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Ruisheng Liu - One of the best experts on this subject based on the ideXlab platform.
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a new mechanism for the sex differences in angiotensin ii induced hypertension the role of Macula Densa nos1β mediated tubuloglomerular feedback
American Journal of Physiology-renal Physiology, 2020Co-Authors: Jie Zhang, Shan Jiang, Lei Wang, Feng Cheng, Jacentha Buggs, Jin Wei, Kun Jiang, Ruisheng LiuAbstract:Females are protected against the development of angiotensin II (ANG II)-induced hypertension compared with males, but the mechanisms have not been completely elucidated. In the present study, we hypothesized that the effect of ANG II on the Macula Densa nitric oxide (NO) synthase 1β (NOS1β)-mediated tubuloglomerular feedback (TGF) mechanism is different between males and females, thereby contributing to the sexual dimorphism of ANG II-induced hypertension. We used microperfusion, micropuncture, clearance of FITC-inulin, and radio telemetry to examine the sex differences in the changes of Macula Densa NOS1β expression and activity, TGF response, natriuresis, and blood pressure (BP) after a 2-wk ANG II infusion in wild-type and Macula Densa-specific NOS1 knockout mice. In wild-type mice, ANG II induced higher expression of Macula Densa NOS1β, greater NO generation by the Macula Densa, and a lower TGF response in vitro and in vivo in females than in males; the increases of glomerular filtration rate, urine flow rate, and Na+ excretion in response to an acute volume expansion were significantly greater and the BP responses to ANG II were significantly less in females than in males. In contrast, these sex differences in the effects of ANG II on TGF, natriuretic response, and BP were largely diminished in knockout mice. In addition, tissue culture of human kidney biopsies (renal cortex) with ANG II resulted in a greater increase in NOS1β expression in females than in males. In conclusion, Macula Densa NOS1β-mediated TGF is a novel and important mechanism for the sex differences in ANG II-induced hypertension.
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new mechanism for the sex differences in salt sensitive hypertension the role of Macula Densa nos1β mediated tubuloglomerular feedback
Hypertension, 2020Co-Authors: Jie Zhang, Shan Jiang, Lei Wang, Feng Cheng, Jacentha Buggs, Jin Wei, Jinxiu Zhu, Kun Yang, Xuerui Tan, Ruisheng LiuAbstract:Females are relatively resistant to salt-sensitive hypertension than males, but the mechanisms are not completely elucidated. We recently demonstrated a decisive role of Macula Densa neuronal NOS1β...
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knockout of na glucose cotransporter sglt1 mitigates diabetes induced upregulation of nitric oxide synthase nos1 in the Macula Densa and glomerular hyperfiltration
American Journal of Physiology-renal Physiology, 2019Co-Authors: Panai Song, Hermann Koepsell, Scott C Thomson, Winnie Huang, Akira Onishi, Rohit Patel, Young Chul Kim, Charlotte Van Ginkel, Brent Freeman, Ruisheng LiuAbstract:Na+-glucose cotransporter (SGLT)1 mediates glucose reabsorption in late proximal tubules. SGLT1 also mediates Macula Densa (MD) sensing of an increase in luminal glucose, which increases nitric oxi...
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Renin-Angiotensin-Aldosterone System Aldosterone Blunts Tubuloglomerular Feedback by
2016Co-Authors: Activating Macula, Luis A Juncos, Densa Mineralocorticoid Receptors, Celso E. Gomez-sanchez, Ruisheng LiuAbstract:Abstract—Chronic aldosterone administration increases glomerular filtration rate, whereas inhibition of mineralocorticoid receptors (MRs) markedly attenuates glomerular hyperfiltration and hypertension associated with primary aldosteronism or obesity. However, the mechanisms by which aldosterone alters glomerular filtration rate regulation are poorly understood. In the present study, we hypothesized that aldosterone suppresses tubuloglomerular feedback (TGF) via activation of Macula Densa MR. First, we observed the expression of MR in Macula Densa cells isolated by laser capture microdissection and by immunofluorescence in rat kidneys. Second, to investigate the effects of aldosterone on TGF in vitro, we microdissected the juxtaglomerular apparatus from rabbit kidneys and perfused the afferent arteriole and distal tubule simultaneously. Under control conditions, TGF was 2.80.2 m. In the presence of aldosterone (108 mol/L), TGF was reduced by 50%. The effect of aldosterone to attenuate TGF was blocked by the MR antagonist eplerenone (105 mol/L). Third, to investigate the effect of aldosterone on TGF in vivo, we performed micropuncture, and TGF was determined by maximal changes in stop-flow pressure Psf when tubular perfusion rate was increased from 0 to 40 nL/min. Aldosterone (107 mol/L) decreased Psf from 10.11.4 to 7.71.2 mm Hg. In the presence of L-NG-mono-methyl arginine citrate (103 mol/L), this effect was blocked. We conclude that MRs are expressed in Macula Densa cells and can be activated by aldosterone, which increases nitric oxide production in the Macula Densa and blunts the TGF response. (Hypertension. 2012;59:599-606.) ● Online Data Supplemen
