Oxygen availability limits renal NADPH-dependent superoxide production

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Abstract
Renal oxygen tension is substantially lower in the medulla than in the cortex and is reduced in hypertensive rats, a model of oxidative stress. Expression of NADPH oxidase, the primary source for superoxide anion (O2−·) in the kidney, is elevated in hypertension. Because molecular oxygen (O2) is required for O2−· formation, we tested the hypothesis that renal NADPH oxidase activity is limited by low O2. O2−· production by rat kidney tissue or cultured cells exposed to levels of Po2that mimics those in the kidney was assessed by lucigenin-enhanced chemiluminescence. NADPH-dependent O2−· production by kidney homogenates decreased reversibly by 60–90% after graded reductions of ambient O2from 10 to 0% (76 to 2 mmHg Po2). The NADPH-dependent O2−· production by the kidney homogenate was reduced by decreasing Po2below ∼30 mmHg. The response of tissue homogenates to low Po2was not different between normotensive and hypertensive rats. Similarly, NADPH-dependent O2−· production was lower during 2% O2compared with 10% O2in rat proximal tubule cells (−57 ± 1%), vascular smooth muscle (−42 ± 5%), cardiomyocytes (−57 ± 1%), and mouse inner medulla collecting duct cells (−58 ± 3%). We conclude that O2−· production by NADPH oxidase is dependent on availability of O2. Therefore, O2−· generation may be limited in the kidney, both in the normal renal medulla and in the cortex of hypertensive kidneys.