Changes of Cell Volume and Nitric Oxide Concentration in Macula Densa Cells Caused by Changes in Luminal NaCl Concentration

Liu, Ruisheng; Pittner, J.; Persson, A. Erik G.

doi:10.1097/01.asn.0000033275.17169.67

Cited by 62 publications

(80 citation statements)

References 42 publications

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“…The simplest route to this end would be for NO formation to vary in proportion to physiologic changes in macula densa salt. The present findings call this into question, but one might reconcile these data, the opposite finding from Liu et al (7), and the micropuncture data from various labs (1,6) by making the reasonable supposition that there are sodium-dependent and sodium-independent pathways competing for control of NOS I in the macula densa and that circumstances can arise where one or the other dominates. In fact, we observed this in micropuncture experiments where NOS I activity was dominated by macula densa salt in normal rats, but not in rats with streptozotocin diabetes (unpublished observation).…”

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confidence: 45%

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Commentary on…Neuronal Nitric Oxide Synthase

Thomson¹

2003

Journal of the American Society of Nephrology

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The macula densa control of renin secretion and tubuloglomerular feedback (TGF) both occur in the juxtaglomerular apparatus (JGA) of nephrons. The renin-angiotensin system has basked in attention for 2 decades, while TGF remains arcane to all but those who study it. Nonetheless, the body's internal environment is regulated, in large part, by these two systems.A decade ago, Wilcox and colleagues (1) identified nitric oxide synthase (NOS) I in the macula densa. This discovery spawned interest and experimentation. Subsequently, a sound consensus emerged that NO from the macula densa suppresses the TGF response. There is a weaker consensus that NO from the macula densa can stimulate renin secretion. It has been difficult to demonstrate a major consequence of NO-dependent renin secretion. In contrast, physiologic relevance of macula densa NOS as a modulator of TGF is easier to postulate and to prove. This is because NO from the macula densa shifts the TGF response rightward and makes it less steep (2). When macula densa NOS I is active, there will be increased distal salt delivery for any given GFR and increased GFR for any given distal salt delivery. The importance of this is revealed by positive salt balance and increased BP that gradually ensue when macula densa NOS I is inhibited (3).There are likely multiple determinants of macula densa NOS I activity. On the basis of the ubiquity of homeostasis-asnegative-feedback throughout physiology, one can expect each determinant of macula densa NO will also be affected by NO so as to serve the cause of homeostasis. To understand the role of macula densa NOS I in physiology, it is important to learn what affects it and what is affected by it. It is also important to quantify these relationships to predict the outcome when they come into conflict.The present study by Kovacs et al. (4) provides new information about certain effectors and affectors of macula densa NOS I. First, these studies confirm that NO from the macula densa suppresses apical Na:2CL:K transport in the same cell. Sodium entry via this symporter is the first step en route to TGF-mediated vasoconstriction, and reduced Na:2Cl:K symport is a leading candidate to explain how NO pushes the TGF response rightward, influencing GFR, distal salt delivery, and BP. Others have inhibited Na:2Cl:K symport using exogenous NO donors in Henle's loop (5), but this is the first demonstration that endogenous NO can have this effect. These authors also confirm that NO from the macula densa diffuses as far as the vascular pole of the glomerulus, where it could act as a paracrine vasodilator to oppose the influence of all locally active vasoconstrictors, including TGF.Is there a way to distinguish between the autocrine (transport) and paracrine (vasodilator) effects of macula densa NO as a modulator of TGF? A future approach might be to eliminate the autocrine effect by permeabilizing the macula densa to salt and then determining whether the TGF response to tubular salt is still being modulated by NOS I activity. Another way mi...

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confidence: 45%

“…Kovacs et al (4) are the second group to measure the effect of macula densa salt on NO production. Recently, Liu et al (7) reported that macula densa NO is salt-dependent. Now, Kovacs et al (4) do likewise, with one critical caveat, namely that the salt stimulus required to elicit NO is supraphysiologic and may not be relevant to daily life.…”

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confidence: 99%

Commentary on…Neuronal Nitric Oxide Synthase

Thomson¹

2003

Journal of the American Society of Nephrology

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“…We, and others, have taken advantage of fluorescent probes that have been developed to measure NO levels. In our studies we monitored extracellular levels of NO using the fluorescent probe DAF-FM and found that increases in luminal [NaCl] resulted in the generation of NO by macula densa cells [63,73]. Further, we found that NO inhibited apical Na:2Cl:K cotransporter activity in macula densa cells.…”