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oxidative status in the Macula Densa modulates tubuloglomerular feedback responsiveness in angiotensin ii induced hypertension
Acta Physiologica, 2015Co-Authors: Lei Wang, Luis A Juncos, Jiangping Song, En Yin Lai, Jin Wei, Kiran Chandrashekar, Shaohui Wang, Chunyu Shen, Ruisheng LiuAbstract:Aim Tubuloglomerular feedback (TGF) is an important mechanism in control of signal nephron glomerular filtration rate. The oxidative stress in the Macula Densa, primarily determined by the interactions between nitric oxide (NO) and superoxide (O2−), is essential in maintaining the TGF responsiveness. However, few studies examining the interactions between and amount of NO and O2− generated by the Macula Densa during normal and hypertensive states. Methods In this study, we used isolated perfused juxtaglomerular apparatus to directly measure the amount and also studied the interactions between NO and O2− in Macula Densa in both physiological and slow pressor Angiotensin II (Ang II)-induced hypertensive mice. Results We found that slow pressor Ang II at a dose of 600 ng kg−1 min−1 for two weeks increased mean arterial pressure by 26.1 ± 5.7 mmHg. TGF response increased from 3.4 ± 0.2 μm in control to 5.2 ± 0.2 μm in hypertensive mice. We first measured O2− generation by the Macula Densa and found it was undetectable in control mice. However, O2− generation by the Macula Densa increased to 21.4 ± 2.5 unit min−1 in Ang II-induced hypertensive mice. We then measured NO generation and found that NO generation by the Macula Densa was 138.5 ± 9.3 unit min−1 in control mice. The NO was undetectable in the Macula Densa in hypertensive mice infused with Ang II. Conclusions Under physiological conditions, TGF response is mainly controlled by the NO generated in the Macula Densa; in Ang II induced hypertension, the TGF response is mainly controlled by the O2− generated by the Macula Densa.
P D Bell - One of the best experts on this subject based on the ideXlab platform.
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Basic Properties and Potential Regulators of the Apical K + Channel in Macula
2013Co-Authors: Densa Cells, A. M. Hurst, -y. J. Lapointe, P D BellAbstract:ABSTRACT These studies examine the properties of an apical potassium (K+) channel in Macula Densa cells, a specialized group of cells involved in tubuloglomerular feedback signal transmission. To this end, individual glomeruli with thick ascending limbs (TAL) and Macula Densa cells were dissected from rabbit kidney and the TAL covering Macula Densa cells was removed. Using patch clamp techniques, we found a high density (up to 54 channels per patch) of K § channels in the apical membrane of Macula Densa cells. An inward conductance of 41.1 4- 4.8 pS was obtained in cell-attached patches (patch pipette, 140 mM K+). In inside-out patches (patch pipette, 140 mM; bath, 5 mM K+), inward currents of 1.1 4- 0.1 pA (n = 11) were observed at 0 mV and single channel current reversed at a pipette potential of-84 mV giving a permeability ratio (PK/PNa) of over 100. In cellattached patches, mean channel open probability (N.Po, where N is number of channels in the patch and Po is single channel open probability) was unaffected by bumetanide, but was reduced from 11.3 4- 2.7 to 1.6 4- 1.3 (n = 5, p < 0.02) by removal of bath sodium (Na § Simultaneous removal of bath Na § and calcium (Ca 2+) prevented the Na § decrease in N.Po indicating that the effect of Na + removal on N.Po was probably mediated by stimulation of Ca 2+ entry. This interpretation was supported by studies where ionomycin, which directly increases intracellular Ca 2+, produced a fall in N.Po from 17.8 4- 4.0 to 5.9-+ 4.1 (n = 7, p < 0.02). In inside-out patches, the apical K + channel was not sensitive to ATP but was directly blocked by 2 mM Ca ~+ and by lowering bath pH from 7.4 to 6.8. These studies constitute the first single channel observations on Macula Densa cells and establish some of the characteristics and regulators of this apical K + channel. This channel is likely to be involved in Macula Densa transepithelial C1- transport and perhaps in the tubuloglomerular feedback signaling process
