Inhibition of Cyclooxygenase-2 in the Rat Renal Medulla Leads to Sodium-Sensitive Hypertension

Zewde, Tewabech; Mattson, David L.

doi:10.1161/01.hyp.0000140924.91479.03

Cited by 86 publications

(71 citation statements)

References 44 publications

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“…Increases in medullary COX-2 expression in response to salt loading were also markedly blunted in ptAadc -/-mice. COX-2-derived prostaglandins are important integrators of vascular tone and salt and water homeostasis in the renal medulla, and inhibition of medullary COX-2 activity can lead to hypertension (17,(22)(23)(24)(25). These results therefore confirm those of previous studies that suggested a potential role for dopamine to increase pronatriuretic renal medullary prostaglandin production (26,27).…”

Section: Figuresupporting

confidence: 88%

Intrarenal dopamine deficiency leads to hypertension and decreased longevity in mice

Zhang

Yao²,

Wang³

et al. 2011

J. Clin. Invest.

110

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In addition to its role as an essential neurotransmitter, dopamine serves important physiologic functions in organs such as the kidney. Although the kidney synthesizes dopamine through the actions of aromatic amino acid decarboxylase (AADC) in the proximal tubule, previous studies have not discriminated between the roles of extrarenal and intrarenal dopamine in the overall regulation of renal function. To address this issue, we generated mice with selective deletion of AADC in the kidney proximal tubules (referred to herein as ptAadc -/-mice), which led to selective decreases in kidney and urinary dopamine. The ptAadc -/-mice exhibited increased expression of nephron sodium transporters, decreased natriuresis and diuresis in response to l-dihydroxyphenylalanine, and decreased medullary COX-2 expression and urinary prostaglandin E 2 excretion and developed salt-sensitive hypertension. They had increased renin expression and altered renal Ang II receptor (AT) expression, with increased AT1b and decreased AT2 and Mas expression, associated with increased renal injury in response to Ang II. They also exhibited a substantially shorter life span compared with that of wild-type mice. These results demonstrate the importance of the intrarenal dopaminergic system in salt and water homeostasis and blood pressure control. Decreasing intrarenal dopamine subjects the kidney to unbuffered responses to Ang II and results in the development of hypertension and a dramatic decrease in longevity.

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Section: Figuresupporting

confidence: 88%

Intrarenal dopamine deficiency leads to hypertension and decreased longevity in mice

Zhang

Yao²,

Wang³

et al. 2011

J. Clin. Invest.

110

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“…For example, the COX-2 enzyme pathway has been found to be upregulated in response to high-salt intake apparently via an NF-B pathway, resulting in increased synthesis of PGE 2 (26,69,105,122,198,200,205,207). Specific inhibition of COX-2 in the renal medulla acutely reduces sodium excretion and when inhibited chronically produces salt-sensitive hypertension in SD rats (104,105,122,183,199,207). This is not the case with COX-1, which is constitutively expressed in the medullary collecting ducts and interstitial cells and is not altered by a salt diet (200).…”

Section: Medullary O 2 ·ϫ No and H 2 O 2 As Determinants Of Blood mentioning

confidence: 99%

Reactive oxygen species as important determinants of medullary flow, sodium excretion, and hypertension

Cowley

Abe

Mori

et al. 2015

American Journal of Physiology-Renal Physiology

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logical evidence linking the production of superoxide, hydrogen peroxide, and nitric oxide in the renal medullary thick ascending limb of Henle (mTAL) to regulation of medullary blood flow, sodium homeostasis, and long-term control of blood pressure is summarized in this review. Data obtained largely from rats indicate that experimentally induced elevations of either superoxide or hydrogen peroxide in the renal medulla result in reduction of medullary blood flow, enhanced Na ϩ reabsorption, and hypertension. A shift in the redox balance between nitric oxide and reactive oxygen species (ROS) is found to occur naturally in the Dahl salt-sensitive (SS) rat model, where selective reduction of ROS production in the renal medulla reduces salt-induced hypertension. Excess medullary production of ROS in SS rats emanates from the medullary thick ascending limbs of Henle [from both the mitochondria and membrane NAD(P)H oxidases] in response to increased delivery and reabsorption of excess sodium and water. There is evidence that ROS and perhaps other mediators such as ATP diffuse from the mTAL to surrounding vasa recta capillaries, resulting in medullary ischemia, which thereby contributes to hypertension.superoxide (O 2 ·Ϫ ); hydrogen peroxide (H2O2); nitric oxide (NO); NAD(P)H oxidase; mTAL; medullary blood flow; kidney; Dahl SS rats REACTIVE OXYGEN SPECIES (ROS) are chemically reactive molecules derived from oxygen, whose role as mediators of intracellular signaling cascades is well recognized. The following is a brief review of physiological data linking superoxide (O 2 ·Ϫ ), hydrogen peroxide (H 2 O 2 ), and nitric oxide (NO) production in the medullary thick ascending limbs of Henle (mTAL) to sodium (Na ϩ ) homeostasis, the regulation of medullary blood flow (MBF), and the long-term regulation of arterial blood pressure. MBF to the renal medulla can be importantly controlled by the constriction and dilation of the descending vasa recta (VR) capillaries, which branch from the efferent arterioles of the juxtamedullary glomeruli (49, 147, 149) and whose tone is controlled by the smooth muscle-like pericytes (49, 90, 146 -149). The role of NO cross talk from mTAL to surrounding VR in the renal medulla has been reviewed in detail elsewhere (19, 33) and will be discussed here largely with regard to its ROS-related counterregulatory functions. The present review will first summarize data showing that either the excess endogenous production or reduced scavenging of O 2 ·Ϫ or H 2 O 2 within the renal medulla results in a decrease in MBF and Na ϩ excretion, leading to hypertension and renal injury. Second, evidence will be summarized supporting the hypothesis that a high dietary salt intake results in increased luminal flow and delivery of NaCl to the mTAL, thereby signaling via both mechanical forces (stretch and shear) and increased Na ϩ transport, an increased mitochondrial and membrane NA-D(P)H oxidase production of O 2 ·Ϫ and H 2 O 2 . Third, studies will be reviewed showing that reduction of MBF leads to hypertension a...

