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Review
. 2014 Jan 1;20(1):74-101.
doi: 10.1089/ars.2013.5259. Epub 2013 Apr 30.

Oxidative stress in hypertension: role of the kidney

Magali Araujo  1 , Christopher S Wilcox
Affiliations
Review

Oxidative stress in hypertension: role of the kidney

Magali Araujo et al. Antioxid Redox Signal. .

Abstract

Significance: Renal oxidative stress can be a cause, a consequence, or more often a potentiating factor for hypertension. Increased reactive oxygen species (ROS) in the kidney have been reported in multiple models of hypertension and related to renal vasoconstriction and alterations of renal function. Nicotinamide adenine dinucleotide phosphate oxidase is the central source of ROS in the hypertensive kidney, but a defective antioxidant system also can contribute.

Recent advances: Superoxide has been identified as the principal ROS implicated for vascular and tubular dysfunction, but hydrogen peroxide (H2O2) has been implicated in diminishing preglomerular vascular reactivity, and promoting medullary blood flow and pressure natriuresis in hypertensive animals.

Critical issues and future directions: Increased renal ROS have been implicated in renal vasoconstriction, renin release, activation of renal afferent nerves, augmented contraction, and myogenic responses of afferent arterioles, enhanced tubuloglomerular feedback, dysfunction of glomerular cells, and proteinuria. Inhibition of ROS with antioxidants, superoxide dismutase mimetics, or blockers of the renin-angiotensin-aldosterone system or genetic deletion of one of the components of the signaling cascade often attenuates or delays the onset of hypertension and preserves the renal structure and function. Novel approaches are required to dampen the renal oxidative stress pathways to reduced O2(-•) rather than H2O2 selectivity and/or to enhance the endogenous antioxidant pathways to susceptible subjects to prevent the development and renal-damaging effects of hypertension.