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ATP as a mediator of Macula Densa cell signalling
Purinergic Signalling, 2009Co-Authors: P D Bell, Peter Komlosi, Zhi-ren ZhangAbstract: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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tubuloglomerular feedback mechanisms in nephron segments beyond the Macula Densa
Current Opinion in Nephrology and Hypertension, 2009Co-Authors: Peter Komlosi, P D Bell, Zhi-ren ZhangAbstract:Purpose of reviewTo summarize recent evidence regarding the role of distal nephron segments other than the Macula Densa in sensing the tubular environment and transmitting this signal to the adjacent vasculature.Recent findingsIn addition to the classical contact site between the Macula Densa plaque
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unraveling the relationship between Macula Densa cell volume and luminal solute concentration osmolality
Kidney International, 2006Co-Authors: Peter Komlosi, Attila Fintha, P D BellAbstract:At the Macula Densa, flow-dependent changes in luminal composition lead to tubuloglomerular feedback and renin release. Apical entry of sodium chloride in both Macula Densa and cortical thick ascending limb (cTAL) cells occurs via furosemide-sensitive sodium–chloride–potassium cotransport. In Macula Densa, apical entry of sodium chloride leads to changes in cell volume, although there are conflicting data regarding the directional change in Macula Densa cell volume with increases in luminal sodium chloride concentration. To further assess volume changes in Macula Densa cells, cTAL-glomerular preparations were isolated and perfused from rabbits, and Macula Densa cells were loaded with fluorescent dyes calcein and 1-(4-trimethylammoniumphenyl)-6-phenyl-1,3,5-hexatriene p -toluenesulfonate. Cell volume was determined with wide-field and multiphoton fluorescence microscopy. Increases in luminal sodium chloride concentration from 0 to 80mmol/l at constant osmolality led to cell swelling in Macula Densa and cTAL cells, an effect that was blocked by luminal application of furosemide. However, increases in luminal sodium chloride concentration from 0 to 80mmol/l with concomitant increases in osmolality caused sustained decreases in Macula Densa cell volume but transient increases in cTAL cell volume. Increases in luminal osmolality with urea also resulted in Macula Densa cell shrinkage. These studies suggest that, under physiologically relevant conditions of concurrent increases in luminal sodium chloride concentration and osmolality, there is Macula Densa cell shrinkage, which may play a role in the Macula Densa cell signaling process.
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Unraveling the relationship between Macula Densa cell volume and luminal solute concentration/osmolality.
Kidney international, 2006Co-Authors: Peter Komlosi, Attila Fintha, P D BellAbstract:At the Macula Densa, flow-dependent changes in luminal composition lead to tubuloglomerular feedback and renin release. Apical entry of sodium chloride in both Macula Densa and cortical thick ascending limb (cTAL) cells occurs via furosemide-sensitive sodium–chloride–potassium cotransport. In Macula Densa, apical entry of sodium chloride leads to changes in cell volume, although there are conflicting data regarding the directional change in Macula Densa cell volume with increases in luminal sodium chloride concentration. To further assess volume changes in Macula Densa cells, cTAL-glomerular preparations were isolated and perfused from rabbits, and Macula Densa cells were loaded with fluorescent dyes calcein and 1-(4-trimethylammoniumphenyl)-6-phenyl-1,3,5-hexatriene p -toluenesulfonate. Cell volume was determined with wide-field and multiphoton fluorescence microscopy. Increases in luminal sodium chloride concentration from 0 to 80mmol/l at constant osmolality led to cell swelling in Macula Densa and cTAL cells, an effect that was blocked by luminal application of furosemide. However, increases in luminal sodium chloride concentration from 0 to 80mmol/l with concomitant increases in osmolality caused sustained decreases in Macula Densa cell volume but transient increases in cTAL cell volume. Increases in luminal osmolality with urea also resulted in Macula Densa cell shrinkage. These studies suggest that, under physiologically relevant conditions of concurrent increases in luminal sodium chloride concentration and osmolality, there is Macula Densa cell shrinkage, which may play a role in the Macula Densa cell signaling process.
Jurgen Schnermann - One of the best experts on this subject based on the ideXlab platform.
