NADPH oxidase in the renal medulla causes oxidative stress and contributes to salt-sensitive hypertension in Dahl S rats.
Dahl salt-sensitive (SS) rats exhibit increased renal medullary oxidative stress and blood pressure salt-sensitivity compared with consomic, salt-resistant SS-13BN rats, despite highly similar genetic backgrounds. The present study examined potential sources of renal medullary superoxide in prehypertensive SS rats fed a 0.4% NaCl diet by assessing activity and protein levels of superoxide producing and scavenging enzymes. Superoxide production was nearly doubled in SS rats compared with SS-13BN rats as determined by urinary 8-isoprostane excretion and renal medullary oxy-ethidium microdialysate levels. Medullary superoxide production in tissue homogenates was greater in SS rats, and the NADPH oxidase inhibitor diphenylene iodonium preferentially reduced SS levels to those found in SS-13BN rats. Dinitrophenol, a mitochondrial uncoupler, eliminated the remaining superoxide production in both strains, whereas inhibition of xanthine oxidase, NO synthase, and cycloxygenase had no effect. L-arginine, NO synthase, superoxide dismutase, catalase, and glutathione peroxidase activities between SS and SS-13BN rats did not differ. Chronic blood pressure responses to a 4% NaCl diet were then determined in the presence or absence of the NADPH oxidase inhibitor apocynin (3.5 microg/kg per minute), chronically delivered directly into the renal medulla. Apocynin infusion reduced renal medullary interstitial superoxide from 1059+/-130 to 422+/-80 (oxyethidium fluorescence units) and mean arterial pressure from 175+/-4 to 157+/-6 mm Hg in SS rats, whereas no effects on either were observed in the SS-13(BN). We conclude that excess renal medullary superoxide production in SS rats contributes to salt-induced hypertension, and NADPH oxidase is the major source of the excess superoxide.
Taylor
Norman E
NE
Department of Physiology, Medical College of Wisconsin, Milwaukee, WI 53226, USA. ntaylor@mcw.edu
Glocka
Padden
P
Liang
Mingyu
M
Cowley
Allen W
AW
D000098:Acetophenones / Q000494:pharmacology; D000818:Animals; D002374:Catalase / Q000378:metabolism; D033481:Chromosomes, Mammalian; D004351:Drug Resistance / Q000235:genetics; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005979:Glutathione Peroxidase / Q000378:metabolism; D006973:Hypertension / Q000209:etiology* / Q000378:metabolism / Q000503:physiopathology*; D007527:Isoenzymes / Q000378:metabolism; D007679:Kidney Medulla / Q000201:enzymology*; D019255:NADPH Oxidases / Q000378:metabolism*; D018384:Oxidative Stress; D051381:Rats; D011914:Rats, Inbred BN / Q000235:genetics; D020303:Rats, Inbred Dahl; D017673:Sodium Chloride, Dietary; D013482:Superoxide Dismutase / Q000378:metabolism; D013481:Superoxides / Q000378:metabolism
D000098:Acetophenones; D004791:Enzyme Inhibitors; D007527:Isoenzymes; D017673:Sodium Chloride, Dietary; D013481:Superoxides; C056165:acetovanillone; D002374:Catalase; D005979:Glutathione Peroxidase; D013482:Superoxide Dismutase; D019255:NADPH Oxidases