Na delivery and ENaC mediate flow regulation of collecting duct endothelin-1 production

Pandit, Meghana M.; Strait, Kevin A.; Matsuda, Takehisa; Kohan, Donald E.

doi:10.1152/ajprenal.00034.2012

Cited by 21 publications

(37 citation statements)

References 32 publications

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“…The flow response was dependent on intracellular and extracellular Ca 2ϩ , phospholipase C (PLC), and protein kinase C (PKC). A subsequent study (67) found that increasing perfusate NaCl concentration increased the ET-1 flow response in mpkCCDcl4 cells and that this effect was due to Na ϩ but not Cl Ϫ or osmolality. The ET-1 flow response was dependent on the epithelial Na ϩ channel (ENaC), being inhibited by amiloride or benzamil and stimulated by aldosterone.…”

Section: Regulation Of Collecting Duct Et Productionmentioning

confidence: 91%

Role of collecting duct endothelin in control of renal function and blood pressure

Kohan

2013

American Journal of Physiology-Regulatory, Integrative and Comp

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Over 26,000 manuscripts have been published dealing with endothelins since their discovery 25 years ago. These peptides, and particularly endothelin-1 (ET-1), are expressed by, bind to, and act on virtually every cell type in the body, influencing multiple biological functions. Among these actions, the effects of ET-1 on arterial pressure and volume homeostasis have been most extensively studied. While ET-1 modulates arterial pressure through regulation of multiple organ systems, the peptide's actions in the kidney in general, and the collecting duct in particular, are of unique importance. The collecting duct produces large amounts of ET-1 that bind in an autocrine manner to endothelin A and B receptors, causing inhibition of Na(+) and water reabsorption; absence of collecting duct ET-1 or its receptors is associated with marked salt-sensitive hypertension. Collecting duct ET-1 production is stimulated by Na(+) and water loading through local mechanisms that include sensing of salt and other solute delivery as well as shear stress. Thus the collecting duct ET-1 system exists, at least in part, to detect alterations in, and maintain homeostasis for, extracellular fluid volume. Derangements in collecting duct ET-1 production may contribute to the pathogenesis of genetic hypertension. Blockade of endothelin receptors causes fluid retention due, in large part, to inhibition of the action of ET-1 in the collecting duct; this side effect has substantially limited the clinical utility of this class of drugs. Herein, the biology of the collecting duct ET-1 system is reviewed, with particular emphasis on key issues and questions that need addressing.

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Section: Regulation Of Collecting Duct Et Productionmentioning

confidence: 91%

Role of collecting duct endothelin in control of renal function and blood pressure

Kohan

2013

American Journal of Physiology-Regulatory, Integrative and Comp

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“…However, the effect of extracellular NaCl or osmolality on CD ET-1 production is controversial, with conflicting findings being reported (27). Recent studies by our group have suggested that tubule fluid flow may be involved: exposure of mpkCCD cells, a cortical CD cell line, to shear stress increased ET-1 mRNA (28,36). Interestingly, this flow augmentation of mpkCCD ET-1 mRNA content was due to Na ϩ delivery; increasing Na ϩ delivery increased epithelial Na ϩ channel (ENaC)-mediated Na ϩ entry, which led to enhanced mitochondrial Na ϩ /Ca 2ϩ exchange (NCLX), increased intracellular Ca 2ϩ concentration ([Ca 2ϩ ] i ), activation of Ca 2ϩ signaling pathways, and, ultimately, increased ET-1 gene transcription (36).…”

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confidence: 99%

Flow regulation of endothelin-1 production in the inner medullary collecting duct

Pandit

Inscho

Zhang

et al. 2015

American Journal of Physiology-Renal Physiology

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Collecting duct-derived endothelin (ET)-1 is an autocrine inhibitor of Na(+) and water reabsorption; its deficiency causes hypertension and water retention. Extracellular fluid volume expansion increases collecting duct ET-1, thereby promoting natriuresis and diuresis; however, how this coupling between volume expansion and collecting duct ET-1 occurs is incompletely understood. One possibility is that volume expansion increases tubular fluid flow. To investigate this, cultured IMCD3 cells were subjected to static or flow conditions. Exposure to a shear stress of 2 dyn/cm(2) for 2 h increased ET-1 mRNA content by ∼2.3-fold. Absence of perfusate Ca(2+), chelation of intracellular Ca(2+), or inhibition of Ca(2+) signaling (calmodulin, Ca(2+)/calmodulin-dependent kinase, calcineurin, PKC, or phospholipase C) prevented the flow response. Evaluation of possible flow-activated Ca(2+) entry pathways revealed no role for transient receptor potential (TRP)C3, TRPC6, and TRPV4; however, cells with TRPP2 (polycystin-2) knockdown had no ET-1 flow response. Flow increased intracellular Ca(2+) was blunted in TRPP2 knockdown cells. Nonspecific blockade of P2 receptors, as well as specific inhibition of P2X7 and P2Y2 receptors, prevented the ET-1 flow response. The ET-1 flow response was not affected by inhibition of either epithelial Na(+) channels or the mitochondrial Na(+)/Ca(2+) exchanger. Taken together, these findings provide evidence that in IMCD3 cells, flow, via polycystin-2 and P2 receptors, engages Ca(2+)-dependent signaling pathways that stimulate ET-1 synthesis.