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Effect of Adenosinel-Receptor Blockade on Renin Release from Rabbit Isolated Perfused Juxtaglomerular Apparatus
2016Co-Authors: H Weihprecht, Jurgen Schnermann, John N Lorenz, Ole T Skett, Josie P. BriggsAbstract:Adenosine has been proposed to act within the juxtaglomerular apparatus (JGA) as a mediator of the inhibition of renin secre-tion produced by a high NaCi concentration at the Macula Densa. To test this hypothesis, we studied the effects of the adenosine, (Al)-receptor blocker 8-cyclopentyl-1,3-dipropyl-xanthine (CPX) on renin release from single isolated rabbit JGAs with Macula Densa perfused. The Al-receptor agonist, N6-cyclohexyladenosine (CHA), applied in the bathing solu-tion at 10-1 M, was found to inhibit renin secretion, an effect that was completely blocked by adding CPX (195 M) to the bath. Applied to the lumen, 10-5 M CPX produced a modest stimulation of renin secretion rates suppressed by a high NaCl concentration at the Macula Densa (P < 0.05). The effect of changing luminal NaCl concentration on renin secretion rate was examined in the presence of CPX (10-7 and 10-5 M) in the bathing solution and in vehicle control experiments. The con-trol response to increasing luminal NaCI concentration was a marked suppression of renin secretion, that was maintained as long as luminal NaCl concentration was high and was promptly reversible when concentration was lowered. CPX did not alter renin release when luminal NaCl was low, but diminished the reduction caused by high NaCl (P < 0.01). It is concluded that Al-receptors are located within the JGA, and that Al-receptor activation inhibits renin release. A high NaCI concentration at the Macula Densa appears to influence Al-receptor activation, but a low NaCl concentration does not. The findings support participation of adenosine in Macula Densa control of renin secretion. (J. Clin. Invest. 1990. 85:1622-1628.) Macula Densa * kidney- adenosine analogue
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integrated control of na transport along the nephron
Clinical Journal of The American Society of Nephrology, 2015Co-Authors: Lawrence G Palmer, Jurgen SchnermannAbstract:The kidney filters vast quantities of Na at the glomerulus but excretes a very small fraction of this Na in the final urine. Although almost every nephron segment participates in the reabsorption of Na in the normal kidney, the proximal segments (from the glomerulus to the Macula Densa) and the distal segments (past the Macula Densa) play different roles. The proximal tubule and the thick ascending limb of the loop of Henle interact with the filtration apparatus to deliver Na to the distal nephron at a rather constant rate. This involves regulation of both filtration and reabsorption through the processes of glomerulotubular balance and tubuloglomerular feedback. The more distal segments, including the distal convoluted tubule (DCT), connecting tubule, and collecting duct, regulate Na reabsorption to match the excretion with dietary intake. The relative amounts of Na reabsorbed in the DCT, which mainly reabsorbs NaCl, and by more downstream segments that exchange Na for K are variable, allowing the simultaneous regulation of both Na and K excretion.
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1 PERMISSIVE ROLE OF NITRIC OXIDE IN Macula Densa CONTROL OF RENIN SECRETION
2013Co-Authors: Hayo Castrop, Armin Kurtz, Jurgen Schnermann, Yuning Huang, Diane Mizel, Frank Schweda, Josie Briggs, Jurgen Schnermann M. DAbstract:Running title: Nitric oxide and Macula Densa control of renin secretion Address for all correspondence
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effect of apocynin treatment on renal expression of cox 2 nos1 and renin in wistar kyoto and spontaneously hypertensive rats
American Journal of Physiology-regulatory Integrative and Comparative Physiology, 2006Co-Authors: Alex Paliege, Jurgen Schnermann, Tianxin Yang, Diane Mizel, A Parsumathy, Sebastian BachmannAbstract:Macula Densa (MD) cells of the juxtaglomerular apparatus (JGA) synthesize type 1 nitric oxide synthase (NOS1) and type 2 cyclooxygenase (COX-2). Both nitric oxide (NO) and prostaglandins have been ...
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Inhibition of nNOS expression in the Macula Densa by COX-2-derived prostaglandin E2
American journal of physiology. Renal physiology, 2004Co-Authors: Alex Paliege, Jurgen Schnermann, Anita Pasumarthy, Diane Mizel, Carmen Medina, Yuning G. Huang, Sebastian Bachmann, Josephine P. Briggs, Tianxin YangAbstract:It is well established that cyclooxygenase-2 (COX-2) and the neuronal form of nitric oxide synthase (nNOS) are coexpressed in Macula Densa cells and that the expression of both enzymes is stimulated in a number of high-renin states. To further explore the role of nNOS and COX-2 in renin secretion, we determined plasma renin activity in mice deficient in nNOS or COX-2. Plasma renin activity was significantly reduced in nNOS -/- mice on a mixed genetic background and in COX-2 -/- mice on either BALB/c or C57/BL6 congenic backgrounds. In additional studies, we accumulated evidence to show an inhibitory influence of PGE(2) on nNOS expression. In a cultured Macula Densa cell line, PGE(2) significantly reduced nNOS mRNA expression, as quantified by real-time RT-PCR. In COX-2 -/- mice, nNOS mRNA expression in the kidney, determined by real-time RT-PCR, was upregulated throughout the postnatal periods, ranging from postnatal day (PND) 3 to PND 60. The induction of nNOS protein expression and NOS activity in COX-2 -/- mice was localized to Macula Densa cells using immunohistochemistry and NADPH-diaphorase staining methods, respectively. Therefore, these findings reveal that the absence of either COX-2 or nNOS is associated with suppressed renin secretion. Furthermore, the inhibitory effect of PGE(2) on nNOS mRNA expression indicates a novel interaction between NO and prostaglandin-mediated pathways of renin regulation.
