scholarly journals Enhanced tubuloglomerular feedback in mice with vascular overexpression of A1 adenosine receptors

2009 ◽  
Vol 297 (5) ◽  
pp. F1256-F1264 ◽  
Author(s):  
Mona Oppermann ◽  
Yan Qin ◽  
En Yin Lai ◽  
Christoph Eisner ◽  
Lingli Li ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Plasma Renin ◽  
Tubuloglomerular Feedback ◽  
Perfusion Flow ◽  
Enhanced Expression ◽  
Single Nephron ◽  
Basal Plasma ◽  
Actin Promoter ◽  
Afferent Arterioles ◽  
Renal Vascular

Adenosine 1 receptors (A1AR) in the kidney are expressed in the vasculature and the tubular system. Pharmacological inhibition or global genetic deletion of A1AR causes marked reductions or abolishment of tubuloglomerular feedback (TGF) responses. To assess the function of vascular A1AR in TGF, we generated transgenic mouse lines in which A1AR expression in smooth muscle was augmented by placing A1AR under the control of a 5.38-kb fragment of the rat smooth muscle α-actin promoter and first intron ( 12 ). Two founder lines with highest expression in the kidney [353 ± 42 and 575 ± 43% compared with the wild type (WT)] were used in the experiments. Enhanced expression of A1AR at the expected site in these lines was confirmed by augmented constrictor responses of isolated afferent arterioles to administration of the A1AR agonist N6-cyclohexyladenosine. Maximum TGF responses (0–30 nl/min flow step) were increased from 8.4 ± 0.9 mmHg in WT ( n = 21) to 14.2 ± 0.7 mmHg in A1AR-transgene (tg) 4 ( n = 22; P < 0.0001), and to 12.6 ± 1.2 mmHg in A1AR-tg7 ( n = 12; P < 0.02). Stepwise changes in perfusion flow caused greater numerical TGF responses in A1AR-tg than WT in all flow ranges with differences reaching levels of significance in the intermediate flow ranges of 7.5–10 and 10–15 nl/min. Proximal-distal single-nephron glomerular filtration rate (SNGFR) differences (free-flow micropuncture) were also increased in A1AR-tg, averaging 6.25 ± 1.5 nl/min compared with 2.6 ± 0.51 nl/min in WT ( P = 0.034). Basal plasma renin concentrations as well as the suppression of renin secretion after volume expansion were similar in A1AR-tg and WT mice, suggesting lack of transgene expression in juxtaglomerular cells. These data indicate that A1AR expression in vascular smooth muscle cells is a critical component for TGF signaling and that changes in renal vascular A1AR expression may determine the magnitude of TGF responses.

scholarly journals The nephron-arterial network and its interactions

2019 ◽  
Vol 316 (5) ◽  
pp. F769-F784 ◽  
Author(s):  
Donald J. Marsh ◽  
Dmitry D. Postnov ◽  
Olga V. Sosnovtseva ◽  
Niels-Henrik Holstein-Rathlou
Keyword(s):  
Information Exchange ◽  
Electrical Signal ◽  
Tubuloglomerular Feedback ◽  
Sustained Oscillation ◽  
Arterial Tree ◽  
Arterial Network ◽  
Dependent Behavior ◽  
Single Nephron ◽  
Arteriolar Wall ◽  
Afferent Arterioles

Tubuloglomerular feedback and the myogenic mechanism form an ensemble in renal afferent arterioles that regulate single-nephron blood flow and glomerular filtration. Each mechanism generates a self-sustained oscillation, the mechanisms interact, and the oscillations synchronize. The synchronization generates a bimodal electrical signal in the arteriolar wall that propagates retrograde to a vascular node, where it meets similar electrical signals from other nephrons. Each signal carries information about the time-dependent behavior of the regulatory ensemble. The converging signals support synchronization of the nephrons participating in the information exchange, and the synchronization can lead to formation of nephron clusters. We review the experimental evidence and the theoretical implications of these interactions and consider additional interactions that can limit the size of nephron clusters. The architecture of the arterial tree figures prominently in these interactions.

