Increased NAD(P)H oxidase-mediated superoxide production in renovascular hypertension: Evidence for an involvement of protein kinase C

Heitzer, Thomas; Wenzel, Ulrich; Hink, Ulrich; Krollner, Dirk; Skatchkov, M.; Stahl, Rolf A.K.; Macharzina, Roland; Bräsen, J.A.N.H.; Meinertz, Thomas; Münzel, Thomas

doi:10.1046/j.1523-1755.1999.00229.x

Cited by 229 publications

(196 citation statements)

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“…4 Therefore, we elected to study the relation between oxidative stress and oxygenation more directly in the present series in a model of extreme Ang II action in the clipped kidney of 2K,1C rats. Previous studies in the 2K,1C pig 15 and rat 16 showed that increased oxidative stress was associated with high renin levels in the early phase. We have consistently observed low pO 2 in the cortex of hypertensive kidneys, which also demonstrate high oxidative stress and deficient NO.…”

Section: Discussionmentioning

confidence: 87%

Roles of Oxidative Stress and AT ₁ Receptors in Renal Hemodynamics and Oxygenation in the Postclipped 2K,1C Kidney

et al. 2003

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Abstract-The spontaneously hypertensive rat (SHR) exhibits angiotensin II (Ang II)-dependent oxidative stress and reduced efficiency of renal oxygen usage (Q O2 ) for tubular sodium transport (T Na ). We tested the hypothesis that oxidative stress determines the reduced T Na :Q O2 ratio in the clipped kidney of the early 2-kidney, Key Words: hypertension, renovascular Ⅲ Goldblatt hypertension Ⅲ renal artery Ⅲ nitric oxide R enal oxygen consumption (Q O2 ) is closely related to the energy required for sodium transport (T Na ). Classic studies have established that variations in sodium delivery and hence, transport, over a broad range are matched by proportionate changes in Q O2.1,2 Prevention of glomerular filtration reduced Q O2 to a low but measurable value, identified as the O 2 required for basal kidney metabolism. However, across a broad range of glomerular filtration rates (GFRs), Q O2 rose linearly with the GFR above the basal level. This defines the normal rate at which O 2 is consumed to satisfy the energy requirements for T Na (15 to 25 mol of Na transported per mol of O 2 consumed).Recent studies have reported that the T Na :Q O2 ratio is variable. Laycock and associates 3 showed that the T Na :Q O2 in the dog kidney was reduced by Ϸ50% during inhibition of nitric oxide (NO) synthase with L-nitroarginine. We showed a similar reduction in T Na :Q O2 in kidneys from spontaneously hypertensive rats (SHR). 4 The SHR is a model of reduced renal NO bioactivity associated with increased superoxide radical (O 2 ⅐Ϫ). 5 There is a complex interrelation between NO, O 2 ⅐Ϫ, and PO 2 or O 2 usage in the tissues. In pulmonary arteries and vascular smooth muscle cells, both chronic hypoxia and hyperoxia can enhance O 2 ⅐Ϫ levels. 6,7 Increased O 2 ⅐Ϫ interacts with NO, which reduces its bioactivity and produces peroxynitrite. Nevertheless, we detected a reduced renal cortical pO 2 in the SHR, which we attributed to inefficient utilization of O 2 for T Na as a consequence of functional NO deficiency during oxidative stress. We found also that the renal cortical hypoxia and reduction in PO 2 in the SHR could be corrected by prolonged administration of the angiotensin receptor antagonist candesartan (Cand) but not by equally effective antihypertensive therapy with agents that do not block the renin-angiotensin system. Moreover, we found that Cand also restored NO bioactivity in the SHR kidney. 8 Angiotensin II (Ang II) stimulates the expression of NADPH oxidase. 9,10 We concluded that the reduced NO bioactivity and inefficient utilization of O 2 in the SHR kidney could have been secondary to oxidative stress. The present study was designed to test this hypothesis in the early phase of 2-kidney, 1-clip (2K,1C) Goldblatt hypertension. The 2K,1C is a pathophysiological model of Ang II-dependent hypertension, which suppresses function in the clipped kidney in response

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Section: Discussionmentioning

confidence: 87%

Roles of Oxidative Stress and AT ₁ Receptors in Renal Hemodynamics and Oxygenation in the Postclipped 2K,1C Kidney

et al. 2003

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“…In line with this, it has been suggested that protein kinase C activity, which is involved in NADPH oxidase activation, is increased constitutively in renovascular hypertension. 21 Moreover, increased wall stretch, angiotensin II, and hypertension per se are known to increase protein kinase C activity. [22][23][24][25] Without a doubt, the impact of renovascular hypertension on endothelium-dependent relaxation was small in the present study compared with previous observations in humans 11 and rats.…”

