scholarly journals Extracellular Nucleotides and P2 Receptors in Renal Function

2020 ◽  
Vol 100 (1) ◽  
pp. 211-269 ◽  
Author(s):  
Volker Vallon ◽  
Robert Unwin ◽  
Edward W. Inscho ◽  
Jens Leipziger ◽  
Bellamkonda K. Kishore
Keyword(s):  
Blood Flow ◽  
Fluid Transport ◽  
Collecting Duct ◽  
Extracellular Nucleotides ◽  
Tubuloglomerular Feedback ◽  
P2 Receptor ◽  
Extracellular Nucleotide ◽  
Membrane Expression ◽  
Receptor System

The understanding of the nucleotide/P2 receptor system in the regulation of renal hemodynamics and transport function has grown exponentially over the last 20 yr. This review attempts to integrate the available data while also identifying areas of missing information. First, the determinants of nucleotide concentrations in the interstitial and tubular fluids of the kidney are described, including mechanisms of cellular release of nucleotides and their extracellular breakdown. Then the renal cell membrane expression of P2X and P2Y receptors is discussed in the context of their effects on renal vascular and tubular functions. Attention is paid to effects on the cortical vasculature and intraglomerular structures, autoregulation of renal blood flow, tubuloglomerular feedback, and the control of medullary blood flow. The role of the nucleotide/P2 receptor system in the autocrine/paracrine regulation of sodium and fluid transport in the tubular and collecting duct system is outlined together with its role in integrative sodium and fluid homeostasis and blood pressure control. The final section summarizes the rapidly growing evidence indicating a prominent role of the extracellular nucleotide/P2 receptor system in the pathophysiology of the kidney and aims to identify potential therapeutic opportunities, including hypertension, lithium-induced nephropathy, polycystic kidney disease, and kidney inflammation. We are only beginning to unravel the distinct physiological and pathophysiological influences of the extracellular nucleotide/P2 receptor system and the associated therapeutic perspectives.

Abstract 062: Regulation of Nephron Afferent Arteriole Resistance in Obesity: Role of Connecting Tubule Glomerular Feedback

Hypertension ◽  
2016 ◽  
Vol 68 (suppl_1) ◽  
Author(s):  
Sumit R Monu ◽  
Mani Maheshwari ◽  
Hong Wang ◽  
Ed Peterson ◽  
Oscar Carretero
Keyword(s):  
Blood Flow ◽  
Renal Blood Flow ◽  
Tubuloglomerular Feedback ◽  
Afferent Arteriole ◽  
Connecting Tubule ◽  
Single Nephron ◽  
Renal Micropuncture ◽  
The Difference

In obesity, renal damage is caused by increase in renal blood flow (RBF), glomerular capillary pressure (P GC ), and single nephron glomerular filtration rate but the mechanism behind this alteration in renal hemodynamics is unclear. P GC is controlled mainly by the afferent arteriole (Af-Art) resistance. Af-Art resistance is regulated by mechanism similar to that in other arterioles and in addition, it is regulated by two intrinsic feedback mechanisms: 1) tubuloglomerular feedback (TGF) that causes Af-Art constriction in response to an increase in sodium chloride (NaCl) in the macula densa, via sodium–potassium-2-chloride cotransporter-2 (NKCC2) and 2) connecting tubule glomerular feedback (CTGF) that causes Af-Art dilatation and is mediated by connecting tubule via epithelial sodium channel (ENaC). CTGF is blocked by the ENaC inhibitor benzamil. Attenuation of TGF reduces Af-Art resistance and allows systemic pressure to get transmitted to the glomerulus that causes glomerular barotrauma/damage. In the current study, we tested the hypothesis that TGF is attenuated in obesity and that CTGF contributes to this effect. We used Zucker obese rats (ZOR) while Zucker lean rats (ZLR) served as controls. We performed in-vivo renal micropuncture of individual rat nephrons while measuring stop-flow pressure (P SF ), an index of P GC. TGF response was measured as a decrease in P SF induced by changing the rate of late proximal perfusion from 0 to 40nl/min in stepwise manner.CTGF was calculated as the difference of P SF value between vehicle and benzamil treatment, at each perfusion rate. Maximal TGF response was significantly less in ZOR (6.16 ± 0.52 mmHg) when compared to the ZLR (8.35 ± 1.00mmHg), p<0.05 , indicating TGF resetting in the ZOR. CTGF was significantly higher in ZOR (6.33±1.95 mmHg) when compared to ZLR (1.38±0.89 mmHg), p<0.05 . When CTGF was inhibited with the ENaC blocker Benzamil (1μM), maximum P SF decrease was 12.30±1.72 mmHg in ZOR and 10.60 ± 1.73 mmHg in ZLR, indicating that blockade of CTGF restored TGF response in ZOR. These observations led us to conclude that TGF is reset in ZOR and that enhanced CTGF contributes to this effect. Increase in CTGF may explain higher renal blood flow, increased P GC and higher glomerular damage in obesity.