Oscar A Carretero - One of the best experts on this subject based on the ideXlab platform.
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mechanisms of carbon monoxide attenuation of tubuloglomerular feedback
Hypertension, 2012Co-Authors: Yilin Ren, Martin A Dambrosio, Jeffrey L. Garvin, Hong Wang, John R Falck, Edward L Peterson, Oscar A CarreteroAbstract:Carbon monoxide (CO) is a physiological messenger with diverse functions in the kidney, including controlling afferent arteriole tone both directly and via tubuloglomerular feedback (TGF). We have reported that CO attenuates TGF, but the mechanisms underlying this effect remain unknown. We hypothesized that CO, acting via cGMP, cGMP-dependent protein kinase, and cGMP-stimulated phosphodiesterase 2, reduces cAMP in the Macula Densa, leading to TGF attenuation. In vitro, microdissected rabbit afferent arterioles and their attached Macula Densa were simultaneously perfused. TGF was measured as the decrease in afferent arteriole diameter elicited by switching Macula Densa NaCl from 10 to 80 mmol/L. Adding a CO-releasing molecule (CORM-3, 5 × 10(-5) mol/L) to the Macula Densa blunted TGF from 3.3 ± 0.3 to 2.0 ± 0.3 μm (P<0.001). The guanylate cyclase inhibitor LY-83583 (10(-6) mol/L) enhanced TGF (5.8 ± 0.6 μm; P<0.001 versus control) and prevented the effect of CORM-3 on TGF (LY-83583+CORM-3, 5.5 ± 0.3 μm). Similarly, the cGMP-dependent protein kinase inhibitor KT-5823 (2 × 10(-6) mol/L) enhanced TGF and prevented the effect of CORM-3 on TGF (KT-5823, 6.0 ± 0.7 μm; KT-5823+CORM-3, 5.9 ± 0.8 μm). However, the phosphodiesterase 2 inhibitor BAY-60-7550 (10(-6) mol/L) did not prevent the effect of CORM-3 on TGF (BAY-60-7550, 4.07 ± 0.31 μm; BAY-60-7550+CORM-3, 1.84 ± 0.31 μm; P<0.001). Finally, the degradation-resistant cAMP analog dibutyryl-cAMP (10(-3) mol/L) prevented the attenuation of TGF by CORM-3 (dibutyryl-cAMP, 4.6 ± 0.5 μm; dibutyryl-cAMP+CORM-3, 5.0 ± 0.6 μm). We conclude that CO attenuates TGF by reducing cAMP via a cGMP-dependent pathway mediated by cGMP-dependent protein kinase rather than phosphodiesterase 2. Our results will lead to a better understanding of the mechanisms that control the renal microcirculation.
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connecting tubule glomerular feedback mediates acute tubuloglomerular feedback resetting
American Journal of Physiology-renal Physiology, 2012Co-Authors: Hong Wang, Martin A Dambrosio, Jeffrey L. Garvin, Oscar A CarreteroAbstract:Tubuloglomerular feedback (TGF) and connecting tubule glomerular feedback (CTGF) are mechanisms that control afferent arteriole (Af-Art) tone. TGF, initiated by increased NaCl at the Macula Densa, ...
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possible mechanism of efferent arteriole ef art tubuloglomerular feedback
Kidney International, 2007Co-Authors: Jeffrey L. Garvin, Oscar A CarreteroAbstract:Adenosine triphosphate (ATP) is liberated from Macula Densa cells in response to increased tubular NaCl delivery. However, it is not known whether ATP from the Macula Densa is broken down to adenosine, or whether this adenosine mediates efferent arteriole (Ef-Art) tubuloglomerular feedback (TGF). We hypothesized that increased Macula Densa Ca 2+ , release of ATP and degradation of ATP to adenosine are necessary for Ef-Art TGF. Rabbit Ef-Arts and adherent tubular segments (with the Macula Densa) were simultaneously microperfused in vitro while changing the NaCl concentration at the Macula Densa. The Ef-Art was perfused orthograde through the end of the afferent arteriole (Af-Art). In Ef-Arts preconstricted with norepinephrine (NE), increasing NaCl concentration from 10 to 80mM at the Macula Densa dilated Ef-Arts from 7.5±0.7 to 11.1±0.3 μ m. Buffering increases in Macula Densa Ca 2+ with the cell-permeant Ca 2+ chelator BAPTA-AM diminished Ef-Art TGF from 3.1±0.3 to 0.1±0.2 μ m. Blocking adenosine formation by adding α - β -methyleneadenosine 5′-diphosphate (MADP) blocked Ef-Art TGF from 2.9±0.5 to 0.1±0.2 μ m. Increasing luminal NaCl at the Macula Densa from 10 to 45mM caused a moderate Ef-Art TGF response, 1.3±0.1 μ m. It was potentiated to 4.0±0.3 μ m by adding hexokinase, which enhances conversion of ATP into adenosine. Our data show that in vitro changes in Macula Densa Ca 2+ and ATP release are necessary for Ef-Art TGF. ATP is broken down to form adenosine, which mediates signal transmission of Ef-Art TGF.