Section: Discussionmentioning

confidence: 99%

“…[22][23][24][25] Without a doubt, the impact of renovascular hypertension on endothelium-dependent relaxation was small in the present study compared with previous observations in humans 11 and rats. 21 However, it is well known that mice are less susceptible to endothelial dysfunction than, for example, rats. The aorta of mice contains large amounts of extracellular SOD, attenuating the impact of oxidative stress on NO bioavailability, 26 a fact that might also explain the relatively mild increase in vascular O 2 Ϫ formation after clipping of WT animals.…”

Section: Discussionmentioning

confidence: 99%

gp91phox-Containing NADPH Oxidase Mediates Endothelial Dysfunction in Renovascular Hypertension

et al. 2004

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Background-Isoforms of the NADPH oxidase contribute to vascular superoxide anion ( · O 2 Ϫ ) formation and limit NO bioavailability. We hypothesized that the endothelial gp91phox-containing NADPH oxidase is predominant in generating the O 2 Ϫ to scavenge endothelial NO and thus is responsible for the development of endothelial dysfunction. Methods and Results-Endothelial dysfunction was studied in aortic rings from wild-type (WT) and gp91phox-knockout (gp91phox Ϫ/Ϫ ) mice with and without renovascular hypertension induced by renal artery clipping (2K1C). Hypertension induced by 2K1C was more severe in WT than in gp91phox Ϫ/Ϫ mice (158Ϯ2 versus 149Ϯ2 mm Hg; PϽ0.05). Endothelium-dependent relaxation to acetylcholine (ACh) was attenuated in rings from clipped WT but not from clipped gp91phox Ϫ/Ϫ mice. The reactive oxygen species (ROS) scavenger Tiron, PEG-superoxide dismutase, and the NADPH oxidase inhibitory peptide gp91ds-tat enhanced ACh-induced relaxation in aortae of clipped WT mice. Inhibition of protein kinase C, Rac, and the epidermal growth factor receptor kinase, elements involved in the activation of the NADPH oxidase, restored normal endothelium-dependent relaxation in vessels from clipped WT mice but had no effect on relaxations in those from gp91phox Ϫ/Ϫ mice. Relaxations to exogenous NO were attenuated in vessels from clipped WT but not clipped gp91phox Ϫ/Ϫ mice. After removal of the endothelium or treatment with PEG-superoxide dismutase, NO-induced relaxations were identical in vessels from clipped and sham-operated WT and gp91phox mice. Conclusions-These data indicate that the formation of O 2Ϫ by the endothelial gp91phox-containing NADPH oxidase accounts for the reduced NO bioavailability in the 2K1C model and contributes to the development of renovascular hypertension and endothelial dysfunction.

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“…62 The effects of endothelin-1 include direct vasoconstriction, a positive feedback increase of angiotensin II production, and the activation of protein kinase C (PKC). 61 In turn, PKC stimulates a NAD(P)H oxidase-mediated ·O 2 Ϫ production 63 and might be autocatalytically activated by ·O 2 Ϫ . 64 In addition, PKC-mediated phosphorylation causes inhibition of NOS, 65 and a recent report demonstrated that angiotensin II, via an ·O 2 Ϫ -and PKC-mediated mechanism, can trigger NOS uncoupling.…”

Section: Neurohormonal Activation and The Control Of ·O 2 ؊ Productionmentioning

confidence: 99%

The Puzzle of Nitrate Tolerance

Gori

Parker

2002

Circulation

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Increased NAD(P)H oxidase-mediated superoxide production in renovascular hypertension: Evidence for an involvement of protein kinase C

Cited by 229 publications

References 28 publications

Roles of Oxidative Stress and AT ₁ Receptors in Renal Hemodynamics and Oxygenation in the Postclipped 2K,1C Kidney

Roles of Oxidative Stress and AT ₁ Receptors in Renal Hemodynamics and Oxygenation in the Postclipped 2K,1C Kidney

gp91phox-Containing NADPH Oxidase Mediates Endothelial Dysfunction in Renovascular Hypertension

The Puzzle of Nitrate Tolerance

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Increased NAD(P)H oxidase-mediated superoxide production in renovascular hypertension: Evidence for an involvement of protein kinase C

Cited by 229 publications

References 28 publications

Roles of Oxidative Stress and AT 1 Receptors in Renal Hemodynamics and Oxygenation in the Postclipped 2K,1C Kidney

Roles of Oxidative Stress and AT 1 Receptors in Renal Hemodynamics and Oxygenation in the Postclipped 2K,1C Kidney

gp91phox-Containing NADPH Oxidase Mediates Endothelial Dysfunction in Renovascular Hypertension

The Puzzle of Nitrate Tolerance

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Roles of Oxidative Stress and AT ₁ Receptors in Renal Hemodynamics and Oxygenation in the Postclipped 2K,1C Kidney

Roles of Oxidative Stress and AT ₁ Receptors in Renal Hemodynamics and Oxygenation in the Postclipped 2K,1C Kidney