Collecting duct–specific knockout of endothelin-1 causes hypertension and sodium retention

Ahn, Dowhan; Ge, Yuqiang; Stricklett, Peter K.; Gill, Pritmohinder; Taylor, Daniel M.; Hughes, Alisa K.; Yanagisawa, Masashi; Miller, Lance; Nelson, Raoul D.; Kohan, Donald E.

doi:10.1172/jci200421064

Cited by 228 publications

(166 citation statements)

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“…A role for renal medullary derived ET-1 in the control of renal excretory function has accumulated over recent years (1,8,21). Multiple studies indicate the importance of this system becomes greater as Na ϩ intake is increased (21).…”

Section: Discussionmentioning

confidence: 99%

“…For example, Pollock and others (4)have shown that renal ET-1 production is enhanced in response to 1 wk of a high-sodium diet, and intramedullary blockade of ET B receptors for 7 days leads to salt-sensitive hypertension. In addition, specific knockout of the ET B receptor gene and the ET-1 gene in the medullary collecting duct produces salt-sensitive hypertension (1,6).…”

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confidence: 99%

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Renal medullary endothelin-1 is decreased in Dahl salt-sensitive rats

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LaMarca

Berry

et al. 2011

American Journal of Physiology-Regulatory, Integrative and Comp

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Although it is well established that the renal endothelin (ET-1) system plays an important role in regulating sodium excretion and blood pressure through activation of renal medullary ETB receptors, the role of this system in Dahl salt-sensitive (DS) hypertension is unclear. The purpose of this study was to determine whether the DS rat has abnormalities in the renal medullary endothelin system when maintained on a high sodium intake. The data indicate that Dahl saltresistant rats (DR) on a high-salt diet had a six-fold higher urinary endothelin excretion than in the DR rats with low Na ϩ intake (17.8 Ϯ 4 pg/day vs. 112 Ϯ 44 pg/day). In sharp contrast, urinary endothelin levels increased only twofold in DS rats in response to a high Na ϩ intake (13 Ϯ 2 pg/day vs. 29.8 Ϯ 5.5 pg/day). Medullary endothelin concentration in DS rats on a high-Na ϩ diet was also significantly lower than DR rats on a high-Na ϩ diet (31 Ϯ 2.8 pg/mg vs. 70.9 Ϯ 5 pg/mg). Furthermore, DS rats had a significant reduction in medullary ET B receptor expression compared with DR rats while on a high-Na ϩ diet. Finally, chronic infusion of ET-1 directly into the renal medulla blunted Dahl salt-sensitive hypertension. These data indicate that a decrease in medullary production of ET-1 in the DS rat could play an important role in the development of salt-sensitive hypertension observed in the DS rat.kidney; blood pressure; hypertension ENDOTHELIN-1 (ET-1) WAS FIRST characterized in 1988 as a potent vasoconstrictor released by endothelial cells (26). Two receptor subtypes have been since identified, ET A and ET B (24). Both of these receptors are located in the kidney with the highest concentration of ET B receptors existing within the medulla (11). Although the role of ET A receptors has been well characterized in the pathophysiology of experimental hypertension, the physiological importance of ET B receptors in modulating sodium excretion and blood pressure regulation in salt-sensitive hypertension is unclear. ET B activation inhibits sodium transport (15,18,19), and growing evidence suggests a critical role for the renal medullary endothelin system in the integrated response to a high-salt diet (6, 20 -21). For example, Pollock and others (4)have shown that renal ET-1 production is enhanced in response to 1 wk of a high-sodium diet, and intramedullary blockade of ET B receptors for 7 days leads to salt-sensitive hypertension. In addition, specific knockout of the ET B receptor gene and the ET-1 gene in the medullary collecting duct produces salt-sensitive hypertension (1, 6).Although there is growing evidence from a number of laboratories that the renal endothelin system via ET B receptor activation plays an important role in modulating renal pressure natriuresis and blood pressure regulation, very little is known about potential abnormalities in renal endothelin system in models of salt-sensitive hypertension. Our laboratory and others have reported that there is a rightward shift in the pressure natriuresis relationship in Dahl salt-sensitive r...

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

Renal medullary endothelin-1 is decreased in Dahl salt-sensitive rats

Speed

LaMarca

Berry

et al. 2011

American Journal of Physiology-Regulatory, Integrative and Comp

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“…New technology that allows deletion or expression of a particular gene in specific tissues in the kidney is an important scientific advance. Over the past few years, various animal models have been developed using such technology 13,[93][94][95] that provide new means of studying the physiological actions of a single NOS isoform in a single cell type at a specific point in time in vivo.…”

Section: Perspectivesmentioning

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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“…185 Moreover, it was shown that altered ET-1 production may contribute to hypertension. 186,187 Several human studies demonstrated a correlation between plasma or urinary levels of ET-1 and markers of DN, such as hyperfiltration, mesangial expansion, macro-and/or microalbuminuria, and uremia. [188][189][190][191][192] In addition, interventional studies using endothelin-receptor-blockers have yielded encouraging results [193][194][195][196][197][198] in rodent models of DMT1 195,198 or DMT2.…”

Section: Endothelin (Et) Blockersmentioning

confidence: 99%

Therapeutic Modalities in Diabetic Nephropathy: Standard and Emerging Approaches

et al. 2011

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Diabetes mellitus is the leading cause of end stage renal disease and is responsible for more than 40% of all cases in the United States. Current therapy directed at delaying the progression of diabetic nephropathy includes intensive glycemic and optimal blood pressure control, proteinuria/albuminuria reduction, interruption of the renin-angiotensin-aldosterone system through the use of angiotensin converting enzyme inhibitors and angiotensin type-1 receptor blockers, along with dietary modification and cholesterol lowering agents. However, the renal protection provided by these therapeutic modalities is incomplete. More effective approaches are urgently needed. This review highlights the available standard therapeutic approaches to manage progressive diabetic nephropathy, including markers for early diagnosis of diabetic nephropathy. Furthermore, we will discuss emerging strategies such as PPAR-gamma agonists, Endothelin blockers, vitamin D activation and inflammation modulation. Finally, we will summarize the recommendations of these interventions for the primary care practitioner.

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Collecting duct–specific knockout of endothelin-1 causes hypertension and sodium retention

Cited by 228 publications

References 52 publications

Renal medullary endothelin-1 is decreased in Dahl salt-sensitive rats

Renal medullary endothelin-1 is decreased in Dahl salt-sensitive rats

Recent Advances in the Regulation of Nitric Oxide in the Kidney

Therapeutic Modalities in Diabetic Nephropathy: Standard and Emerging Approaches

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