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increased intracellular ph at the Macula Densa activates nnos during tubuloglomerular feedback
Kidney International, 2005Co-Authors: Ruisheng Liu, Oscar A Carretero, Yilin Ren, Jeffrey L. GarvinAbstract:Increased intracellular pH at the Macula Densa activates nNOS during tubuloglomerular feedback. Background The Macula Densa senses increasing NaCl concentrations in tubular fluid and increases afferent arteriole tone by a process known as tubuloglomerular feedback (TGF). Nitric oxide (NO) production by Macula Densa neuronal nitric oxide synthase (nNOS) is enhanced by increasing NaCl in the Macula Densa lumen, and the NO thus formed inhibits TGF. Blocking apical Na + /H + exchange with amiloride augments TGF and mimics the effect of nNOS inhibition. We hypothesized that increasing NaCl in the Macula Densa lumen raises Macula Densa intracellular pH (pH i ) and activates nNOS. Methods The thick ascending limb and a portion of the distal tubule with intact Macula Densa plaque adherent to the glomerulus were microdissected and perfused. Macula Densa perfusate was changed from a low (10 mmol/L) to high NaCl solution (80 mmol/L) to mimic the conditions that induce TGF. Osmolality of both solutions was 180 mOsm, so that changing the solutions did not alter cell volume. Results Macula Densa pH i increased significantly from 7.0 ± 0.5 to 7.8 ± 0.6 when the perfusate was changed from low to high ( P N = 5). When amiloride was added to inhibit Na + /H + exchange, the increase in pH i during TGF was blocked ( N = 5). Fluorescence intensity of DAF-2, an NO-sensitive dye, increased by 28.8 ± 4.1% after increasing luminal NaCl ( N = 5), indicating an increase in NO production. In the presence of the Na + /H + exchanger inhibitor amiloride or the nNOS inhibitor 7-NI, the increase in NO induced by switching the Macula Densa perfusate from low to high was blunted. To study whether changes in pH i can directly alter NO production, we used nigericin, a K + /H + ionophore, to equilibrate luminal and intracellular pH. When Macula Densa pH was raised from 7.3 to 7.8 in the presence of 10 −5 mol/L nigericin in the low NaCl solution, fluorescence of DAF-2 in the Macula Densa increased by 17.9 ± 1.3% ( P N = 5). In the presence of 7-NI, the increase in NO induced by raising pH i was blocked ( N = 5). Conclusion We concluded that Macula Densa pH i increases during TGF, and this increase in pH i activates nNos.
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inhibition of apical na h exchangers on the Macula Densa cells augments tubuloglomerular feedback
Hypertension, 2003Co-Authors: Hong Wang, Oscar A Carretero, Jeffrey L. GarvinAbstract:NO produced by neuronal NO synthase (nNOS) in the Macula Densa blunts tubuloglomerular feedback (TGF). nNOS activity is strongly pH-dependent. Increasing luminal NaCl concentration increases nNOS activity, NO production, and apical Na + /H + exchange. Na + /H + exchange alkalinizes the Macula Densa. We hypothesized that inhibiting apical Na + /H + exchange in Macula Densa cells would augment TGF by blunting nNOS activation caused by increasing luminal NaCl concentration. Rabbit afferent arterioles and attached Macula Densas were microperfused in vitro. TGF response was defined as the change in afferent arteriole diameter caused by increasing the NaCl concentration in the Macula Densa perfusate. 7-Nitroindazole (7-NI; 10 μmol/L) alone in the Macula Densa lumen increased the TGF response from 2.4±0.1 to 3.8±0.2 μm ( P + /H + exchange inhibitor, was added to the Macula Densa lumen, it increased the TGF response from 2.5±0.3 to 3.7±0.5 μm ( P + /H + exchange in the Macula Densa mimics the effect of inhibiting NO production by nNOS in the Macula Densa on TGF. Thus, it is possible that increased apical Na + /H + exchange caused by increasing the sodium concentration in the lumen of the Macula Densa activates Macula Densa nNOS. The link between nNOS and Na + /H + exchange may be intracellular pH.
