Lion Street 1#, Wuhan, Hubei 430070, China. huangxj554@sohu.com
Wang
Xu
X
Ihsan
Awais
A
Liu
Qin
Q
Xue
Xi-Juan
XJ
Su
Shi-Jia
SJ
Yang
Chun-Hui
CH
Zhou
Wen
W
Yuan
Zong-Hui
ZH
D000311:Adrenal Glands / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D000450:Aldosterone / Q000378:metabolism*; D000818:Animals; D004305:Dose-Response Relationship, Drug; D015870:Gene Expression / Q000187:drug effects; D005978:Glutathione / Q000378:metabolism; D007668:Kidney / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D008297:Male; D008315:Malondialdehyde / Q000378:metabolism; D019255:NADPH Oxidases / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects; D011810:Quinoxalines / Q000633:toxicity*; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism*; D018161:Receptors, Mineralocorticoid / Q000378:metabolism; D012084:Renin-Angiotensin System / Q000187:drug effects*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000254:Sodium-Potassium-Exchanging ATPase / Q000378:metabolism; D013482:Superoxide Dismutase / Q000378:metabolism
C545385:Mequindox; D011810:Quinoxalines; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D018161:Receptors, Mineralocorticoid; D000450:Aldosterone; D008315:Malondialdehyde; D013482:Superoxide Dismutase; D019255:NADPH Oxidases; D000254:Sodium-Potassium-Exchanging ATPase; D005978:Glutathione