Section: Modulators Of Tgf Produced By Macula Densa Cellsmentioning

confidence: 76%

ATP as a mediator of macula densa cell signalling

Bell

Komlósi

Zhang

2009

Purinergic Signalling

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Within each nephro-vascular unit, the tubule returns to the vicinity of its own glomerulus. At this site, there are specialised tubular cells, the macula densa cells, which sense changes in tubular fluid composition and transmit information to the glomerular arterioles resulting in alterations in glomerular filtration rate and blood flow. Work over the last few years has characterised the mechanisms that lead to the detection of changes in luminal sodium chloride and osmolality by the macula densa cells. These cells are true "sensor cells" since intracellular ion concentrations and membrane potential reflect the level of luminal sodium chloride concentration. An unresolved question has been the nature of the signalling molecule(s) released by the macula densa cells. Currently, there is evidence that macula densa cells produce nitric oxide via neuronal nitric oxide synthase (nNOS) and prostaglandin E 2 (PGE 2 ) through cyclooxygenase 2 (COX 2)-microsomal prostaglandin E synthase (mPGES). However, both of these signalling molecules play a role in modulating or regulating the macula-tubuloglomerular feedback system. Direct macula densa signalling appears to involve the release of ATP across the basolateral membrane through a maxi-anion channel in response to an increase in luminal sodium chloride concentration. ATP that is released by macula densa cells may directly activate P2 receptors on adjacent mesangial cells and afferent arteriolar smooth muscle cells, or the ATP may be converted to adenosine. However, the critical step in signalling would appear to be the regulated release of ATP across the basolateral membrane of macula densa cells.

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“…It was shown recently by using ATP-sensitive reporter cells that MD cells release ATP and that this release is stimulated by raising NaCl concentration (8). Enhanced release of ATP may be related to the swelling of MD cells, which is another consequence of elevating luminal NaCl (21)(22)(23). It is likely that ecto-ATPases dephosphorylating ATP to AMP are present in cells adjacent to the MD.…”

Section: Figurementioning

confidence: 99%

Impairment of tubuloglomerular feedback regulation of GFR in ecto-5′-nucleotidase/CD73–deficient mice

Castrop¹,

Huang²,

Hashimoto³

et al. 2004

J. Clin. Invest.

166

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Adenosine coordinates organ metabolism and blood supply, and it modulates immune responses. In the kidney it mediates the vascular response elicited by changes in NaCl concentration in the macula densa region of the nephron, thereby serving as an important regulator of GFR. To determine whether adenosine formation depends on extracellular nucleotide hydrolysis, we studied NaCl-dependent GFR regulation (tubuloglomerular feedback) in mice with targeted deletion of ecto-5′-nucleotidase/CD73 (e-5′NT/CD73), the enzyme responsible for adenosine formation from AMP. e-5′NT/CD73 -/-mice were viable and showed no gross anatomical abnormalities. Blood pressure, blood and urine chemistry, and renal blood flow were not different between e-5′NT/CD73 +/+ and e-5′NT/CD73 -/-mice. e-5′NT/CD73 -/-mice had a significantly reduced fall in stop flow pressure and superficial nephron glomerular filtration rate in response to a saturating increase of tubular perfusion flow. Furthermore, whereas tubuloglomerular feedback responses did not change significantly during prolonged loop of Henle perfusion in e-5′NT/CD73 +/+ mice, a complete disappearance of the residual feedback response was noted in e-5′NT/CD73 -/-mice over 10 minutes of perfusion. The contractile response of isolated afferent arterioles to adenosine was normal in e-5′NT/CD73 -/-mice. We conclude that the generation of adenosine at the glomerular pole depends to a major extent on e-5′NT/CD73-mediated dephosphorylation of 5′-AMP, presumably generated from released ATP. IntroductionAdenosine is a multifunctional nucleoside that coordinates cellular oxygen supply and demand by adapting organ blood flow to metabolic rate (1). In addition, adenosine plays a major role in immune responsiveness with its net effect being either pro-or anti-inflammatory, depending on adenosine receptor subtype representation (2). Studies in adenosine receptor KO mice have contributed importantly to further defining nonredundant roles of adenosine in both processes. Our focus has been to elucidate the role of adenosine in the local hemodynamic control mechanism, called tubuloglomerular feedback, that operates in the kidney at the level of the juxtaglomerular apparatus (JGA). Tubuloglomerular feedback describes a functional connection between the tubular epithelium at the site of the macula densa (MD) and the underlying smooth muscle cells of the afferent and efferent glomerular arterioles. An increase in NaCl concentration in the luminal fluid at the MD cells causes an activation of smooth muscle cells and arteriolar vasoconstriction. As a consequence, glomerular filtration pressure and filtration rate fall. Both pharmacological and gene-targeting approaches have shown that tubuloglomerular feedback-induced vasoconstriction has an absolute requirement for functional A1 adenosine receptors (A1ARs), suggesting that adenosine as their natural ligand

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Changes of Cell Volume and Nitric Oxide Concentration in Macula Densa Cells Caused by Changes in Luminal NaCl Concentration

Cited by 62 publications

References 42 publications

Commentary on…Neuronal Nitric Oxide Synthase

Commentary on…Neuronal Nitric Oxide Synthase

ATP as a mediator of macula densa cell signalling

Impairment of tubuloglomerular feedback regulation of GFR in ecto-5′-nucleotidase/CD73–deficient mice

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