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“…Increases in the expression of renal medullary COX-2, but not COX-1, are seen in response to chronic salt loading (8,15,40). Emerging evidence suggests that renal medullary COX-2 may play a role in the promotion of sodium excretion and, thereby, the stabilization of BP (41). Major goals of the present study are as follows: 1) to resolve cellular localization of high-saltinduced COX-2 expression in the renal medulla, 2) to provide further evidence for the antihypertensive function of renal medullary COX-2 with use of chronic infusion and telemetry techniques, and 3) to examine the potential role of renal medullary COX-1 in BP regulation.…”

mentioning

confidence: 99%

Expression and function of COX isoforms in renal medulla: evidence for regulation of salt sensitivity and blood pressure

Zhang

Hillas

et al. 2006

American Journal of Physiology-Renal Physiology

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Expression and function of COX isoforms in renal medulla: evidence for regulation of salt sensitivity and blood pressure. Am J Physiol Renal Physiol 290: F542-F549, 2006. First published September 27, 2005; doi:10.1152/ajprenal.00232.2005.-Expression of cyclooxygenase (COX)-2, but not COX-1, in the renal medulla is stimulated by chronic salt loading; yet the functional implication of this phenomenon is incompletely understood. The present study examined the cellular localization and antihypertensive function of high-salt-induced COX-2 expression in the renal medulla, with a parallel assessment of the function of COX-1. COX-2 protein expression in response to high-salt loading, assessed by immunostaining, was found predominantly in inner medullary interstitial cells, whereas COX-1 protein was abundant in collecting duct (CD) and inner medullary interstitial cells and was not affected by high salt. We compared mRNA expressions of COX-1 and COX-2 in CD vs. non-CD cells isolated from aquaporin 2-green fluorescent protein transgenic mice. A low level of COX-2 mRNA, but a high level of COX-1 mRNA, as determined by real-time RT-PCR, was detected in CD compared with non-CD segments. During high-salt intake, chronic infusions of the COX-2 blocker NS-398 and the COX-1 blocker SC-560 into the renal medulla of Sprague-Dawley rats for 5 days induced ϳ30-and 15-mmHg increases in mean arterial pressure, respectively. During similar high-salt intake, COX-1 knockout mice exhibited a gradual, but significant, increase in systolic blood pressure that was associated with a marked suppression of urinary PGE2 excretion. Therefore, we conclude that the two COX isoforms in the renal medulla play a similar role in the stabilization of arterial blood pressure during salt loading.cyclooxygenase-1; cyclooxygenase-2; mean blood pressure; prostaglandins; renal medullary interstitial cells PROSTAGLANDINS (PGs) are important autocrine/paracrine factors that contribute to salt balance and blood pressure (BP) control through mechanisms that primarily involve the regulation of vascular tone and renal excretory function. The vascular endothelium is a rich source of prostacyclin (PGI 2 ) and a potent vasodilator and inhibitor of platelet aggregation (5), whereas platelets produce thromboxane A 2 , a potent vasoconstrictor (9). The PGI 2 -thromboxane A 2 balance is considered to play an important role in the maintenance of normal vascular tone. The kidney is capable of synthesizing all types of PGs, especially PGE 2 and PGI 2 , which influence urinary sodium excretion directly through inhibition of tubular transport function and indirectly through regulation of activity of the reninangiotensin system (4). Within the kidney, the inner medulla has the greatest capacity for PG synthesis. In vitro studies have demonstrated that PGs, such as PGE 2 , can directly inhibit NaCl transport in isolated thick ascending limbs (30) and collecting ducts (CDs) (11, 31). In addition, PGE 1 augments renal medullary blood flow and attenuates the hydroosmotic effect o...

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Inhibition of Cyclooxygenase-2 in the Rat Renal Medulla Leads to Sodium-Sensitive Hypertension

Cited by 86 publications

References 44 publications

Intrarenal dopamine deficiency leads to hypertension and decreased longevity in mice

Intrarenal dopamine deficiency leads to hypertension and decreased longevity in mice

Reactive oxygen species as important determinants of medullary flow, sodium excretion, and hypertension

Expression and function of COX isoforms in renal medulla: evidence for regulation of salt sensitivity and blood pressure

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