Adenosine formed by 5′-nucleotidase mediates tubuloglomerular feedback

Thomson, Scott C.; Bao, Dingjiu; Deng, Aihua; Vallon, Volker

doi:10.1172/jci8761

Cited by 166 publications

(134 citation statements)

References 16 publications

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“…More likely, however, nucleotides are secreted under basal conditions and in response to a variety of mechanical, osmotic, and chemical stimuli by most-if not all-cells of the glomerulus and its associated vasculature, as well as the proximal tubule cells rich in mitochondria [4][5][6]. Ecto-ATPases and ectoadenosine 5′ diphosphatases (ADPases) are also present throughout the nephron [7][8][9][10][11][12], although their nephron-specific localization has not been studied in depth. Their action generates metabolites that are also active at P2 receptors [ADP and uridine 5′ diphosphate (UDP)] [13][14][15].…”

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confidence: 99%

Purinergic signaling in the lumen of a normal nephron and in remodeled PKD encapsulated cysts

Hovater

Olteanu

Welty

et al. 2008

Purinergic Signalling

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The nephron is the functional unit of the kidney. Blood and plasma are continually filtered within the glomeruli that begin each nephron. Adenosine 5′ triphosphate (ATP) and its metabolites are freely filtered by each glomerulus and enter the lumen of each nephron beginning at the proximal convoluted tubule (PCT). Flow rate, osmolality, and other mechanical or chemical stimuli for ATP secretion are present in each nephron segment. These ATP-release stimuli are also different in each nephron segment due to water or salt permeability or impermeability along different luminal membranes of the cells that line each nephron segment. Each of the above stimuli can trigger additional ATP release into the lumen of a nephron segment. Each nephron-lining epithelial cell is a potential source of secreted ATP. Together with filtered ATP and its metabolites derived from the glomerulus, secreted ATP and adenosine derived from cells along the nephron are likely the principal two of several nucleotide and nucleoside candidates for renal autocrine and paracrine ligands within the tubular fluid of the nephron. This minireview discusses the first principles of purinergic signaling as they relate to the nephron and the urinary bladder. The review discusses how the lumen of a renal tubule presents an ideal purinergic signaling microenvironment. The review also illustrates how remodeled and encapsulated cysts in autosomal dominant polycystic kidney disease (ADPKD) and remodeled pseudocysts in autosomal recessive PKD (ARPKD) of the renal collecting duct likely create an even more ideal microenvironment for purinergic signaling. Once trapped in these closed microenvironments, purinergic signaling becomes chronic and likely plays a significant epigenetic and detrimental role in the secondary progression of PKD, once the remodeling of the renal tissue has begun. In PKD cystic microenvironments, we argue that normal purinergic signaling within the lumen of the nephron provides detrimental acceleration of ADPKD once remodeling is complete.

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confidence: 99%

Purinergic signaling in the lumen of a normal nephron and in remodeled PKD encapsulated cysts

Hovater

Olteanu

Welty

et al. 2008

Purinergic Signalling

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“…7,16 Finally, a complex interaction among the vascular effects of adenosine, Ang II, and NO has been described to determine the characteristics of the TGF mechanism. [17][18][19][20][21] The present study was performed to investigate the mechanisms behind the increased TGF response in hydronephrosis that could contribute to the development of hypertension.…”

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confidence: 99%

Nitric Oxide Deficiency and Increased Adenosine Response of Afferent Arterioles in Hydronephrotic Mice With Hypertension

et al. 2008

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Abstract-Afferent arterioles were used to investigate the role of adenosine, angiotensin II, NO, and reactive oxygen species in the pathogenesis of increased tubuloglomerular feedback response in hydronephrosis. Hydronephrosis was induced in wild-type mice, superoxide dismutase-1 overexpressed mice (superoxide-dismutase-1 transgenic), and deficient mice (superoxide dismutase-1 knockout). Isotonic contractions in isolated perfused arterioles and mRNA expression of NO synthase isoforms, adenosine, and angiotensin II receptors were measured. In wild-type mice, N G -nitro-L-arginine methyl ester (L-NAME) did not change the basal arteriolar diameter of hydronephrotic kidneys (Ϫ6%) but reduced it in control (Ϫ12%) and contralateral arterioles (Ϫ43%). Angiotensin II mediated a weaker maximum contraction of hydronephrotic arterioles (Ϫ18%) than in control (Ϫ42%) and contralateral arterioles (Ϫ49%). The maximum adenosine-induced constriction was stronger in hydronephrotic (Ϫ19%) compared with control (Ϫ8%) and contralateral kidneys (Ϯ0%). The response to angiotensin II became stronger in the presence of adenosine in hydronephrotic kidneys and attenuated in contralateral arterioles. L-NAME increased angiotensin II responses of all of the groups but less in hydronephrotic kidneys. The mRNA expression of endothelial NO synthase and inducible NO synthase was upregulated in the hydronephrotic arterioles. No differences were found for adenosine or angiotensin II receptors. In superoxide dismutase-1 transgenic mice, strong but similar L-NAME response (Ϫ40%) was observed for all of the groups. This response was totally abolished in arterioles of hydronephrotic superoxide dismutase-1 knockout mice. In conclusion, hydronephrosis is associated with changes in the arteriolar reactivity of both hydronephrotic and contralateral kidneys. Increased oxidative stress, reduced NO availability, and stronger reactivity to adenosine of the hydronephrotic kidney may contribute to the enhanced tubuloglomerular feedback responsiveness in hydronephrosis and be involved in the development of hypertension. Key Words: angiotensin II Ⅲ L-NAME Ⅲ oxidative stress Ⅲ NO synthase Ⅲ superoxide dismutase Ⅲ tubuloglomerular feedback H ydronephrosis because of uretero-pelvic junction obstruction is a common condition in newborns, with an incidence of Ϸ1%. Both rats and mice with hydronephrosis, because of chronic partial ureteral obstruction, develop renal injury 1 and salt-sensitive hypertension 2,3 that can be attenuated by relief of the obstruction. 4 The mechanisms are thought to be associated with increased activity of the renin-angiotensin system, 2 increased oxidative stress, and reduced NO availability in the diseased kidney. 5 In micropuncture studies of hydronephrotic animals, the tubuloglomerular feedback (TGF) has a higher responsiveness in the hydronephrotic kidney. 5,6 An increased TGF response, as seen in hydronephrotic kidneys, has also been described in spontaneously hypertensive rats, 7 Milan hypertensive rats 8 during development of hyperte...