Tubuloglomerular feedback and blood flow autoregulation during DA1-induced renal vasodilation

1990 ◽  
Vol 258 (3) ◽  
pp. F627-F635 ◽  
Author(s):  
D. M. Pollock ◽  
W. J. Arendshorst
Keyword(s):  
Blood Flow ◽  
Feedback Control ◽  
Arterial Pressure ◽  
Receptor Activation ◽  
Tubuloglomerular Feedback ◽  
Doppler Flowmetry ◽  
Single Nephron ◽  
Electromagnetic Flow Probe ◽  
Induced Changes ◽  
Renal Vascular

The effect of renal vasodilation produced by the dopamine DA1-receptor agonist, fenoldopam (SKF-82526), on tubuloglomerular feedback (TGF) activity and the autoregulation of renal blood flow (RBF) was determined in euvolemic rats. Fenoldopam (2.5 micrograms.kg-1.min-1 iv) increased RBF by 17% (electromagnetic flow probe) while glomerular filtration rate (GFR) was unchanged; mean arterial pressure was decreased by 6%. Superficial cortical blood flow was increased by 12% (laser-Doppler flowmetry) while single-nephron GFR (SNGFR) and estimated glomerular capillary pressure (stop-flow pressure, Psf) were stable. SNGFR measured at proximal and distal sites along the same nephron was not affected by fenoldopam. Partial inhibition of TGF was indicated by the constancy of distal SNGFR and the proximal-distal SNGFR difference in the presence of increased distal delivery of native fluid. However, fenoldopam did not affect feedback control of Psf evaluated by perfusing artificial fluid through Henle's loop at 0-62 nl/min. Despite the decrease in renal vascular resistance over an arterial pressure range of 130 to 70 mmHg, RBF was autoregulated efficiently during fenoldopam infusion. These results indicate that DA1-receptor activation dilates the preglomerular and efferent arterioles without affecting GFR or glomerular pressure. However, this vasodilatory mechanism operates independent of autoregulation and TGF-induced changes in glomerular pressure such that preglomerular vessels remain responsive to the appropriate signals from these intrinsic control systems. The ability of fenoldopam to blunt feedback control of SNGFR may depend on changes in the filtration coefficient independent of glomerular pressure and/or a constituent of natural tubular fluid.

scholarly journals Renal afferent arteriolar and tubuloglomerular feedback reactivity in mice with conditional deletions of adenosine 1 receptors

2012 ◽  
Vol 303 (8) ◽  
pp. F1166-F1175 ◽  
Author(s):  
Lingli Li ◽  
En Yin Lai ◽  
Yuning Huang ◽  
Christoph Eisner ◽  
Diane Mizel ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Mesangial Cells ◽  
Smooth Muscle Actin ◽  
Critical Role ◽  
Muscle Cells ◽  
Tubuloglomerular Feedback ◽  
Loop Of Henle ◽  
Actin Promoter

Adenosine 1 receptors (A1AR) have been shown in previous experiments to play a major role in the tubuloglomerular feedback (TGF) constrictor response of afferent arterioles (AA) to increased loop of Henle flow. Overexpression studies have pointed to a critical role of vascular A1AR, but it has remained unclear whether selective deletion of A1AR from smooth muscle cells is sufficient to abolish TGF responsiveness. To address this question, we have determined TGF response magnitude in mice in which vascular A1AR deletion was achieved using the loxP recombination approach with cre recombinase being controlled by a smooth muscle actin promoter (SmCre/A1ARff). Effective vascular deletion of A1AR was affirmed by absence of vasoconstrictor responses to adenosine or cyclohexyl adenosine (CHA) in microperfused AA. Elevation of loop of Henle flow from 0 to 30 nl/min caused a 22.1 ± 3.1% reduction of stop flow pressure in control mice and of 7.2 ± 1.5% in SmCre/A1ARff mice ( P < 0.001). Maintenance of residual TGF activity despite absence of A1AR-mediated responses in AA suggests participation of extravascular A1AR in TGF. Support for this notion comes from the observation that deletion of A1ARff by nestin-driven cre causes an identical TGF response reduction (7.3 ± 2.4% in NestinCre/A1ARff vs. 20.3 ± 2.7% in controls), whereas AA responsiveness was reduced but not abolished. A1AR on AA smooth muscle cells are primarily responsible for TGF activation, but A1AR on extravascular cells, perhaps mesangial cells, appear to contribute to the TGF response.