P2 receptors in the regulation of renal transport mechanisms

2008 ◽  
Vol 294 (1) ◽  
pp. F10-F27 ◽  
Author(s):  
Volker Vallon
Keyword(s):  
Collecting Duct ◽  
P2 Receptors ◽  
Extracellular Nucleotides ◽  
Receptor Subtype ◽  
Receptor Subtypes ◽  
Inhibitory Influence ◽  
P2 Receptor ◽  
Transport Mechanisms ◽  
Renal Epithelia ◽  
Regulation Of Transport

Extracellular nucleotides (e.g., ATP) regulate physiological and pathophysiological processes through activation of nucleotide P2 receptors in the plasma membrane. Examples include such diverse processes as communication from taste buds to gustatory nerves, platelet aggregation, nociception, or neutrophil chemotaxis. Over approximately the last 15 years, evidence has also accumulated that cells in renal epithelia release nucleotides in response to physiological stimuli and that these nucleotides act in a paracrine and autocrine way to activate P2 receptors and play a significant role in the regulation of transport mechanisms and cell volume regulation. This review discusses potential stimuli and mechanisms involved in nucleotide release in renal epithelia and summarizes the available data on the expression and function of nucleotide P2 receptors along the native mammalian tubular and collecting duct system. Using established agonist profiles for P2 receptor subtypes, significant insights have been gained particularly into a potential role for P2Y2-like receptors in the regulation of transport mechanisms in the collecting duct. Due to the lack of receptor subtype-specific antagonists, however, the in vivo relevance of P2 receptor subtypes is unclear. Studies in gene knockout mice provided first insights including an antihypertensive activity of P2Y2receptors that is linked to an inhibitory influence on renal Na+and water reabsorption. We are only beginning to unravel the important roles of extracellular nucleotides and P2 receptors in the regulation of the diverse transport mechanisms of the kidney.

A novel mechanism of renal blood flow autoregulation and the autoregulatory role of A1 adenosine receptors in mice

2007 ◽  
Vol 293 (5) ◽  
pp. F1489-F1500 ◽  
Author(s):  
Armin Just ◽  
William J. Arendshorst
Keyword(s):  
Blood Flow ◽  
Renal Blood Flow ◽  
Adenosine Receptors ◽  
Time Course ◽  
Tubuloglomerular Feedback ◽  
The Third ◽  
A1 Adenosine Receptors ◽  
The Impact ◽  
Renal Blood Flow Autoregulation

Autoregulation of renal blood flow (RBF) is mediated by a fast myogenic response (MR; ∼5 s), a slower tubuloglomerular feedback (TGF; ∼25 s), and potentially additional mechanisms. A1 adenosine receptors (A1AR) mediate TGF in superficial nephrons and contribute to overall autoregulation, but the impact on the other autoregulatory mechanisms is unknown. We studied dynamic autoregulatory responses of RBF to rapid step increases of renal artery pressure in mice. MR was estimated from autoregulation within the first 5 s, TGF from that at 5–25 s, and a third mechanism from 25–100 s. Genetic deficiency of A1AR (A1AR−/−) reduced autoregulation at 5–25 s by 50%, indicating a residual fourth mechanism resembling TGF kinetics but independent of A1AR. MR and third mechanism were unaltered in A1AR−/−. Autoregulation in A1AR−/− was faster at 5–25 than at 25–100 s suggesting two separate mechanisms. Furosemide in wild-type mice (WT) eliminated the third mechanism and enhanced MR, indicating TGF-MR interaction. In A1AR−/−, furosemide did not further impair autoregulation at 5–25 s, but eliminated the third mechanism and enhanced MR. The resulting time course was the same as during furosemide in WT, indicating that A1AR do not affect autoregulation during furosemide inhibition of TGF. We conclude that at least one novel mechanism complements MR and TGF in RBF autoregulation, that is slower than MR and TGF and sensitive to furosemide, but not mediated by A1AR. A fourth mechanism with kinetics similar to TGF but independent of A1AR and furosemide might also contribute. A1AR mediate classical TGF but not TGF-MR interaction.

