Endothelin Inhibits NPR-A and Stimulates eNOS Gene Expression in Rat IMCD Cells

Ye, Qiong; Chen, Songcang; Gardner, David G.

doi:10.1161/01.hyp.0000047204.72286.34

Cited by 44 publications

(32 citation statements)

References 34 publications

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“…The IMCD cells from Wistar rats were isolated and cultured using the method described previously (Ye et al, 2003). In brief, adult Wistar male rats were killed by cervical dislocation after CO 2 narcosis.…”

Section: Methodsmentioning

confidence: 99%

Glucocorticoids Improve Renal Responsiveness to Atrial Natriuretic Peptide by Up-Regulating Natriuretic Peptide Receptor-A Expression in the Renal Inner Medullary Collecting Duct in Decompensated Heart Failure

Liu

Chen²,

Kang³

et al. 2011

J Pharmacol Exp Ther

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In heart failure, the renal responsiveness to exogenous and endogenous atrial natriuretic peptide (ANP) is blunted. The mechanisms of renal hyporesponsiveness to ANP are complex, but one potential mechanism is decreased expression of natriuretic peptide receptor-A (NPR-A) in inner medullary collecting duct (IMCD) cells. Newly emerging evidence shows that glucocorticoids could produce potent diuresis and natriuresis in patients with heart failure, but the precise mechanism is unclear. In the present study, we found dexamethasone (Dex) dramatically increased the expression of NPR-A in IMCD cells in vitro. The NPR-A overexpression induced by Dex presented in a time-and dose-dependent manner, which emerged after 12 h and peaked after 48 h. The cultured IMCD cells were then stimulated with exogenous rat ANP. Consistent with the findings with NPR-A expression, Dex greatly increased cGMP (the second messenger for the ANP) generation in IMCD cells, which presented in a time-and dose-dependent manner as well. In rats with decompensated heart failure, Dex dramatically increased NPR-A expression in inner renal medulla, which was accompanied by a remarkable increase in renal cGMP generation, urine flow rate, and renal sodium excretion. It is noteworthy that Dex dramatically lowered plasma ANP, cGMP levels, and left ventricular end diastolic pressure. These favorable effects induced by Dex were glucocorticoid receptor (GR)-mediated and abolished by the GR antagonist 17␤-hydroxy-11␤-[4-dimethylamino phenyl]-17␣-[1-propynyl]estra-4,9-dien-3-one (RU486). Collectively, glucocorticoids could improve renal responsiveness to ANP by up-regulating NPR-A expression in the IMCD and induce a potent diuretic action in rats with decompensated heart failure.

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Section: Methodsmentioning

confidence: 99%

Glucocorticoids Improve Renal Responsiveness to Atrial Natriuretic Peptide by Up-Regulating Natriuretic Peptide Receptor-A Expression in the Renal Inner Medullary Collecting Duct in Decompensated Heart Failure

Liu

Chen²,

Kang³

et al. 2011

J Pharmacol Exp Ther

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“…6,7 ET-1 induces NO release in CD cells via activation of NOS1, 5 whereas ET-1 increases expression of NOS3 in CD cells. 29 High Na intake increases medullary NOS activity and ET-1 production. 30 High Na intake increased NOS1 and NOS3 activities in the inner medulla in both mouse genotypes similarly, suggesting that the high-salt diet-induced NOS activity may not be via CD-derived ET.…”

Section: Schneider Et Al Collecting Duct Et-1 Affects Blood Pressure mentioning

confidence: 99%

Collecting Duct-Derived Endothelin Regulates Arterial Pressure and Na Excretion via Nitric Oxide

