Influence of Dietary Sodium Intake on Renal Medullary Nitric Oxide Synthase

Mattson, David L.; Higgins, Dan

doi:10.1161/01.hyp.27.3.688

Cited by 185 publications

(157 citation statements)

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“…High salt increases the expression of all 3 NOS isoforms in the medulla. 68 The mechanisms by which this occurs have not been worked out for NOS 1 and 2, but have been defined for NOS 3 in medullary thick ascending limbs. 69 High salt increased outer medullary osmolality and hyperosmolality enhanced NOS 3 expression in primary thick ascending limb cultures, and an ET B receptor antagonist could block this effect.…”

Section: Regulation Of Expressionmentioning

confidence: 99%

Recent Advances in the Regulation of Nitric Oxide in the Kidney

Herrera

Garvin

2005

Hypertension

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Abstract-Nitric oxide (NO) plays important roles in the regulation of renal function and the long-term control of blood pressure. New roles of NO have been proposed recently in diabetes, nephrotoxicity, and pregnancy. NO derived from all 3 NOS isoforms contributes to the overall regulation of kidney function, and recent advances in our understanding of their regulation have been made lately. In this regard, substrate and cofactor availability play important roles in regulating nitric oxide synthase (NOS) activity not only by limiting enzyme activity but also by influencing the coupling of NOS with its cofactors, tetrahydrobiopterin and NADPH. Protein-protein interactions are now recognized to be important negative and positive regulators of NOS. Phosphorylation is another component of the mechanism whereby NOS is activated or deactivated. Increased NOS expression can also influence enzyme activity; however, the degree of expression does not always correlate with enzyme activity because increased NO levels can result in inhibition of NOS. Finally, other potential regulators of NOS such as endogenous L-arginine analogs may also be important. In this article, we summarize recent advances in the regulation of activity and expression of the NOS isoforms within the kidney. renal function and long-term regulation of blood pressure. [1][2][3][4] This is best evidenced by the fact that inhibiting intrarenal NO production increased blood pressure. 5 In addition, reduced NO has been identified as a common denominator of many hypertensive models. 6 -9 The effects of NO on blood pressure via actions in the kidney occur through multiple mechanisms. These include increasing renal blood flow caused by vasodilatation, 10 increasing glomerular filtration, 11 inhibiting sodium transport along the nephron, 12-14 and regulating release of renin. 15 NO produced by each of the 3 nitric oxide synthases (NOS), NOS 1, NOS 2, and NOS 3, reportedly contributes to the regulation of renal function. Inhibition of NOS activity within the kidney is known to lead to sodium retention and hypertension. This review addresses recent advances in our understanding of the role played by renal NO in various physiological and pathophysiological conditions, as well as how NO production is regulated. Roles for Renal NOHistorically, NO produced by the kidney has been thought of primarily as a factor that regulates urinary volume and sodium excretion. The physiological effects of NO can be mediated via changes in renal hemodynamics and/or salt and water absorption by the nephron. NO reduces renal vascular tone in part by dilating the afferent arteriole. 16 It also increases glomerular filtration rate. 11 NO modulates renin secretion by the juxtaglomerular apparatus 15 and tubuloglomerular feedback. 3 Finally, NO regulates transport in various nephron segments as reviewed recently by Ortiz and Garvin. 12 More recently it has been recognized that in a number of pathophysiological conditions, the actions of NO on renal hemodynamics and/or nephron transport are ...

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Section: Regulation Of Expressionmentioning

confidence: 99%

Recent Advances in the Regulation of Nitric Oxide in the Kidney

Herrera

Garvin

2005

Hypertension

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“…Tojo et al 11 described positive immunolabeling of constitutive NOS in THALs. More recently, Mattson and Higgins,12 with the use of Western blots, showed that the rat outer medulla expresses all 3 NOS isoforms.Currently, the isoform(s) of NOS mediating the effects of L-Arg on THAL transport have not been extensively studied. We hypothesized that L-Arg inhibits mouse THAL chloride absorption through stimulation of eNOS rather than either iNOS or the neuronal (nNOS) isoform.…”

mentioning

confidence: 99%

“…7 In addition, others have reported detection of both transcript and protein for all 3 isoforms of NOS in the thick ascending limb. 8,10,12,15 Accordingly, we evaluated the response to L-Arg in isolated perfused thick ascending limbs from control and selective NOS isoform knockout mice to L-Arg.We first determined whether the mouse thick ascending limb contains active NOS and whether endogenously produced NO inhibits transport. Figure 1 illustrates the effect of the substrate for NOS, L-Arg (0.5 mmol/L), on chloride flux in 6 isolated thick ascending limbs from C57BL/6J controls.…”

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confidence: 99%

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confidence: 99%

“…10 NOS protein expression has also been demonstrated in the THAL. Tojo et al 11 12 with the use of Western blots, showed that the rat outer medulla expresses all 3 NOS isoforms.…”

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eNOS Mediates l -Arginine–Induced Inhibition of Thick Ascending Limb Chloride Flux