Jeffrey L. Garvin - One of the best experts on this subject based on the ideXlab platform.
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mechanisms of carbon monoxide attenuation of tubuloglomerular feedback
Hypertension, 2012Co-Authors: Yilin Ren, Martin A Dambrosio, Jeffrey L. Garvin, Hong Wang, John R Falck, Edward L Peterson, Oscar A CarreteroAbstract:Carbon monoxide (CO) is a physiological messenger with diverse functions in the kidney, including controlling afferent arteriole tone both directly and via tubuloglomerular feedback (TGF). We have reported that CO attenuates TGF, but the mechanisms underlying this effect remain unknown. We hypothesized that CO, acting via cGMP, cGMP-dependent protein kinase, and cGMP-stimulated phosphodiesterase 2, reduces cAMP in the Macula Densa, leading to TGF attenuation. In vitro, microdissected rabbit afferent arterioles and their attached Macula Densa were simultaneously perfused. TGF was measured as the decrease in afferent arteriole diameter elicited by switching Macula Densa NaCl from 10 to 80 mmol/L. Adding a CO-releasing molecule (CORM-3, 5 × 10(-5) mol/L) to the Macula Densa blunted TGF from 3.3 ± 0.3 to 2.0 ± 0.3 μm (P<0.001). The guanylate cyclase inhibitor LY-83583 (10(-6) mol/L) enhanced TGF (5.8 ± 0.6 μm; P<0.001 versus control) and prevented the effect of CORM-3 on TGF (LY-83583+CORM-3, 5.5 ± 0.3 μm). Similarly, the cGMP-dependent protein kinase inhibitor KT-5823 (2 × 10(-6) mol/L) enhanced TGF and prevented the effect of CORM-3 on TGF (KT-5823, 6.0 ± 0.7 μm; KT-5823+CORM-3, 5.9 ± 0.8 μm). However, the phosphodiesterase 2 inhibitor BAY-60-7550 (10(-6) mol/L) did not prevent the effect of CORM-3 on TGF (BAY-60-7550, 4.07 ± 0.31 μm; BAY-60-7550+CORM-3, 1.84 ± 0.31 μm; P<0.001). Finally, the degradation-resistant cAMP analog dibutyryl-cAMP (10(-3) mol/L) prevented the attenuation of TGF by CORM-3 (dibutyryl-cAMP, 4.6 ± 0.5 μm; dibutyryl-cAMP+CORM-3, 5.0 ± 0.6 μm). We conclude that CO attenuates TGF by reducing cAMP via a cGMP-dependent pathway mediated by cGMP-dependent protein kinase rather than phosphodiesterase 2. Our results will lead to a better understanding of the mechanisms that control the renal microcirculation.
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connecting tubule glomerular feedback mediates acute tubuloglomerular feedback resetting
American Journal of Physiology-renal Physiology, 2012Co-Authors: Hong Wang, Martin A Dambrosio, Jeffrey L. Garvin, Oscar A CarreteroAbstract:Tubuloglomerular feedback (TGF) and connecting tubule glomerular feedback (CTGF) are mechanisms that control afferent arteriole (Af-Art) tone. TGF, initiated by increased NaCl at the Macula Densa, ...
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possible mechanism of efferent arteriole ef art tubuloglomerular feedback
Kidney International, 2007Co-Authors: Jeffrey L. Garvin, Oscar A CarreteroAbstract:Adenosine triphosphate (ATP) is liberated from Macula Densa cells in response to increased tubular NaCl delivery. However, it is not known whether ATP from the Macula Densa is broken down to adenosine, or whether this adenosine mediates efferent arteriole (Ef-Art) tubuloglomerular feedback (TGF). We hypothesized that increased Macula Densa Ca 2+ , release of ATP and degradation of ATP to adenosine are necessary for Ef-Art TGF. Rabbit Ef-Arts and adherent tubular segments (with the Macula Densa) were simultaneously microperfused in vitro while changing the NaCl concentration at the Macula Densa. The Ef-Art was perfused orthograde through the end of the afferent arteriole (Af-Art). In Ef-Arts preconstricted with norepinephrine (NE), increasing NaCl concentration from 10 to 80mM at the Macula Densa dilated Ef-Arts from 7.5±0.7 to 11.1±0.3 μ m. Buffering increases in Macula Densa Ca 2+ with the cell-permeant Ca 2+ chelator BAPTA-AM diminished Ef-Art TGF from 3.1±0.3 to 0.1±0.2 μ m. Blocking adenosine formation by adding α - β -methyleneadenosine 5′-diphosphate (MADP) blocked Ef-Art TGF from 2.9±0.5 to 0.1±0.2 μ m. Increasing luminal NaCl at the Macula Densa from 10 to 45mM caused a moderate Ef-Art TGF response, 1.3±0.1 μ m. It was potentiated to 4.0±0.3 μ m by adding hexokinase, which enhances conversion of ATP into adenosine. Our data show that in vitro changes in Macula Densa Ca 2+ and ATP release are necessary for Ef-Art TGF. ATP is broken down to form adenosine, which mediates signal transmission of Ef-Art TGF.
