Autoregulation of renal blood flow in the conscious dog and the contribution of the tubuloglomerular feedback

To decide whether tubuloglomerular feedback (TGF) can account for renal autoregulation, we tested predictions of a TGF simulation. Broad-band and single-frequency perturbations were applied to arterial pressure; arterial blood pressure, renal blood flow and proximal tubule pressure were measured. Data were analyzed by linear systems analysis. Broad-band forcings of arterial pressure were also applied to the model to compare experimental results with simulations. With arterial pressure as the input and tubular pressure, renal blood flow, or renal vascular resistance as outputs, the model correctly predicted gain and phase only in the low-frequency range. Experimental results revealed a second component of vascular control active at 100-150 mHz that was not predicted by the simulation. Forcings at single frequencies showed that the system behaves linearly except in the band of 33-50 mHz in which, in addition, there are autonomous oscillations in TGF. Higher amplitude forcings in this band were attenuated by autoregulatory mechanisms, but low-amplitude forcings entrained the autonomous oscillations and provoked amplified oscillations in blood flow, showing an effect of TGF on whole kidney blood flow. We conclude that two components can be detected in the dynamic regulation of renal blood flow, i.e., a slow component that represents TGF and a faster component that most likely represents an intrinsic vascular myogenic mechanism.

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

Hypertension ◽

10.1161/hyp.68.suppl_1.062 ◽

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.

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Tonic and phasic influences of nitric oxide on renal blood flow autoregulation in conscious dogs

AJP Renal Physiology ◽

10.1152/ajprenal.1999.276.3.f442 ◽

1999 ◽

Vol 276 (3) ◽

pp. F442-F449 ◽

Cited By ~ 20

Author(s):

Armin Just ◽

Heimo Ehmke ◽

Uwe Wittmann ◽

Hartmut R. Kirchheim

Keyword(s):

Blood Flow ◽

Renal Blood Flow ◽

Transfer Functions ◽

High Gain ◽

Tubuloglomerular Feedback ◽

Myogenic Response ◽

No Donor ◽

The Mean ◽

Spontaneous Fluctuations ◽

Elevated Heart Rate

The aim of this study was to investigate the influence of the mean level and phasic modulation of NO on the dynamic autoregulation of renal blood flow (RBF). Transfer functions were calculated from spontaneous fluctuations of RBF and arterial pressure (AP) in conscious resting dogs for 2 h under control conditions, after NO synthase (NOS) inhibition [ N G-nitro-l-arginine methyl ester hydrochloride (l-NAME)] and afterl-NAME followed by a continuous infusion of an NO donor [ S-nitroso- N-acetyl-dl-penicillamine (SNAP)]. After l-NAME ( n = 7) AP was elevated, heart rate (HR) and RBF were reduced. The gain of the transfer function above 0.08 Hz was increased, compatible with enhanced resonance of the myogenic response. A peak of high gain around 0.03 Hz, reflecting oscillations of the tubuloglomerular feedback (TGF), was not affected. The gain below 0.01 Hz, was elevated, but still less than 0 dB, indicating diminished but not abolished autoregulation. Afterl-NAME and SNAP ( n = 5), mean AP and RBF were not changed, but HR was slightly elevated. The gain above 0.08 Hz and the peak of high gain at 0.03 Hz were not affected. The gain below 0.01 Hz was elevated, but smaller than 0 dB. It is concluded that NO may help to prevent resonance of the myogenic response depending on the mean level of NO. The feedback oscillations of the TGF are not affected by NO. NO contributes to the autoregulation below 0.01 Hz due to phasic modulation independent of its mean level.

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The step response: a method to characterize mechanisms of renal blood flow autoregulation

AJP Renal Physiology ◽

10.1152/ajprenal.00420.2002 ◽

2003 ◽

Vol 285 (4) ◽

pp. F758-F764 ◽

Cited By ~ 30

Author(s):

T. Wronski ◽

E. Seeliger ◽

P. B. Persson ◽

C. Forner ◽

C. Fichtner ◽

...

