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Division of Nephrology, Department of Medicine, and Department of Physiology, New York Medical College, Valhalla, New York 10595
Submitted 23 February 2004 ; accepted in final form 4 July 2004
Oxidant stress is an important contributor to renal dysfunction and hypertension. We have previously demonstrated that regulation of renal oxygen consumption by nitric oxide (NO) is impaired in the kidney of spontaneously hypertensive rats (SHR) due to increased superoxide production. We further explored the mechanisms of enhanced oxidant stress in the kidney of SHR. Suppression of cortical oxygen consumption by bradykinin (BK) or enalaprilat (Enal), which act through stimulation of endogenous NO, was impaired in SHR (BK: –14.1 ± 1.2%; Enal: –15.5 ± 1.2%) and was restored by addition of apocynin, an inhibitor of assembly of the NAD(P)H oxidase complex (BK: –21.0 ± 0.6%; Enal: –25.3 ± 1.4%), suggesting this as the source of enhanced superoxide production. Addition of an angiotensin type 1 receptor blocker, losartan, also restored responsiveness to control levels (BK: –22.0 ± 1.1%; Enal: –23.6 ± 1.3%), suggesting that ANG II is responsible for enhanced oxidase activity. A similar defect in responsiveness to BK and Enal could be induced in Wistar-Kyoto kidneys by ANG II and was reversed by a superoxide scavenger (tempol), apocynin or losartan. Immunoblotting of cortical samples demonstrated enhanced expression of endothelial NO synthase (eNOS 1.9x) and NAD(P)H oxidase components (gp91phox 1.6x and Rac-1 4.5x). Expression of SOD-1 and -2 were unchanged, but SOD-3 was significantly decreased in SHR (0.5x). Thus NO bioavailability is impaired in SHR owing to an ANG II-mediated increase in superoxide production in association with enhanced expression of NAD(P)H oxidase components, despite increased expression of eNOS. Loss of SOD-3, an important superoxide scavenger, may also contribute to enhanced oxidant stress.
nitric oxide; oxygen radicals; renal physiology
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