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increased intracellular ph at the Macula Densa activates nnos during tubuloglomerular feedback
Kidney International, 2005Co-Authors: Ruisheng Liu, Oscar A Carretero, Yilin Ren, Jeffrey L. GarvinAbstract:Increased intracellular pH at the Macula Densa activates nNOS during tubuloglomerular feedback. Background The Macula Densa senses increasing NaCl concentrations in tubular fluid and increases afferent arteriole tone by a process known as tubuloglomerular feedback (TGF). Nitric oxide (NO) production by Macula Densa neuronal nitric oxide synthase (nNOS) is enhanced by increasing NaCl in the Macula Densa lumen, and the NO thus formed inhibits TGF. Blocking apical Na + /H + exchange with amiloride augments TGF and mimics the effect of nNOS inhibition. We hypothesized that increasing NaCl in the Macula Densa lumen raises Macula Densa intracellular pH (pH i ) and activates nNOS. Methods The thick ascending limb and a portion of the distal tubule with intact Macula Densa plaque adherent to the glomerulus were microdissected and perfused. Macula Densa perfusate was changed from a low (10 mmol/L) to high NaCl solution (80 mmol/L) to mimic the conditions that induce TGF. Osmolality of both solutions was 180 mOsm, so that changing the solutions did not alter cell volume. Results Macula Densa pH i increased significantly from 7.0 ± 0.5 to 7.8 ± 0.6 when the perfusate was changed from low to high ( P N = 5). When amiloride was added to inhibit Na + /H + exchange, the increase in pH i during TGF was blocked ( N = 5). Fluorescence intensity of DAF-2, an NO-sensitive dye, increased by 28.8 ± 4.1% after increasing luminal NaCl ( N = 5), indicating an increase in NO production. In the presence of the Na + /H + exchanger inhibitor amiloride or the nNOS inhibitor 7-NI, the increase in NO induced by switching the Macula Densa perfusate from low to high was blunted. To study whether changes in pH i can directly alter NO production, we used nigericin, a K + /H + ionophore, to equilibrate luminal and intracellular pH. When Macula Densa pH was raised from 7.3 to 7.8 in the presence of 10 −5 mol/L nigericin in the low NaCl solution, fluorescence of DAF-2 in the Macula Densa increased by 17.9 ± 1.3% ( P N = 5). In the presence of 7-NI, the increase in NO induced by raising pH i was blocked ( N = 5). Conclusion We concluded that Macula Densa pH i increases during TGF, and this increase in pH i activates nNos.
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inhibition of apical na h exchangers on the Macula Densa cells augments tubuloglomerular feedback
Hypertension, 2003Co-Authors: Hong Wang, Oscar A Carretero, Jeffrey L. GarvinAbstract:NO produced by neuronal NO synthase (nNOS) in the Macula Densa blunts tubuloglomerular feedback (TGF). nNOS activity is strongly pH-dependent. Increasing luminal NaCl concentration increases nNOS activity, NO production, and apical Na + /H + exchange. Na + /H + exchange alkalinizes the Macula Densa. We hypothesized that inhibiting apical Na + /H + exchange in Macula Densa cells would augment TGF by blunting nNOS activation caused by increasing luminal NaCl concentration. Rabbit afferent arterioles and attached Macula Densas were microperfused in vitro. TGF response was defined as the change in afferent arteriole diameter caused by increasing the NaCl concentration in the Macula Densa perfusate. 7-Nitroindazole (7-NI; 10 μmol/L) alone in the Macula Densa lumen increased the TGF response from 2.4±0.1 to 3.8±0.2 μm ( P + /H + exchange inhibitor, was added to the Macula Densa lumen, it increased the TGF response from 2.5±0.3 to 3.7±0.5 μm ( P + /H + exchange in the Macula Densa mimics the effect of inhibiting NO production by nNOS in the Macula Densa on TGF. Thus, it is possible that increased apical Na + /H + exchange caused by increasing the sodium concentration in the lumen of the Macula Densa activates Macula Densa nNOS. The link between nNOS and Na + /H + exchange may be intracellular pH.