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“…A number of such mediators, including adenosine triphosphate (ATP), prostaglandin E 2 , and nitric oxide have been invoked on the basis of pharmacological inhibitor studies. Rather solid pharmacological evidence derived from various in vivo and in vitro preparations has implicated adenosine as a major mediator of the TGF response [17][18][19]. In vitro, using an isolated double-perfused Af-Art and distal tubule containing the macula densa, we found that the adenosine A 1 receptor antagonist FK838 fully prevented Af-Art constriction in response to an increase in the luminal NaCl concentration of the macula densa [10].…”

Section: Nih Public Accessmentioning

confidence: 71%

Cross-talk between arterioles and tubules in the kidney

et al. 2009

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In hypertension the pressure natriuresis set point is shifted to a higher pressure due to an increase in both renal vascular resistance and sodium (Na) reabsorption. The afferent arterioles (Af-Arts) and efferent arterioles (Ef-Arts) account for most renal vascular resistance; they control glomerular filtration rate (GFR) and peritubular pressure, and, consequently, renal function. Af-Art and Ef-Art resistance is regulated by factors similar to those in other arterioles and also by tubuloglomerular feedback (TGF). TGF operates via the macula densa, which senses increases in sodium chloride (NaCl) and sends a signal that constricts the Af-Art and dilates the Ef-Art. In the outer renal cortex, the connecting tubule (CNT) returns to the glomerular hilus and contacts the Af-Art. This morphology is compatible with cross-talk between the CNT and Af-Art, so-called connecting tubule glomerular feedback (CTGF). Our studies show that increasing NaCl delivery to the CNT results in Af-Art dilatation that can be blocked by inhibitors of Na transport. We believe cross-talk between the CNT and Af-Art is a novel mechanism that may contribute to regulation of renal blood flow and GFR. KeywordsAfferent arteriole; Macula densa; Connecting tubule; Tubuloglomerular feedback; Na transporterThe afferent arteriole (Af-Art) accounts for most renal vascular resistance. It controls glomerular filtration rate (GFR) and peritubular pressure, and consequently renal function. The hormonal and neural influences on vascular resistance that participate in the control of blood flow and GFR have been fairly well defined. Anatomical contact between the end of the thick ascending limb of the loop of Henle and its own glomerulus was described for the first time more than 100 years ago. In each nephron of the mammalian kidney, the tubule returns to the hilus of the parent glomerulus, forming the juxtaglomerular apparatus (JGA). The JGA is made up of (a) a plaque of specialized tubular epithelial cells called the macula densa; (b) the extraglomerular mesangium; and (c) the glomerular Af-Art and efferent arteriole (Ef-Art). This anatomical connection is thought to be crucial for tubuloglomerular feedback (TGF) control of GFR [1][2][3]. Therefore, Af-Art resistance is regulated not only by factors similar to those in other arterioles but also by the macula densa. TGF describes a functional connection between the tubular epithelium at the site of the macula densa and the underlying smooth muscle cells of the Af-Art and Ef-Art. An increase or decrease in sodium chloride (NaCl) concentration in the luminal fluid at the macula densa cells activates arteriolar constriction or dilation, respectively, and hence alters single-nephron GFR (SNGFR).Experimental studies of TGF began with the microinjection experiment designed and initiated by Klaus Thurau [4]. After the proximal segments belonging to the same nephron had been © IPNA 2008 Correspondence to: YiLin Ren, yren1@hfhs.org. Thomson and Blantz [9] evaluated the ability of TGF to stabilize tubula...

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Adenosine formed by 5′-nucleotidase mediates tubuloglomerular feedback

Cited by 166 publications

References 16 publications

Purinergic signaling in the lumen of a normal nephron and in remodeled PKD encapsulated cysts

Purinergic signaling in the lumen of a normal nephron and in remodeled PKD encapsulated cysts

Nitric Oxide Deficiency and Increased Adenosine Response of Afferent Arterioles in Hydronephrotic Mice With Hypertension

Cross-talk between arterioles and tubules in the kidney

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