Expression of NTPDase1 and NTPDase2 in murine kidney: relevance to regulation of P2 receptor signaling

2005 ◽  
Vol 288 (5) ◽  
pp. F1032-F1043 ◽  
Author(s):  
Bellamkonda K. Kishore ◽  
Jorge Isaac ◽  
Michel Fausther ◽  
Sheryl R. Tripp ◽  
Huihui Shi ◽  
...  
Keyword(s):  
Blood Vessels ◽  
Degradation Products ◽  
Collecting Duct ◽  
Extracellular Nucleotides ◽  
Tubuloglomerular Feedback ◽  
Nucleoside Triphosphate ◽  
Cellular Expression ◽  
Peritubular Capillaries ◽  
Pelvic Wall ◽  
Glomerular Arterioles

The regulation of renal function by extracellular nucleotides encompasses alterations in glomerular hemodynamics, microvascular function, tubuloglomerular feedback, tubular transport, cell growth or apoptosis, and transport of water and solutes in the medullary collecting duct. Nearly all cells can release ATP or other nucleotides that are then rapidly hydrolyzed in the extracellular milieu. However, little information is available on the cellular expression of ectoenzymes that hydrolyze extracellular nucleotides within the kidney. Nucleoside triphosphate diphosphohydrolases (NTPDases) are plasma membrane-bound ectonucleotidases. NTPDase1 has identity with CD39, a B lymphocyte activation marker, and hydrolyzes extracellular ATP and ADP to AMP within the vasculature, whereas NTPDase2/CD39L(ike)1 preferentially converts ATP to ADP outside of blood vessels. Using immunohistochemical and in situ hybridization approaches, we localized the protein and mRNA of NTPDase1 and 2 in murine renal tissues. In the renal cortex, NTPDase1 is expressed by vascular smooth muscle cells and endothelium in interlobular arteries, afferent glomerular arterioles, and peritubular capillaries. In the inner medulla, NTPDase1 is expressed in ascending thin limbs of Henle's loop, ducts of Bellini, and in the pelvic wall. In contrast, NTPDase2 is expressed in Bowman's capsule, glomerular arterioles, adventitia of blood vessels, and pelvic wall. Thus the distribution patterns of NTPDases have parallels to the known distribution of P2 receptors within the kidney. NTPDases may modulate regulatory effects of ATP and degradation products within the vasculature and other sites and thereby potentially influence physiological as well as multiple pathological events in the kidney.

Immunoregulation through extracellular nucleotides

Blood ◽  
2012 ◽  
Vol 120 (3) ◽  
pp. 511-518 ◽  
Author(s):  
Laura Vitiello ◽  
Stefania Gorini ◽  
Giuseppe Rosano ◽  
Andrea la Sala
Keyword(s):  
Inflammatory Responses ◽  
Receptor Expression ◽  
Extracellular Nucleotides ◽  
P2 Receptor ◽  
Murine Models ◽  
Danger Signal ◽  
Chronic Stimulation ◽  
P2 Purinergic Receptors ◽  
Human Immune

Abstract Extracellular ATP (eATP), the most abundant among nucleotides, can act as a mediator during inflammatory responses by binding to plasmamembrane P2 purinergic receptors, which are widely expressed on cells of the immune system. eATP is generally considered as a classical danger signal, which stimulates immune responses in the presence of tissue damage. Converging evidence from several studies using murine models of chronic inflammation have supported this hypothesis; however, the role of eATP in the regulation of human immune function appears to be more complex. Chronic stimulation with micromolar eATP concentrations inhibits the proliferation of T and NK lymphocytes and enhances the capacity of dendritic cells to promote tolerance. The effect of eATP depends on multiple factors, such as the extent of stimulation, eATP concentration, presence/absence of other mediators in the microenvironment, and pattern of P2 receptor engagement. Small but significant differences in the pattern of P2 receptor expression in mice and humans confer the diverse capacities of ATP in regulating the immune response. Such diversity, which is often overlooked, should therefore be carefully considered when evaluating the role of eATP in human inflammatory and autoimmune diseases.

