Oxidant stress in kidneys of spontaneously hypertensive rats involves both oxidase overexpression and loss of extracellular superoxide dismutase

Abstract

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 (gp91(phox) 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.

Activation of the Renin-Angiotensin System and Chronic Hypoxia of the Kidney

“…Tempol blunted all these effects of angiotensin II (55). Further, Adler and Huang showed that NO bioavailability in SHR is impaired due to an angiotensin II-mediated increase in superoxide production in association with enhanced expression of NADPH oxidase components (56). These results suggest that the oxidative stress induced by angiotensin II is associated with augmented oxygen consumption and subsequent hypoxia in the kidney.…”

Induction of Glomerular Heparanase Expression in Rats with Adriamycin Nephropathy Is Regulated by Reactive Oxygen Species and the Renin-Angiotensin System

“…All three elements (ROS, angiotensin II, and proteinuria), in our opinion, could be sequentially responsible for the persistence of heparanase overexpression. Although the generation of ROS can be induced by angiotensin II (33)(34)(35), ROS also are thought to be induced by Adriamycin per se. The beneficial effects of DMTU treatment during the induction phase of AN support a role for ROS in the induction of changed charge-selective properties of the GBM, as a result of both a direct effect of ROS on HS and ROSinduced heparanase expression.…”

Increased ANG II sensitivity following recovery from acute kidney injury: role of oxidant stress in skeletal muscle resistance arteries

“…Other studies indicate treatment with antioxidant supplements reduce oxidative stress during hypertension and kidney disease (1,18). In the present study, we sought to determine the role of ROS generation in contributing to the enhanced reactivity of isolated GA to ANG II.…”