Schneider

Pollock

et al. 2008

Hypertension

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Abstract-Mice with a collecting duct-specific deletion of endothelin-1 are hypertensive and have impaired Na excretion.Because endothelin-1 activates NO synthase (NOS) in the collecting duct, we hypothesized that impaired renal NO production in knockout mice exacerbates the hypertensive state. Control and knockout mice were treated chronically with N G -nitro-Larginine methyl ester, and blood pressure (BP) and urinary nitrate/nitrite excretion were assessed. On a normal Na diet, knockout systolic BP was 18 mm Hg greater than in controls. N G -nitro-L-arginine methyl ester increased BP in control mice by 30 mm Hg and 10 mm Hg in collecting duct-specific deletion of endothelin-1 knockout mice, thereby abolishing the difference in systolic BP between the groups. A high-Na diet increased BP similarly in both groups. Urinary nitrate/nitrite excretion was lower in knockout mice than in controls on normal or high Na intake. In separate experiments, renal perfusion pressure was adjusted in anesthetized mice, and urinary nitrate/nitrite and Na excretion were determined. Similar elevations of BP increased urinary Na and nitrate/nitrite excretion in control mice but to a significantly lesser extent in knockout mice. Isoform-specific NOS activity and expression were determined in renal inner medulla homogenates from control and knockout mice. NOS1 and NOS3 activities were lower in knockout than in control mice given normal or high-Na diets. However, NOS1 or NOS3 protein expressions were similar in both groups on normal or high-Na intake. These data demonstrate that collecting duct-derived endothelin-1 is important in the following: (1) Key Words: ET-1 Ⅲ NO Ⅲ Na Ⅲ natriuresis Ⅲ diuresis Ⅲ blood pressure C ollecting duct (CD)-derived endothelin-1 (ET-1) is an important regulator of blood pressure (BP) and renal Na excretion. 1 ET-1 inhibits distal nephron Na/K ATPase and epithelial Na channel activity, 2,3 whereas CD-specific knockout of ET-1 causes hypertension and impaired Na excretion. 1 The natriuretic effect of ET-1 is attributable, at least partially, to activation of CD endothelin B (ET B ) receptors, because CDspecific deletion of ET B receptors causes hypertension and reduced Na excretion. 4 How ET-1 modulates renal Na excretion and BP is unknown; however, the NO pathway may be involved. ET-1 stimulates NO production in inner medullary CD via the ET B receptor and NO synthase (NOS) 1 (also known as nNOS). 5 Inner medullary NOS1 and NOS3 (latter also known as eNOS) activity are reduced in rats with dysfunctional ET B receptors. 6,7 In thick-ascending limbs, ET-1 enhances NO production through increased NOS3 activity with resultant inhibition of chloride transport. 8,9 NO also inhibits Na transport in isolated cortical CD. 10 Taken together, these studies suggest that NO is an important mediator of the natriuretic and antihypertensive effects of CD-derived ET-1.One condition under which the CD ET-1/NO pathway may be of particular importance is increased Na excretion in response to elevations of renal perfusion pressur...

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“…72 Similarly, endothelin-1 stimulates NOS 3 expression in inner medullary collecting ducts. 73 However, unlike the thick ascending limb where the effect was mediated only by ET B receptors, 72 in the inner medullary collecting duct both ET A and ET B were involved. Osmotic stimuli have also been shown to increase NOS 3 expression in inner medullary collecting ducts in culture.…”

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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Endothelin Inhibits NPR-A and Stimulates eNOS Gene Expression in Rat IMCD Cells

Cited by 44 publications

References 34 publications

Glucocorticoids Improve Renal Responsiveness to Atrial Natriuretic Peptide by Up-Regulating Natriuretic Peptide Receptor-A Expression in the Renal Inner Medullary Collecting Duct in Decompensated Heart Failure

Glucocorticoids Improve Renal Responsiveness to Atrial Natriuretic Peptide by Up-Regulating Natriuretic Peptide Receptor-A Expression in the Renal Inner Medullary Collecting Duct in Decompensated Heart Failure

Collecting Duct-Derived Endothelin Regulates Arterial Pressure and Na Excretion via Nitric Oxide

Recent Advances in the Regulation of Nitric Oxide in the Kidney

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