Endothelin-1 Inhibits Thick Ascending Limb Transport via Akt-stimulated Nitric Oxide Production

Herrera, Marcela; Hong, Nancy J.; Ortíz, Pablo; Garvin, Jeffrey L.

doi:10.1074/jbc.m804322200

Cited by 60 publications

(56 citation statements)

References 44 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…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%

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

View full text Add to dashboard Cite

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...

show abstract

Section: Discussionmentioning

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

View full text Add to dashboard Cite

show abstract

“…Finally, TNF-␣ reduces NOS3 expression and NO production in this nephron segment (116). NO produced in response to arginine (103,110) endothelin-1 (109,56) and clonidine (108) reduces NaCl reabsorption mainly by decreasing NKCC2 activity by the thick ascending limb. These data suggest that TNF-␣ affects Na transport regulation by the thick ascending limb by reducing basal Na reabsorption while blunting the ability of other natriuretic autacoids and hormones to further decrease transport.…”

Section: Na Water Urea and Glucose Transportmentioning

confidence: 99%

Tumor necrosis factor-α: regulation of renal function and blood pressure

Ramseyer

Garvin

2013

American Journal of Physiology-Renal Physiology

Self Cite

149

106

View full text Add to dashboard Cite

show abstract

“…In addition, activation of P2X receptors by ATP increases phosphatidylinositol (3,4,5)-trisphosphate (PIP3) production by PI3 kinase and stimulates Akt activity (10,15). In the thick ascending limb, the PI3 kinase/Akt pathway is an important signaling cascade involved in NO synthase 3 (NOS3) activation (12,27,29). Therefore, it is possible that ATP also stimulates NOS via Akt in this segment.…”

mentioning

confidence: 99%

Akt1 mediates purinergic-dependent NOS3 activation in thick ascending limbs

Silva

Garvin

2009

American Journal of Physiology-Renal Physiology

Self Cite

View full text Add to dashboard Cite

Silva GB, Garvin JL. Akt1 mediates purinergic-dependent NOS3 activation in thick ascending limbs. Am J Physiol Renal Physiol 297: F646 -F652, 2009. First published July 1, 2009 doi:10.1152/ajprenal.00270.2009.-Extracellular ATP regulates many physiological processes via release of nitric oxide (NO). ATP stimulates NO in thick ascending limbs (TALs), but the signaling cascade involved in the cells of this nephron segment, as well as many other types of cells, is poorly understood. We hypothesized that ATP enhances NO synthase (NOS) activity by stimulating PI3 kinase and Akt. We measured 1) NO in TALs using the NO-sensitive dye DAF-2 DA and 2) Akt activity by fluorescence resonance energy transfer and phosphorylation of Akt isoforms. ATP (100 M) stimulated NO in wild-type mice [26 Ϯ 4 arbitrary units (AU)], but not in NOS3 Ϫ/Ϫ mice (2 Ϯ 2 AU; P Ͻ 0.04). In the presence of the NOS1-and NOS2-selective inhibitors 7-NI and 1400W, ATP stimulated NO by 30 Ϯ 2 and 33 Ϯ 3 AU, respectively (not significant vs. control). In the presence of the PI3 kinase inhibitor LY294002, ATP-increased NO was reduced by 85% (5 Ϯ 2 vs. 28 Ϯ 4 AU; P Ͻ 0.02). ATP alone increased Akt activity and this effect was significantly blocked by suramin, a P2 receptor antagonist. In the presence of an Akt-selective inhibitor, ATP-induced NO was blocked by 90 Ϯ 4%. ATP significantly stimulated Akt1 phosphorylation at Ser 473 by 91 Ϯ 13%, whereas Akt2 phosphorylation remained unchanged and Akt3 phosphorylation decreased. In vivo transduction of TALs with a dominantnegative Akt1 significantly decreased ATP-induced NO by 88 Ϯ 6%. We concluded that ATP increases NOS3-derived NO via Akt1 activation in the TAL. purinergic signaling; adenosine triphosphate; Na-K-2Cl cotransporter IN THE KIDNEY, ADENOSINE triphosphate (ATP) is released from several types of cells. Macula densa cells release ATP in response to an increase in luminal NaCl (19), while mesangial cells release ATP in response to elevated glucose (35). The cells that constitute the thick ascending limb release ATP in response to decreases in osmolality (34) and increases in luminal flow (16). The ATP released from these and other cells has pleotrophic effects. In vivo studies showed that extracellular ATP inhibits fluid absorption (1). In the collecting duct extracellular ATP also decreases Na (32) and water (18) reabsorption. Increases in ATP in the renal interstitium correlate with decreases in renal blood flow (26), most likely related to afferent arterial autoregulation (14). Moreover, we recently demonstrated that extracellular ATP stimulates nitric oxide (NO) by thick ascending limbs via activation of purinergic 2X (P2X) receptors (33). Indeed, ATP has been shown to stimulate NO production in a variety of cells, including platelets (20), endothelial cells (37), and cells of the central nervous system (31). However, the mechanisms by which ATP stimulates NO production are poorly understood.Activation of P2X receptors may lead to stimulation of several signaling cascades. These include glycoge...

show abstract

Endothelin-1 Inhibits Thick Ascending Limb Transport via Akt-stimulated Nitric Oxide Production

Cited by 60 publications

References 44 publications

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

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

Tumor necrosis factor-α: regulation of renal function and blood pressure

Akt1 mediates purinergic-dependent NOS3 activation in thick ascending limbs

Contact Info

Product

Resources

About