Angiotensin-induced defects in renal oxygenation: role of oxidative stress.
We tested the hypothesis that superoxide anion (O(2)(-).) generated in the kidney by prolonged angiotensin II (ANG II) reduces renal cortical Po(2) and the use of O(2) for tubular sodium transport (T(Na):Q(O(2))). Groups (n = 8-11) of rats received angiotensin II (ANG II, 200 ng.kg(-1).min(-1) sc) or vehicle for 2 wk with concurrent infusions of a permeant nitroxide SOD mimetic 4-hydroxy-2,2,6,6-tetramethylpiperidine 1-oxyl (Tempol, 200 nmol.kg(-1).min(-1)) or vehicle. Rats were studied under anesthesia with measurements of renal oxygen usage and Po(2) in the cortex and tubules with a glass electrode. Compared with vehicle, ANG II increased mean arterial pressure (107 +/- 4 vs. 146 +/- 6 mmHg; P < 0.001), renal vascular resistance (42 +/- 3 vs. 65 +/- 7 mmHg.ml(-1).min(-1).100 g(-1); P < 0.001), renal cortical NADPH oxidase activity (2.3 +/- 0.2 vs. 3.6 +/- 0.4 nmol O(2)(-)..min(-1).mg(-1) protein; P < 0.05), mRNA and protein expression for p22(phox) (2.1- and 1.8-fold respectively; P < 0.05) and reduced the mRNA for extracellular (EC)-SOD (-1.8 fold; P < 0.05). ANG II reduced the Po(2) in the proximal tubule (39 +/- 1 vs. 34 +/- 2 mmHg; P < 0.05) and throughout the cortex and reduced the T(Na):Q(O(2)) (17 +/- 1 vs. 9 +/- 2 mumol/mumol; P < 0.001). Tempol blunted or prevented all these effects of ANG II. The effects of prolonged ANG II to cause hypertension, renal vasoconstriction, renal cortical hypoxia, and reduced efficiency of O(2) usage for Na(+) transport, activation of NADPH oxidase, increased expression of p22(phox), and reduced expression of EC-SOD can be ascribed to O(2)(-). generation because they are prevented by an SOD mimetic.
Welch
William J
WJ
Division of Nephrology and Hypertension and Cardiovascular Kidney Institute, Georgetown University, Washington, DC, USA.
Blau
Jonathan
J
Xie
Hui
H
Chabrashvili
Tina
T
Wilcox
Christopher S
CS
D000804:Angiotensin II / Q000008:administration & dosage / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D003497:Cyclic N-Oxides / Q000494:pharmacology; D004334:Drug Administration Schedule; D007668:Kidney / Q000378:metabolism*; D026901:Membrane Transport Proteins / Q000235:genetics; D009252:NADPH Dehydrogenase / Q000235:genetics; D019255:NADPH Oxidases; D018384:Oxidative Stress / Q000502:physiology*; D010100:Oxygen / Q000097:blood; D010101:Oxygen Consumption / Q000187:drug effects*; D010313:Partial Pressure; D010750:Phosphoproteins / Q000235:genetics; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D011921:Rats, Inbred WKY; D012079:Renal Circulation / Q000187:drug effects; D013113:Spin Labels; D013482:Superoxide Dismutase / Q000235:genetics; D013481:Superoxides / Q000378:metabolism
D000975:Antioxidants; D003497:Cyclic N-Oxides; D026901:Membrane Transport Proteins; D010750:Phosphoproteins; D012333:RNA, Messenger; D013113:Spin Labels; D013481:Superoxides; D000804:Angiotensin II; C499089:Sod3 protein, rat; D013482:Superoxide Dismutase; D019255:NADPH Oxidases; C086986:CYBA protein, human; D009252:NADPH Dehydrogenase; D010100:Oxygen; C001803:tempol