Vasodilatation of afferent arterioles and paradoxical increase of renal vascular resistance by furosemide in mice

2007 ◽  
Vol 293 (1) ◽  
pp. F279-F287 ◽  
Author(s):  
Mona Oppermann ◽  
Pernille B. Hansen ◽  
Hayo Castrop ◽  
Jurgen Schnermann
Keyword(s):  
Blood Flow ◽  
Angiotensin Ii ◽  
Tubuloglomerular Feedback ◽  
Intact Mouse ◽  
Peritubular Capillaries ◽  
Intact Kidney ◽  
Afferent Arterioles ◽  
Renal Vascular ◽  
Dose Dependent Increase

Loop diuretics like furosemide have been shown to cause renal vasodilatation in dogs and humans, an effect thought to result from both a direct vascular dilator effect and from inhibition of tubuloglomerular feedback. In isolated perfused afferent arterioles preconstricted with angiotensin II or NG-nitro-l-arginine methyl ester, furosemide caused a dose-dependent increase of vascular diameter, but it was without effect in vessels from NKCC1−/− mice suggesting that inhibition of NKCC1 mediates dilatation in afferent arterioles. In the intact kidney, however, furosemide (2 mg/kg iv) caused a 50.5 ± 3% reduction of total renal blood flow (RBF) and a 27% reduction of superficial blood flow (SBF) accompanied by a marked and immediate increase of tubular pressure and volume. At 10 mg/kg, furosemide reduced RBF by 60.4 ± 2%. Similarly, NKCC1−/− mice responded to furosemide with a 45.4% decrease of RBF and a 29% decrease of SBF. Decreases in RBF and SBF and increases of tubular pressure by furosemide were ameliorated by renal decapsulation. In addition, pretreatment with candesartan (2 mg/kg) or indomethacin (5 mg/kg) attenuated the reduction of RBF and peak urine flows caused by furosemide. Our data indicate that furosemide, despite its direct vasodilator potential in isolated afferent arterioles, causes a marked increase in flow resistance of the vascular bed of the intact mouse kidney. We suggest that generation of angiotensin II and/or a vasoconstrictor prostaglandin combined with compression of peritubular capillaries by the expanding tubular compartment are responsible for the reduction of RBF in vivo.

scholarly journals Impaired myogenic constriction of the renal afferent arteriole in a mouse model of reduced βENaC expression

2012 ◽  
Vol 302 (11) ◽  
pp. F1486-F1493 ◽  
Author(s):  
Ying Ge ◽  
Kimberly Gannon ◽  
Monette Gousset ◽  
Ruishing Liu ◽  
Beau Murphey ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Mouse Model ◽  
Vascular Resistance ◽  
Perfusion Pressure ◽  
Rate Of Change ◽  
Renal Vascular Resistance ◽  
Myogenic Tone ◽  
Afferent Arteriole ◽  
Afferent Arterioles ◽  
Renal Vascular