scholarly journals Mouse Models and the Urinary Concentrating Mechanism in the New Millennium

2007 ◽  
Vol 87 (4) ◽  
pp. 1083-1112 ◽  
Author(s):  
Robert A. Fenton ◽  
Mark A. Knepper
Keyword(s):  
Water Conservation ◽  
Collecting Duct ◽  
Tubuloglomerular Feedback ◽  
Water Excretion ◽  
Renal Transporters ◽  
Concentrating Mechanism ◽  
New Information ◽  
Renal Micropuncture ◽  
Key Questions

Our understanding of urinary concentrating and diluting mechanisms at the end of the 20th century was based largely on data from renal micropuncture studies, isolated perfused tubule studies, tissue analysis studies and anatomical studies, combined with mathematical modeling. Despite extensive data, several key questions remained to be answered. With the advent of the 21st century, a new approach, transgenic and knockout mouse technology, is providing critical new information about urinary concentrating processes. The central goal of this review is to summarize findings in transgenic and knockout mice pertinent to our understanding of the urinary concentrating mechanism, focusing chiefly on mice in which expression of specific renal transporters or receptors has been deleted. These include the major renal water channels (aquaporins), urea transporters, ion transporters and channels (NHE3, NKCC2, NCC, ENaC, ROMK, ClC-K1), G protein-coupled receptors (type 2 vasopressin receptor, prostaglandin receptors, endothelin receptors, angiotensin II receptors), and signaling molecules. These studies shed new light on several key questions concerning the urinary concentrating mechanism including: 1) elucidation of the role of water absorption from the descending limb of Henle in countercurrent multiplication, 2) an evaluation of the feasibility of the passive model of Kokko-Rector and Stephenson, 3) explication of the role of inner medullary collecting duct urea transport in water conservation, 4) an evaluation of the role of tubuloglomerular feedback in maintenance of appropriate distal delivery rates for effective regulation of urinary water excretion, and 5) elucidation of the importance of water reabsorption in the connecting tubule versus the collecting duct for maintenance of water balance.

Evidence for cardiac volume-receptor regulation of feline jejunal blood flow and fluid transport

1984 ◽  
Vol 246 (4) ◽  
pp. G401-G410 ◽  
Author(s):  
H. Sjovall ◽  
S. Redfors ◽  
B. Biber ◽  
J. Martner ◽  
O. Winso
Keyword(s):  
Blood Flow ◽  
Fluid Transport ◽  
Positive Pressure Ventilation ◽  
Intestinal Secretion ◽  
Vagal Afferents ◽  
Positive Pressure ◽  
Cardiac Volume ◽  
Jejunal Segment ◽  
Inspiratory Resistance

The aim of the study was to investigate the role of cardiac mechanoreceptors in the reflex regulation of intestinal blood flow and fluid transport. Feline cardiac mechanoreceptor activity was modified with two noninvasive techniques: positive-pressure ventilation (PPV) and inspiratory resistance breathing (IRB). A jejunal segment with intact vascular and nervous supply was isolated and exposed to cholera toxin as a model for intestinal secretion. The results revealed that PPV induced a pronounced intestinal vasoconstriction and a marked inhibition of choleraic secretion. IRB had the opposite effects. The responses were well correlated with changes in central blood volume and either markedly reduced or abolished by vagotomy, intestinal alpha-adrenoreceptor blockade, or postganglionic mesenteric denervation. The results indicate that cardiac mechanoreceptors with vagal afferents may mediate the observed reflex responses, and hence this receptor station may be of importance in the normal reflex control of intestinal hemodynamics and fluid transport.

Phospholemman expression in extraglomerular mesangium and afferent arteriole of the juxtaglomerular apparatus

2003 ◽  
Vol 285 (1) ◽  
pp. F121-F129 ◽  
Author(s):  
Randall K. Wetzel ◽  
Kathleen J. Sweadner
Keyword(s):  
Blood Flow ◽  
Membrane Protein ◽  
Molecular Mechanisms ◽  
Juxtaglomerular Apparatus ◽  
Macula Densa ◽  
Tubuloglomerular Feedback ◽  
Afferent Arteriole ◽  
Γ Subunit ◽  
Goormaghtigh Cells

