Ouabain stimulates Na-K-ATPase through a sodium/hydrogen exchanger-1 (NHE-1)-dependent mechanism in human kidney proximal tubule cells

Holthouser, Kristine; Mandal, Amritlal; Merchant, Michael L.; Schelling, Jeffrey R.; Delamere, Nicholas A.; Valdes, Roland R; Tyagi, Suresh C.; Lederer, Eleanor; Khundmiri, Syed Jalal

doi:10.1152/ajprenal.00581.2009

Cited by 63 publications

(62 citation statements)

References 62 publications

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“…Recent studies from our laboratory have demonstrated that treatment with low-dose ouabain, concentrations similar to those present in ESRD patients, increases blood pressure in rats and increases Na C /K C ATPase activity in basolateral membranes prepared from kidney cortex. The increase in activity was dependent upon the presence of NHE1 (SLC9A1) expression and was inhibited by specific inhibitors of NHE1 (Holthouser et al 2010). We also demonstrated that low-dose cardiotonic steroids increase the association between Na C /K C ATPase and NHE1 and that this association is critical for activation of the Src-EGFR signaling cascade.…”

Section: Atpase Activitymentioning

confidence: 60%

“…Therefore, it remains to be determined whether different Na C /K C ATPase isoforms play such different roles in cardiotonic steroid-mediated blood pressure development in humans. This review highlights recent exciting studies investigating the effects of physiological and pathophysiological concentrations of cardiotonic steroids on renal salt reabsorption (Aizman et al 2001, Abramowitz et al 2003, Aizman & Aperia 2003, Contreras et al 2006, Khundmiri et al 2006, Aperia 2007, Nguyen et al 2007, Holthouser et al 2010, Jansson et al 2012, Bignami et al 2013, Blanco & Wallace 2013). …”

Section: Introductionmentioning

confidence: 97%

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Advances in understanding the role of cardiac glycosides in control of sodium transport in renal tubules

Khundmiri¹

2014

Journal of Endocrinology

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Cardiotonic steroids have been used for the past 200 years in the treatment of congestive heart failure. As specific inhibitors of membrane-bound Na C /K C ATPase, they enhance cardiac contractility through increasing myocardial cell calcium concentration in response to the resulting increase in intracellular Na concentration. The half-minimal concentrations of cardiotonic steroids required to inhibit Na C /K C ATPase range from nanomolar to micromolar concentrations. In contrast, the circulating levels of cardiotonic steroids under physiological conditions are in the low picomolar concentration range in healthy subjects, increasing to high picomolar levels under pathophysiological conditions including chronic kidney disease and heart failure. Little is known about the physiological function of low picomolar concentrations of cardiotonic steroids. Recent studies have indicated that physiological concentrations of cardiotonic steroids acutely stimulate the activity of Na C /K C ATPase and activate an intracellular signaling pathway that regulates a variety of intracellular functions including cell growth and hypertrophy. The effects of circulating cardiotonic steroids on renal salt handling and total body sodium homeostasis are unknown. This review will focus on the role of low picomolar concentrations of cardiotonic steroids in renal Na C /K C ATPase activity, cell signaling, and blood pressure regulation.

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Section: Atpase Activitymentioning

confidence: 60%

Section: Introductionmentioning

confidence: 97%

Advances in understanding the role of cardiac glycosides in control of sodium transport in renal tubules

Khundmiri¹

2014

Journal of Endocrinology

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“…Ouabain also enhances LPS-down-regulated inducible nitric-oxide synthase activity in peritoneal macrophages (51). Interestingly, at low concentrations (nanomolar and picomolar), ouabain stimulates Na ϩ /K ϩ -ATPase activity (28) and activates complex signaling cascades in kidney cells (30). In subnanomolar concentrations, ouabain stimulates proliferation and differentiation of cardiac and smooth muscle cells (52).…”

Section: Discussionmentioning

confidence: 99%

Naloxone and Ouabain in Ultralow Concentrations Restore Na+/K+-ATPase and Cytoskeleton in Lipopolysaccharide-treated Astrocytes