Previous studies demonstrate a role for β epithelial Na+ channel (βENaC) protein as a mediator of myogenic constriction in renal interlobar arteries. However, the importance of βENaC as a mediator of myogenic constriction in renal afferent arterioles, the primary site of development of renal vascular resistance, has not been determined. We colocalized βENaC with smooth muscle α-actin in vascular smooth muscle cells in renal arterioles using immunofluorescence. To determine the importance of βENaC in myogenic constriction in renal afferent arterioles, we used a mouse model of reduced βENaC (βENaC m/m) and examined pressure-induced constrictor responses in the isolated afferent arteriole-attached glomerulus preparation. We found that, in response to a step increase in perfusion pressure from 60 to 120 mmHg, the myogenic tone increased from 4.5 ± 3.7 to 27.3 ± 5.2% in +/+ mice. In contrast, myogenic tone failed to increase with the pressure step in m/m mice (3.9 ± 0.8 to 6.9 ± 1.4%). To determine the importance of βENaC in myogenic renal blood flow (RBF) regulation, we examined the rate of change in renal vascular resistance following a step increase in perfusion pressure in volume-expanded animals. We found that, following a step increase in pressure, the rate of myogenic correction of RBF is inhibited by 75% in βENaC m/m mice. These findings demonstrate that myogenic constriction in afferent arterioles is dependent on normal expression of βENaC.

Tubuloglomerular feedback response in the prenatal and postnatal ovine kidney

2011 ◽  
Vol 300 (6) ◽  
pp. F1368-F1374 ◽  
Author(s):  
Russell D. Brown ◽  
Anita J. Turner ◽  
Mattias Carlström ◽  
A. Erik G. Persson ◽  
Karen J. Gibson
Keyword(s):  
Feedback Mechanism ◽  
Late Gestation ◽  
Tubuloglomerular Feedback ◽  
Maximal Response ◽  
Fetal Life ◽  
Single Nephron ◽  
Developing Kidney ◽  
Tubular Flow ◽  
Arteriolar Tone ◽  
Renal Vascular

The tubuloglomerular feedback mechanism (TGF) plays an important role in regulating single-nephron glomerular filtration rate (GFR) by coupling distal tubular flow to arteriolar tone. It is not known whether TGF is active in the developing kidney or whether it can regulate renal vascular tone and thus GFR during intrauterine life. TGF characteristics were examined in late-gestation ovine fetuses and lambs under normovolemic and volume-expanded (VE) conditions. Lambs and pregnant ewes were anesthetized and the fetuses were delivered via a caesarean incision into a heated water bath, with the umbilical cord intact. Under normovolemic conditions, mean arterial pressure of the fetuses was lower than lambs (51 ± 1 vs. 64 ± 3 mmHg). The maximum TGF response (ΔPSFmax) was found to be lower in fetuses than lambs when tubular perfusion was increased from 0 to 40 nl/min (5.4 ± 0.7 vs. 10.6 ± 0.4 mmHg). Furthermore, the flow rate eliciting half-maximal response [turning point (TP)] was 15.7 ± 0.9 nl/min in fetuses compared with 19.3 ± 1.0 nl/min in lambs, indicating a greater TGF sensitivity of the prenatal kidney. VE decreased ΔPSFmax (4.2 ± 0.4 mmHg) and increased TP to 23.7 ± 1.3 nl/min in lambs. In fetuses, VE increased stop-flow pressure from 26.6 ± 1.5 to 30.3 ± 0.8 mmHg, and reset TGF sensitivity so that TP increased to 21.3 ± 0.7 nl/min, but it had no effect on ΔPSFmax. This study provides direct evidence that the TGF mechanism is active during fetal life and responds to physiological stimuli. Moreover, reductions in TGF sensitivity may contribute to the increase in GFR at birth.

scholarly journals Electrotonic vascular signal conduction and nephron synchronization

2009 ◽  
Vol 296 (4) ◽  
pp. F751-F761 ◽  
Author(s):  
Donald J. Marsh ◽  
Ildiko Toma ◽  
Olga V. Sosnovtseva ◽  
Janos Peti-Peterdi ◽  
Niels-Henrik Holstein-Rathlou
Keyword(s):  
Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Radial Artery ◽  
Juxtaglomerular Apparatus ◽  
Muscle Cells ◽  
Signal Propagation ◽  
Tubuloglomerular Feedback ◽  
Thick Ascending Limb ◽  
Single Nephron ◽  
Mechanism Control