The molecular mechanisms with which the juxtaglomerular apparatus accomplishes its twin functions, acute regulation of glomerular blood flow and secretion of renin, are still not clearly understood. Least understood is the role of the extraglomerular mesangial (EM) cells, also known as lacis or Goormaghtigh cells, which lie sandwiched between the macula densa and the afferent and efferent arterioles. Here, we report that immunoreactivity for phospholemman (FXYD1), a single-span membrane protein homologous to the gamma (γ) sub-unit of the Na,K-ATPase, is found in the kidney in EM cells with the Na,K-ATPase β2-subunit and in cortical blood vessels and the afferent arteriole with Na,K-ATPase α2 and β2. Phospholemman's distribution in EM cells is distinct from that of the Na,K-ATPase γ-subunit, which is found on the basolateral surface of macula densa cells with Na,K-ATPase α1 and β1. Phospholemman is a major kinase target, and its location in the juxtaglomerular apparatus suggests that it is involved in tubuloglomerular feedback.

P2 receptors in regulation of renal microvascular function

2001 ◽  
Vol 280 (6) ◽  
pp. F927-F944 ◽  
Author(s):  
Edward W. Inscho
Keyword(s):  
Mesangial Cells ◽  
Strong Support ◽  
Receptor Activation ◽  
P2 Receptors ◽  
Microvascular Function ◽  
Extracellular Nucleotides ◽  
P2 Receptor

In the last 10–15 years, interest in the physiological role of P2 receptors has grown rapidly. Cellular, tissue, and organ responses to P2 receptor activation have been described in numerous in vivo and in vitro models. The purpose of this review is to provide an update of the recent advances made in determining the involvement of P2 receptors in the control of renal hemodynamics and the renal microcirculation. Special attention will be paid to work published in the last 5–6 years directed at understanding the role of P2 receptors in the physiological control of renal microvascular function. Several investigators have begun to evaluate the effects of P2 receptor activation on renal microvascular function across several species. In vivo and in vitro evidence consistently supports the hypothesis that P2 receptor activation by locally released extracellular nucleotides influences microvascular function. Extracellular nucleotides selectively influence preglomerular resistance without having an effect on postglomerular tone. P2 receptor inactivation blocks autoregulatory behavior whereas responsiveness to other vasoconstrictor agonists is retained. P2 receptor stimulation activates multiple intracellular signal transduction pathways in preglomerular smooth muscle cells and mesangial cells. Renal microvascular cells and mesangial cells express multiple subtypes of P2 receptors; however, the specific role each plays in regulating vascular and mesangial cell function remains unclear. Accordingly, the results of studies performed to date provide strong support for the hypothesis that P2 receptors are important contributors to the physiological regulation of renal microvascular and/or glomerular function.

scholarly journals Dominant factors that govern pressure natriuresis in diuresis and antidiuresis: a mathematical model

2014 ◽  
Vol 306 (9) ◽  
pp. F952-F969 ◽  
Author(s):  
Robert Moss ◽  
Anita T. Layton
Keyword(s):  
Blood Flow ◽  
Collecting Duct ◽  
Proximal Convoluted Tubule ◽  
Tubuloglomerular Feedback ◽  
Hydration Status ◽  
Renal Autoregulation ◽  
Medullary Blood Flow ◽  
Collecting Duct Epithelium ◽  
Pressure Natriuresis ◽  
Solute Composition

We have developed a whole kidney model of the urine concentrating mechanism and renal autoregulation. The model represents the tubuloglomerular feedback (TGF) and myogenic mechanisms, which together affect the resistance of the afferent arteriole and thus glomerular filtration rate. TGF is activated by fluctuations in macula densa [Cl−] and the myogefnic mechanism by changes in hydrostatic pressure. The model was used to investigate the relative contributions of medullary blood flow autoregulation and inhibition of transport in the proximal convoluted tubule to pressure natriuresis in both diuresis and antidiuresis. The model predicts that medullary blood flow autoregulation, which only affects the interstitial solute composition in the model, has negligible influence on the rate of NaCl excretion. However, it exerts a significant effect on urine flow, particularly in the antidiuretic kidney. This suggests that interstitial washout has significant implications for the maintenance of hydration status but little direct bearing on salt excretion, and that medullary blood flow may only play a signaling role for stimulating a pressure-natriuresis response. Inhibited reabsorption in the model proximal convoluted tubule is capable of driving pressure natriuresis when the known actions of vasopressin on the collecting duct epithelium are taken into account.

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