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“…However, this effect quickly reverses and would most likely dissipate by the time the kidney is removed to the time that whole cell recordings are made. A recent paper suggests that endothelin-1 (ET-1) production in the CCD is directly correlated with Na ϩ delivery and tubular flow rate (30). As ET-1 has been shown to be a potent inhibitor of ENaC activity (5,32), it is another potential regulator of I Na during acute sodium loading.…”

Section: Discussionmentioning

confidence: 99%

Feedback inhibition of ENaC during acute sodium loading in vivo

Patel

Frindt

Palmer

2013

American Journal of Physiology-Renal Physiology

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The epithelial Na ϩ channel (ENaC) is tightly regulated by sodium intake to maintain whole body sodium homeostasis. In addition, ENaC is inhibited by high levels of intracellular Na ϩ [Na ϩ ]i, presumably to prevent cell Na ϩ overload and swelling. However, it is not clear if this regulation is relevant in vivo. We show here that in rats, an acute (4 h) oral sodium load decreases whole-cell amiloride-sensitive currents (INa) in the cortical collecting duct (CCD) even when plasma aldosterone levels are maintained high by infusing the hormone. This was accompanied by decreases in whole-kidney cleaved ␣-ENaC (2.6 fold), total ␤-ENaC (1.7 fold), and cleaved ␥-ENaC (6.2 fold). In addition, cell-surface ␤-and ␥-ENaC expression was measured using in situ biotinylation. There was a decrease in cell-surface core-glycosylated (2.2 fold) and maturely glycosylated (4.9 fold) ␤-ENaC and cleaved ␥-ENaC (4.7 fold). There were no significant changes for other apical sodium transporters. To investigate the role of increases in Na ϩ entry and presumably [Na ϩ ]i on ENaC, animals were infused with amiloride prior to and during sodium loading. Blocking Na ϩ entry did not inhibit the effect of resalting on INa. However, amiloride did prevent decreases in ENaC expression, an effect that was not mimicked by hydrochlorothiazide administration. Na ϩ entry and presumably [Na ϩ ]i can regulate ENaC expression but does not fully account for the aldosterone-independent decrease in I Na during an acute sodium load. Na channel; Na transporters; amiloride; intracellular Na THE MAMMALIAN KIDNEY plays an integral role in maintaining whole body sodium homeostasis by regulating the amount of sodium that is reabsorbed from the glomerular filtrate. The aldosterone-sensitive distal nephron (ASDN) serves as the final site of sodium reabsorption and plays a key role in matching sodium intake with excretion. The epithelial Na ϩ channel (ENaC) mediates sodium entry across the apical membrane and is thought to be the predominant site for regulating sodium reabsorption in the ASDN (7,19,21,27,28). The mineralocorticoid aldosterone serves as a signal to increase ENaC activity in response to a low-Na diet by increasing channel activity as well as overall and apical surface expression of ENaC subunits (23,26,45). With an acute sodium load, serum aldosterone levels rapidly decrease with a concomitant decrease in ENaC activity and expression (12,27). However, it is unknown if the decrease in aldosterone is necessary for downregulating ENaC activity under these conditions.During an acute sodium load, there is a rapid increase in urinary sodium excretion. This is likely to enhance Na ϩ entry in the ENaC-expressing cells due to increased Na ϩ delivery to the ASDN. The rate of sodium entry could serve as another signal to downregulate ENaC activity. Previous studies found that inhibiting sodium entry with amiloride in isolated toad bladder (40) and rat CCD (18) increases sodium channel activity. Conversely, inhibiting basolateral efflux of Na ϩ in frog skin (24), t...

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Na delivery and ENaC mediate flow regulation of collecting duct endothelin-1 production

Cited by 21 publications

References 32 publications

Role of collecting duct endothelin in control of renal function and blood pressure

Role of collecting duct endothelin in control of renal function and blood pressure

Flow regulation of endothelin-1 production in the inner medullary collecting duct

Feedback inhibition of ENaC during acute sodium loading in vivo

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