2000

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Abstract-We recently reported that the rat thick ascending limb (THAL) possesses an active isoform of nitric oxide synthase (NOS) that is substrate-limited in vitro. NO produced by THAL NOS inhibits chloride flux. Protein and transcript for each of the primary NOS isoformsϪendothelial (eNOS), inducible (iNOS), and neuronal (nNOS)Ϫhave been demonstrated in THALs. However, the NOS isoform that mediates NO-induced inhibition of chloride flux is unknown. We hypothesized that NO produced from eNOS in the THAL inhibits NaCl transport. THALs from male eNOS, iNOS, and nNOS knockout mice and C57BL/6J wild-type controls were perfused in vitro and the response of transepithelial chloride flux (J Cl ) to L-arginine (L-Arg), the substrate for NOS, and spermine NONOate (SPM), an NO donor was measured. We first tested whether isolated mouse THALs could synthesize NO and whether this NO inhibits transport. Addition of 0.5 mmol/L L-Arg to the bath decreased J Cl from 105.8Ϯ17.5 to 79.2Ϯ15.8 pmol/mm per minute (PϽ0.01) in C57BL/6J wild-type mice, whereas addition of D-Arginine had no effects on J Cl. In contrast, addition of 0.5 mmol/L L-Arg to the bath did not alter J Cl of THALs from eNOS knockout mice. When 10 mol/L SPM was added to the bath of eNOS knockout THALs, J Cl decreased from 89.1Ϯ8.6 to 74.8Ϯ7.5 pmol/mm/min (PϽ0.05). Thus the lack of responsiveness of eNOS knockout THALs to L-Arg was not due to an inability to respond to NO. We next evaluated the role of iNOS and nNOS in the response to L-Arg. Addition of 0.5 mmol/L L-Arg to the bath decreased J Cl in THALs from iNOS and nNOS knockout mice by 37.7Ϯ6.4% (PϽ0.05) and 31.8Ϯ8.3% (PϽ0.01), respectively. We conclude that eNOS is the active isoform of NOS in the THAL under basal conditions. Mouse THAL eNOS responds to exogenous L-Arg by increasing NO production, which, in turn, inhibits J Cl . Key Words: nitric oxide Ⅲ kidney Ⅲ mice R enal nitric oxide (NO) is an important controller of urinary sodium excretion. NO may enhance natriuresis by inhibiting transport along the nephron as well as altering renal hemodynamics and glomerular filtration rate. 1 Several in vivo studies support the hypothesis that NO directly inhibits tubular sodium reabsorption. Urinary sodium excretion increases when NO production is stimulated 2 and decreases when NO synthase (NOS) is inhibited 3 in the absence of altered renal hemodynamics.In vitro studies indicate that NO directly affects tubular absorption. 4 -6 We recently reported that L-Arginine (L-Arg) inhibits chloride flux through the thick ascending limb of the loop of Henle (THAL) of rats via an L-NAME-sensitive mechanism. These data indicate that endogenously produced NO inhibits THAL transport. 7 However, these studies did not address the NOS isoform(s) mediating tubular NO synthesis.mRNA for each of the NOS isoforms has been detected in THALs. With the use of reverse transcription polymerase chain reaction (RT-PCR) of microdissected nephrons, Ujiie et al 8 detected endothelial (eNOS) mRNA in rat THALs, whereas Mohaupt et al 9 used com...

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Salt, Angiotensin II, Superoxide, and Endothelial Function

Boegehold¹,

Drenjančević-Perić²,

Lombard³

2015

Comprehensive Physiology

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Proper function of the vascular endothelium is essential for cardiovascular health, in large part due to its antiproliferative, antihypertrophic, and anti-inflammatory properties. Crucial to the protective role of the endothelium is the production and liberation of nitric oxide (NO), which not only acts as a potent vasodilator, but also reduces levels of reactive oxygen species, including superoxide anion (O2•-). Superoxide anion is highly injurious to the vasculature because it not only scavenges NO molecules, but has other damaging effects, including direct oxidative disruption of normal signaling mechanisms in the endothelium and vascular smooth muscle cells. The renin-angiotensin system plays a crucial role in the maintenance of normal blood pressure. This function is mediated via the peptide hormone angiotensin II (ANG II), which maintains normal blood volume by regulating Na+ excretion. However, elevation of ANG II above normal levels increases O2•- production, promotes oxidative stress and endothelial dysfunction, and plays a major role in multiple disease conditions. Elevated dietary salt intake also leads to oxidant stress and endothelial dysfunction, but these occur in the face of salt-induced ANG II suppression and reduced levels of circulating ANG II. While the effects of abnormally high levels of ANG II have been extensively studied, far less is known regarding the mechanisms of oxidant stress and endothelial dysfunction occurring in response to chronic exposure to abnormally low levels of ANG II. The current article focuses on the mechanisms and consequences of this less well understood relationship among salt, superoxide, and endothelial function.

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Influence of Dietary Sodium Intake on Renal Medullary Nitric Oxide Synthase

Cited by 185 publications

References 20 publications

Recent Advances in the Regulation of Nitric Oxide in the Kidney

Recent Advances in the Regulation of Nitric Oxide in the Kidney

eNOS Mediates l -Arginine–Induced Inhibition of Thick Ascending Limb Chloride Flux

Salt, Angiotensin II, Superoxide, and Endothelial Function

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