Antioxid Redox Signal 20(1): 74-101

Oxidative Stress in Hypertension: Role of the Kidney

Hypertension, Kidney and Vascular Research Center, Georgetown University, Washington, District of Columbia.

^{Corresponding author.}

Address correspondence to:, Dr. Christopher S. Wilcox, Hypertension, Kidney and Vascular Research Center, Georgetown University Medical Center, 3800 Reservoir Rd. NW, Room PHCF 6003, Washington, DC 20007, E-mail:Email: ude.nwotegroeg@hcxocliw

Received 2013 Feb 13; Accepted 2013 Mar 9.

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 H}₂O₂ selectivity and/or to enhance the endogenous antioxidant pathways to susceptible subjects to prevent the development and renal-damaging effects of hypertension. Antioxid. Redox Signal. 20, 74–101.

Abstract

Abbreviations Used

7-NI	7-nitroindazole
8-iso	8-isoprostane F₂-alpha
A1AR	adenosine receptors type-1
AA	arachidonate
ACE	angiotensin-converting enzyme
AGT	angiotensinogen
ANG II	angiotensin II
ARB	angiotensin II type-1 receptor blocker
AT1R	angiotensin II receptors type-1
AT2R	angiotensin II receptor type-2
ATP	adenosine triphosphate
BH4	tetrahydrobiopterin
BP	blood pressure
cAMP	3′-5′-cyclic adenosine monophosphate
Cand	candesartan
CCD	cortical collecting duct
CD	collecting duct
CKD	chronic kidney disease
CNT	connecting tubule
COX	cyclooxygenase
cTAL	cortical thick ascending limb
CTGF	connecting tubule tubuloglomerular feedback
DOCA	deoxycorticosterone acetate
DR	Dahl salt-resistant
DS	Dahl salt-sensitive
DT	distal tubule
EA	efferent arteriole
ECs	endothelial cells
EDCF	endothelium-dependent constrictor factor
EDRF/NO	endothelium-derived relaxation factor/nitric oxide
ET-1	endothelin-1
ET_B	endothelin receptor type-B
GFR	glomerular filtration rate
GLOM	glomerulus
GPX	glutathione peroxidase
GRK4	G protein-coupled receptor kinase type 4
GSH	glutathione
H₂O₂	hydrogen peroxide
HETE	hydroxyeicosatetraenoic acid
HHR	hydrochlorothiazide, hydralazine, and reserpine
HR	heart rate
ICV	intracerebroventricular
JGA	juxtaglomerular apparatus
LH	loop of Henle
L-NAME	N_ω-Nitro-l-arginine methyl ester
L-NMMA	N^-Methyl-l-arginine acetate
L-NNA	N^-nitro-l-arginine
MAP	mean arterial pressure
MBF	medullary blood flow
MCD	medullary collecting duct
MC	mesangial cells
MD	macula densa
MR	mineralocorticoid receptors
mTAL	medullary thick ascending limb
NAC	N-acetylcysteine
NADPH	nicotinamide adenine dinucleotide phosphate
NaPi2	Na^{–phosphate cotransporter}
NE	norepinephrine
NHE3	Na^/H^exchanger
NHERF2	Na^/H^{exchanger regulatory factor}
NKCC2	Na^/K^/2Cl^{transporter type-2}
NOS	nitric oxide synthase
NOX	neutrophil oxidase
O₂^−•	superoxide
OH^−•	hydroxyl anion
ONOO⁻	peroxynitrite
PEG-CAT	polyethylene glycol covalently linked to catalase
PEG-SOD	polyethylene glycol covalently linked to superoxide dismutase
PGG₂/PGH₂	prostaglandins/endoperoxides
PGs	prostaglandins
PH	posterior hypothalamic nuclei
PKA	phosphokinase A
PKC	protein kinase C
PLC	phospholipase C
PLD	phospholipase D
Podo	podocytes
P	phosphate
Prx	peroxiredoxin
PT	proximal tubule
RAAS	renin-angiotensin-aldosterone system
RBF	renal blood flow
ROS	reactive oxygen species
RRM	reduced renal mass
RSNA	renal sympathetic nerve activity
RVR	renal vascular resistance
SHR	spontaneously hypertensive rats
SHRSP	spontaneously hypertensive rats stroke-prone
SNGFR	single-nephron glomerular filtration rate
SNS	sympathetic nervous system
SOD	superoxide dismutase
T1DM	type 1 diabetes mellitus
TGF	tubuloglomerular feedback
TP	thromboxane prostanoid receptor
TrxR	thioredoxin reductase
Trx	thioredoxin
TxA₂	thromboxane A₂
Veh	vehicle
VSMC	vascular smooth muscle cell
WKY	Wistar Kyoto
WT	wild-type mice
XOR	xanthine oxireductase
XO	xanthine oxidase

Abbreviations Used

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