Tubuloglomerular feedback (TGF) and the myogenic mechanism control afferent arteriolar diameter in each nephron and regulate blood flow. Both mechanisms generate self-sustained oscillations, the oscillations interact, TGF modulates the frequency and amplitude of the myogenic oscillation, and the oscillations synchronize; a 5:1 frequency ratio is the most frequent. TGF oscillations synchronize in nephron pairs supplied from a common cortical radial artery, as do myogenic oscillations. We propose that electrotonic vascular signal propagation from one juxtaglomerular apparatus interacts with similar signals from other nephrons to produce synchronization. We tested this idea in tubular-vascular preparations from mice. Vascular smooth muscle cells were loaded with a fluorescent voltage-sensitive dye; fluorescence intensity was measured with confocal microscopy. Perfusion of the thick ascending limb activated TGF and depolarized afferent arteriolar smooth muscle cells. The depolarization spread to the cortical radial artery and other afferent arterioles and declined with distance from the perfused juxtaglomerular apparatus, consistent with electrotonic vascular signal propagation. With a mathematical model of two coupled nephrons, we estimated the conductance of nephron coupling by fitting simulated vessel diameters to experimental data. With this value, we simulated nephron pairs to test for synchronization. In single-nephron simulations, the frequency of the TGF oscillation varied with nephron length. Coupling nephrons of different lengths forced TGF frequencies of both pair members to converge to a common value. The myogenic oscillations also synchronized, and the synchronization between the TGF and the myogenic oscillations showed an increased stability against parameter perturbations. Electronic vascular signal propagation is a plausible mechanism for nephron synchronization. Coupling increased the stability of the various oscillations.

Influence of right atrial stretch on plasma renin activity in the conscious rat

1987 ◽  
Vol 65 (2) ◽  
pp. 257-259 ◽  
Author(s):  
Susan Kaufman
Keyword(s):  
Plasma Renin Activity ◽  
Superior Vena ◽  
Vena Cava ◽  
Extracellular Fluid ◽  
Plasma Renin ◽  
Renin Activity ◽  
Right Atrial ◽  
Balloon Inflation ◽  
Conscious Rat ◽  
Basal Plasma

Rats were prepared with inflatable balloons at the superior vena cava – right atrium junction. After recovery 1 week later, when blood was taken from conscious, normovolaemic animals plasma renin activity was found not to be influenced by right atrial stretch. Plasma renin activity was then measured in rats in which an extracellular fluid deficit had been produced by peritoneal dialysis against a hyperoncotic, isotonic solution. Although basal plasma renin activity was elevated (6.8 ± 0.9 from 1.5 ± 0.2 ng∙mL∙h, n = 19), no depression was observed in the experimental group after 15 or 90 min of balloon inflation. In rats pretreated with isoprenaline (10 μg/kg body wt.) plasma renin activity was also increased over basal levels, but again balloon inflation caused no reduction in plasma renin activity. It would appear that right atrial stretch has little, if any, influence on renin release in the conscious rat.

Abstract 261: Endothelial Cells Contribute to RAS Activation in Microvascular Smooth Muscle Cells

2012 ◽  
Vol 111 (suppl_1) ◽  
Author(s):  
Kayoko Miyata ◽  
Ryousuke Satou ◽  
L Gabriel Navar
Keyword(s):  
Endothelial Cells ◽  
Smooth Muscle ◽  
Mrna Expression ◽  
Culture Medium ◽  
Primary Cultures ◽  
Mrna Levels ◽  
Ang Ii ◽  
Relative Ratio ◽  
Renin Mrna ◽  
Afferent Arterioles

