Oxidant stress leads to impaired regulation of renal cortical oxygen consumption by nitric oxide in the aging kidney.
Structural and functional changes occur in the kidney with aging. Previous studies have suggested that loss of nitric oxide production contributes to these changes. The authors therefore explored regulation of renal cortical oxygen consumption, a nitric oxide mediated effect, in tissue from Fischer 344 rats at different ages (4, 13, and 23 mo) to characterize changes in renal nitric oxide production with age. Bradykinin, enalaprilat, and amlodipine significantly suppressed cortical oxygen consumption in 4-mo-old rats (bradykinin: -2.5 +/- 0.9% to -21 +/- 1.5%; enalaprilat: -0.7 +/- 0.5% to -26 +/- 1.2%; amlodipine: -1.3 +/- 0.9% to -18 +/- 1.2%; P < 0.05). Similar results were obtained in 13-mo-old animals. However, in 23-mo-old animals, the responses to bradykinin and enalaprilat were attenuated (bradykinin: 0 +/- 0% to -13 +/- 0.9%; enalaprilat: -0.3 +/- 0.3% to -17 +/- 2.1%; P < 0.05), whereas the response to an NO donor was unaffected, suggesting decreased bioavailability of NO. Addition of the superoxide radical scavenger tempol restored the ability of bradykinin, enalaprilat, and amlodipine to suppress oxygen consumption in tissue from 23-mo-old animals to levels seen in younger animals, suggesting NO destruction by superoxide as the reason for decreased NO availability. Apocynin, an inhibitor of NAD(P)H oxidase, similarly restored the ability of all three drugs to suppress oxygen consumption, suggesting NAD(P)H oxidase as the enzyme responsible for enhanced superoxide production in aging. Levels of eNOS protein, assessed by immunoblotting, did not change significantly with age. These results suggest that NO availability is decreased in the aging kidney and that this is due to scavenging of NO by superoxide produced by NAD(P)H oxidase. Oxidant stress, by depleting NO, may contribute to the structural and hemodynamic changes characteristic of the aging kidney.
Adler
Stephen
S
Division of Nephrology, Department of Medicine, New York Medical College, Valhalla, New York, USA. stephen@nymc.edu
Huang
Harer
H
Wolin
Michael S
MS
Kaminski
Pawel M
PM
D000367:Age Factors; D017311:Amlodipine / Q000494:pharmacology; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology; D000818:Animals; D001920:Bradykinin / Q000494:pharmacology; D003497:Cyclic N-Oxides / Q000494:pharmacology; D015773:Enalaprilat / Q000494:pharmacology; D016166:Free Radical Scavengers / Q000494:pharmacology; D007672:Kidney Cortex / Q000187:drug effects / Q000378:metabolism* / Q000503:physiopathology; D008297:Male; D009569:Nitric Oxide / Q000502:physiology*; D018384:Oxidative Stress; D010101:Oxygen Consumption; D051381:Rats; D011916:Rats, Inbred F344; D013113:Spin Labels
D000806:Angiotensin-Converting Enzyme Inhibitors; D003497:Cyclic N-Oxides; D016166:Free Radical Scavengers; D013113:Spin Labels; D017311:Amlodipine; D009569:Nitric Oxide; D015773:Enalaprilat; D001920:Bradykinin; C001803:tempol