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Figures

<b>FIG. 1.</b>
FIG. 1.
Effects of knockout of SOD isoforms on blood pressure in mice. Mean±SEM values of blood pressure in conscious or anesthetized mice. p<0.05 compared to wild-type mice. Redrawn from Refs.: A [a (144); b (28); c, d (53)]; B [a (38); b (243)], C [a (49); b (128); c, d (304)]. MAP, mean arterial pressure; SOD, superoxide dismutase; NS, not significant.
<b>FIG. 2.</b>
FIG. 2.
Blood pressure during prolonged infusion of ANG II in the SOD gene-deleted mice. Mean±SEM values of blood pressure in conscious mice. (A) SOD-1 (+/+) and (−/−) mice; (B) SOD-2 (+/+) and (+/−) mice; (C, D) SOD-3 (+/+) and (−/−) mice. *p<0.05, **p<0.001 compared to wild-type mice. Redrawn from Refs. [A (28); B (38), C (304), D (89)]. ANG II, angiotensin II.
<b>FIG. 3.</b>
FIG. 3.
Interaction between macula densa derived nitric oxide and superoxide in the juxtaglomerular apparatus of the SHR. Comparison of protein expression for eNOS (A) and nNOS (B) and the change in tubuloglomerular feedback (TGF) with 7-nitroindazole (7-NI) in WKY rats (open bars, n=6) and SHR (solid bars, n=6) (C, D). (E) represents the experimental protocol for the subsequent study. (F, G) represent the effects of efferent arteriolar tempol on TGF responses to 7-NI compared to vehicle in WKY rats and SHR after 2 weeks of vehicle, candesartan (3 mg/kg/24 h), or hydralazine plus hydrochlorothiazide plus reserpine (30, 10, and 0.2 mg/kg/24 h). ***Significance of change: p<0.001. Redrawn from (310, 311). Veh, vehicle; HHR, hydrochlorothiazide, hydralazine and reserpine; Cand, candesartan; JGA, juxtaglomerular apparatus; NOS, nitric oxide synthase; nNOS, neuronal NOS; SHR, spontaneously hypertensive rats; WKY, Wistar Kyoto.
<b>FIG. 4.</b>
FIG. 4.
Mean±SEM values for contractions of mouse isolated and perfused renal afferent arterioles. (A, B) depicts dose–response effects of bath addition of ANG II. In (A) are shown responses of afferent arterioles from normal wild-type mice, mice with deletion of SOD-1, or normal mice after the bath addition of 10−4M of l-nitroarginine methyl ester. In (B) are shown responses of p47phox knockout and wild-type mice. (C, D) depict the effects of graded increases in the afferent arteriolar perfusion pressure. In (C) are shown the responses of the afferent arteriole from normal mice after incubation with a vehicle, pegylated SOD, or pegylated catalase. In (D) are shown the responses of arterioles from wild-type mice or endothelial nitric oxide synthase or p47phox gene-deleted mice. *p<0.05, **p<0.01, and ***p<0.005 compared to wild-type or vehicle. Redrawn from Refs. [A (28); B, D (153); C (154)]. WT, wild-type mice; L-NAME, Nw-Nitro-l-arginine methyl ester; PEG-SOD, polyethylene glycol covalently linked to SOD; PEG-CAT, polyethylene glycol covalently linked to catalase.
<b>FIG. 5.</b>
FIG. 5.
Hypothesis for proximal tubule signaling via reactive oxygen species after ANG II type-1 receptor or dopamine receptor activation or inhibition in hypertension. Activation of AT1R stimulates the NADPH-oxidase dependent O2−·production, which increases the expression of the NHE3 inhibitor factor (NHERF2) and decreases Na+ reabsorption in the proximal tubule by inhibition of NHE3. Superoxide (O2−·)- and G-coupled receptor kinase type 4 (GRK4)-dependent phosphorylation (P)/uncoupling of D1 and D3 leads to an impairment of these receptors, while AT1R impairs the D5 receptor (for explanation, see text). Drawn after Refs. (127, 224, 343–345). AT1R, angiotensin II receptor type-1; PLD, phospholipase D; GRK4, G-protein-coupled receptor kinase type 4; cAMP, 3′-5′-cyclic adenosine monophosphate; P, phosphate; PKA, phosphokinase A; PLC, phospholipase C; PKC, protein kinase C; NHE3, Na+/H+ exchanger; NHERF, Na+/H+ exchanger regulatory factor; NADPH, nicotinamide dinucleotide phosphate.
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References

    1. Abadir PM, Foster DB, Crow M, Cooke CA, Rucker JJ, Jain A, Smith BJ, Burks TN, Cohn RD, Fedarko NS, Carey RM, O'Rourke B, and Walston JD. Identification and characterization of a functional mitochondrial angiotensin system. Proc Natl Acad Sci U S A 108: 14849–14854, 2011 - PMC - PubMed
    1. Adler S. and Huang H. Oxidant stress in kidneys of spontaneously hypertensive rats involves both oxidase overexpression and loss of extracellular superoxide dismutase. Am J Physiol Renal Physiol 287: F907–F913, 2004 - PubMed
    1. Ahmeda AF. and Johns EJ. The regulation of blood perfusion in the renal cortex and medulla by reactive oxygen species and nitric oxide in the anaesthetised rat. Acta Physiol (Oxf) 204: 443–450, 2012 - PubMed
    1. Aldred KL, Harris PJ, and Eitle E. Increased proximal tubule NHE-3 and H+-ATPase activities in spontaneously hypertensive rats. J Hypertens 18: 623–628, 2000 - PubMed
    1. Alexander MY, Brosnan MJ, Hamilton CA, Fennell JP, Beattie EC, Jardine E, Heistad DD, and Dominiczak AF. Gene transfer of endothelial nitric oxide synthase but not Cu/Zn superoxide dismutase restores nitric oxide availability in the SHRSP. Cardiovasc Res 47: 609–617, 2000 - PubMed

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