Introduction: We have demonstrated that Ang II augments angiotensinogen (AGT) expression in rat preglomerular vascular smooth muscle cells (VSMCs). However, it is unclear if endothelial cells (ECs) are involved in augmentation of AGT in renal afferent arterioles. Hypothesis: We assessed the hypothesis that the ECs respond to paracrine signals that Ang II contribute to AGT augmentation in VSMCs. Objective: We established primary cultures of preglomerular ECs and examined the effects of Ang II and/or culture medium from ECs on AGT expression in preglomerular VSMCs. Methods and Results: We established primary cultures of preglomerular ECs, isolated from afferent arterioles of Sprague-Dawley rats. The cells were identified as ECs by being positive for a marker, CD34 and endothelial NOS and negative for alpha-SMA (a marker for VSMCs) and P4H-b (a marker for Fibroblasts) by immnostaining. The expression levels of AGT mRNA and renin mRNA in preglomerular ECs were examined by real-time RT-PCR. Ang II (100 pmol/L) increased AGT mRNA levels (1.34 +/- 0.16, by 100 pmol/L, N=4) and Renin mRNA levels (6.16 +/- 0.96, by 100 nmol/L, N=4) in ECs. On the other hand, the same dose of Ang II suppressed Renin mRNA expression in isolated Juxtaglomerular cells (JGs). These results indicate that preglomerular ECs are respond to Ang II and exclude the possible contamination of JGs into ECs. 100 pmol/L of Ang II increased AGT mRNA expression levels (1.37 +/- 0.03, relative ratio, N=4) in preglomerular VSMCs and the culture medium of ECs without Ang II treatment also more increased AGT mRNA expression (1.62 +/- 0.13, relative ratio, N=4) in preglomerular VSMCs. The AGT mRNA expression augmentation was enhanced when preglomerular VSMCs were treated with culture medium of Ang II-treated preglomerular ECs (2.39 +/- 0.41, relative ratio, N=4). The synergistic effects of Ang II and preglomerular ECs were also observed in PAI-1 expression in preglomerular VSMCs. Conclusion: These data demonstrate that preglomerular ECs contribute to Ang II-upregulation of AGT in renal afferent arterioles leading to further Ang II augmentation, which leads to increases in inflammatory and sclerotic factors in preglomerular VSMCs.

Angiotensin II effects on microvascular diameters of in vitro blood-perfused juxtamedullary nephrons

1986 ◽  
Vol 251 (4) ◽  
pp. F610-F618 ◽  
Author(s):  
P. K. Carmines ◽  
T. K. Morrison ◽  
L. G. Navar
Keyword(s):  
Angiotensin Ii ◽  
Constant Pressure ◽  
Ang Ii ◽  
Experimental Conditions ◽  
Vasoactive Hormones ◽  
Juxtamedullary Nephron ◽  
Single Nephron ◽  
Afferent Arterioles ◽  
Dose Dependent

The purpose of this study was to determine the specific renal microvascular segments that are functionally responsive to angiotensin II (ANG II) and other vasoactive hormones. Experiments were performed on juxtamedullary tissue from captopril-treated rats during perfusion with blood at a constant pressure of 110 mmHg. Epifluorescence videomicroscopy was utilized to measure diameters of arcuate and interlobular arteries (ART), mid- (MA) and late- (LA) afferent arterioles, and efferent arterioles (EA). Norepinephrine (700 nM) significantly decreased, and sodium nitroprusside (380 nM) increased, inside diameters of all segments. Topical application of ANG II (0.01 to 1 nM) induced significant reductions in diameters of all vessel segments: ART, 17.5 +/- 2.0%; MA, 19.6 +/- 2.5%; LA, 13.5 +/- 1.5%; and EA, 16.9 +/- 2.7%. The preglomerular response to ANG II was blocked by saralasin (10 microM) and, in most cases, was dose dependent; however, an initial hypersensitivity to low ANG II doses (30% decrease in diameter) was exhibited by 38% of the preglomerular vessels studied. Under these experimental conditions, single-nephron glomerular filtration rate decreased significantly in response to 0.01 nM ANG II exposure. These observations demonstrate that physiological concentrations of ANG II can elicit receptor-dependent and reversible vasoconstriction of the juxtamedullary nephron microvasculature at both pre- and postglomerular sites.

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