Forshammar

Block

Lundborg

et al. 2011

Journal of Biological Chemistry

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Infection, tissue damage, or other conditions can lead to a neuroinflammatory state. Lipopolysaccharide (LPS) exposure can be used experimentally as a model to generate an inflammatory response both in vitro and in vivo. Endotoxin, or LPS, is a potent inflammatory activator (1) in astrocytes and microglia, with stimulation of Toll-like receptor 4 (TLR4) (2). The expression of TLR4 is up-regulated in astrocytes under neuroinflammatory conditions (3). Activation of TLR4 leads to activation of nuclear factor-B, a factor that regulates expression of genes involved in immune responses, including release of the proinflammatory cytokines tumor necrosis factor-␣ (TNF-␣) and interleukin-1␤ (IL-1␤) (2).Astrocytes in networks, positioned between the vasculature and synapses, monitor neuronal signaling, including rebuilding of synapses (4, 5). Astrocytes express almost the same repertoire of receptors and ion channels as neurons. They regulate synaptic transmission via a bidirectional communication with neurons, and they release gliotransmitters as well as factors, including cytokines, fatty acid metabolites, and free radicals (6 -8).The Ca 2ϩ signaling in astrocytes over long distances is analogous to, but much slower than, the propagation of action potentials in neurons (9). These astrocytic Ca 2ϩ waves (10, 11) can be evoked by transmitters released from neurons and glial cells, followed by activation of especially G protein-coupled receptors. Cytosolic Ca 2ϩ plays a key role as a second messenger, and the control of Ca 2ϩ signals is therefore critical. This involves coordination of Ca 2ϩ entry across the plasma membrane (PM), 2 Ca 2ϩ release from the endoplasmatic reticulum (ER), refilling of the ER stores, and extrusion across the PM (12). The Na ϩ -Ca 2ϩ exchanger, a Ca 2ϩ transporter that controls the intracellular Ca 2ϩ concentrations, is driven by the Na ϩ electrochemical gradient across the PM. This Na ϩ pump, Na ϩ /K ϩ -ATPase, indirectly modulates Ca 2ϩ signaling (13), and inflammatory stimuli influence Ca 2ϩ homeostasis in the astrocyte networks (5, 14 -16).The cytoskeleton seems to be important in this system for controlling of PM microdomains and the ER complex. The adaptor protein ankyrin B is associated with the Na ϩ pump and also with ER proteins, such as the inositol 1,4,5-trisphosphate (IP 3 ) receptor. The main cytoplasmic matrix of proteins, spectrin and actin, are attached to ankyrin B. An intact cytoskeleton is required for the propagation of astrocytic Ca 2ϩ waves (17)

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“…In addition, the ability of NHE1 to contribute to adaptive regulation in renal tubules may take on broader significance as additional functions for NHE1 in vectorial transport are recognized. For example, recent studies suggest that NHE1 can interact with the Na ϩ -K ϩ -ATPase ␣-subunit to modulate sodium pump activity in proximal tubule cell lines (37). Last, our studies provide a basis for future investigations into other physiological conditions and disease states that may alter renal tubule functions through adaptations in NHE1.…”

Section: Of Hcomentioning

confidence: 66%

High sodium intake increases HCO₃⁻absorption in medullary thick ascending limb through adaptations in basolateral and apical Na⁺/H⁺exchangers

Good

George²,

Watts³

2011

American Journal of Physiology-Renal Physiology

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A high sodium intake increases the capacity of the medullary thick ascending limb (MTAL) to absorb HCO(3)(-). Here, we examined the role of the apical NHE3 and basolateral NHE1 Na(+)/H(+) exchangers in this adaptation. MTALs from rats drinking H(2)O or 0.28 M NaCl for 5-7 days were perfused in vitro. High sodium intake increased HCO(3)(-) absorption rate by 60%. The increased HCO(3)(-) absorptive capacity was mediated by an increase in apical NHE3 activity. Inhibiting basolateral NHE1 with bath amiloride eliminated 60% of the adaptive increase in HCO(3)(-) absorption. Thus the majority of the increase in NHE3 activity was dependent on NHE1. A high sodium intake increased basolateral Na(+)/H(+) exchange activity by 89% in association with an increase in NHE1 expression. High sodium intake increased apical Na(+)/H(+) exchange activity by 30% under conditions in which basolateral Na(+)/H(+) exchange was inhibited but did not change NHE3 abundance. These results suggest that high sodium intake increases HCO(3)(-) absorptive capacity in the MTAL through 1) an adaptive increase in basolateral NHE1 activity that results secondarily in an increase in apical NHE3 activity; and 2) an adaptive increase in NHE3 activity, independent of NHE1 activity. These studies support a role for NHE1 in the long-term regulation of renal tubule function and suggest that the regulatory interaction whereby NHE1 enhances the activity of NHE3 in the MTAL plays a role in the chronic regulation of HCO(3)(-) absorption. The adaptive increases in Na(+)/H(+) exchange activity and HCO(3)(-) absorption in the MTAL may play a role in enabling the kidneys to regulate acid-base balance during changes in sodium and volume balance.

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Ouabain stimulates Na-K-ATPase through a sodium/hydrogen exchanger-1 (NHE-1)-dependent mechanism in human kidney proximal tubule cells

Cited by 63 publications

References 62 publications

Advances in understanding the role of cardiac glycosides in control of sodium transport in renal tubules

Advances in understanding the role of cardiac glycosides in control of sodium transport in renal tubules

Naloxone and Ouabain in Ultralow Concentrations Restore Na+/K+-ATPase and Cytoskeleton in Lipopolysaccharide-treated Astrocytes

High sodium intake increases HCO₃⁻absorption in medullary thick ascending limb through adaptations in basolateral and apical Na⁺/H⁺exchangers

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Ouabain stimulates Na-K-ATPase through a sodium/hydrogen exchanger-1 (NHE-1)-dependent mechanism in human kidney proximal tubule cells

Cited by 63 publications

References 62 publications

Advances in understanding the role of cardiac glycosides in control of sodium transport in renal tubules

Advances in understanding the role of cardiac glycosides in control of sodium transport in renal tubules

Naloxone and Ouabain in Ultralow Concentrations Restore Na+/K+-ATPase and Cytoskeleton in Lipopolysaccharide-treated Astrocytes

High sodium intake increases HCO3−absorption in medullary thick ascending limb through adaptations in basolateral and apical Na+/H+exchangers

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High sodium intake increases HCO₃⁻absorption in medullary thick ascending limb through adaptations in basolateral and apical Na⁺/H⁺exchangers