Keyword(s):

Blood Flow ◽

Renal Blood Flow ◽

Renal Perfusion ◽

Oscillation Period ◽

Tubuloglomerular Feedback ◽

Step Response ◽

Myogenic Response ◽

Renal Vasculature ◽

The Individual ◽

Reported Data

Response of renal vasculature to changes in renal perfusion pressure (RPP) involves mechanisms with different frequency characteristics. Autoregulation of renal blood flow (RBF) is mediated by the rapid myogenic response, by the slower tubuloglomerular feedback (TGF) mechanism, and, possibly, by an even slower third mechanism. To evaluate the individual contribution of these mechanisms to RBF autoregulation, we analyzed the response of RBF to a step increase in RPP. In anesthetized rats, the suprarenal aorta was occluded for 30 s, and then the occlusion was released to induce a step increase in RPP. Three dampened oscillations were observed; their oscillation periods ranged from 9.5 to 13 s, from 34.2 to 38.6 s, and from 100.5 to 132.2 s, respectively. The two faster oscillations correspond with previously reported data on the myogenic mechanism and the TGF. In accordance, after furosemide, the amplitude of the intermediate oscillation was significantly reduced. Inhibition of nitric oxide synthesis by Nω-nitro-l-arginine methyl ester significantly increased the amplitude of the 10-s oscillation. It is concluded that the parameters of the dampened oscillations induced by the step increase in RPP reflect properties of autoregulatory mechanisms. The oscillation period characterizes the individual mechanism, the dampening is a measure for the stability of the regulation, and the square of the amplitudes characterizes the power of the respective mechanism. In addition to the myogenic response and the TGF, a third rather slow mechanism of RBF autoregulation exists.

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Frequency encoding in renal blood flow regulation

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00540.2004 ◽

2005 ◽

Vol 288 (5) ◽

pp. R1160-R1167 ◽

Cited By ~ 43

Author(s):

Donald J. Marsh ◽

Olga V. Sosnovtseva ◽

Alexey N. Pavlov ◽

Kay-Pong Yip ◽

Niels-Henrik Holstein-Rathlou

Keyword(s):

Blood Pressure ◽

Blood Flow ◽

Renal Blood Flow ◽

Amplitude Modulation ◽

Wavelet Transforms ◽

Modulation Frequency ◽

Flow Regulation ◽

Tubuloglomerular Feedback ◽

Conscious Rat ◽

Blood Flow Regulation

With a model of renal blood flow regulation, we examined consequences of tubuloglomerular feedback (TGF) coupling to the myogenic mechanism via voltage-gated Ca channels. The model reproduces the characteristic oscillations of the two mechanisms and predicts frequency and amplitude modulation of the myogenic oscillation by TGF. Analysis by wavelet transforms of single-nephron blood flow confirms that both amplitude and frequency of the myogenic oscillation are modulated by TGF. We developed a double-wavelet transform technique to estimate modulation frequency. Median value of the ratio of modulation frequency to TGF frequency in measurements from 10 rats was 0.95 for amplitude modulation and 0.97 for frequency modulation, a result consistent with TGF as the modulating signal. The simulation predicted that the modulation was regular, while the experimental data showed much greater variability from one TGF cycle to the next. We used a blood pressure signal recorded by telemetry from a conscious rat as the input to the model. Blood pressure fluctuations induced variability in the modulation records similar to those found in the nephron blood flow results. Frequency and amplitude modulation can provide robust communication between TGF and the myogenic mechanism.

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

AJP Renal Physiology ◽

10.1152/ajprenal.00256.2007 ◽

2007 ◽

Vol 293 (5) ◽

pp. F1489-F1500 ◽

Cited By ~ 28

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.

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Connexin 40 Mediates the Tubuloglomerular Feedback Contribution to Renal Blood Flow Autoregulation

Journal of the American Society of Nephrology ◽

10.1681/asn.2008090943 ◽

2009 ◽

Vol 20 (7) ◽

pp. 1577-1585 ◽

Cited By ~ 37

Author(s):

Armin Just ◽

Lisa Kurtz ◽

Cor de Wit ◽

Charlotte Wagner ◽

Armin Kurtz ◽

...

Keyword(s):

Blood Flow ◽

Renal Blood Flow ◽

Tubuloglomerular Feedback ◽

Connexin 40 ◽

Renal Blood Flow Autoregulation

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Spontaneous renal blood flow autoregulation curves in conscious sinoaortic baroreceptor-denervated rats

AJP Renal Physiology ◽

10.1152/ajprenal.0186.2001 ◽

2002 ◽

Vol 282 (1) ◽

pp. F51-F58 ◽

Cited By ~ 10

Author(s):

Silene L. S. Pires ◽

Claude Julien ◽

Bruno Chapuis ◽

Jean Sassard ◽

Christian Barrès

Keyword(s):

Blood Flow ◽

Arterial Pressure ◽

Renal Blood Flow ◽

Coefficient Of Variation ◽

Tubuloglomerular Feedback ◽

Before And After ◽

Renal Blood Flow Autoregulation ◽

Limited Accuracy ◽

Weibull Equation ◽

Intact Rats

These experiments examined whether the conscious sinoaortic baroreceptor-denervated (SAD) rat, owing to its high spontaneous arterial pressure (AP) variability, might represent a model for renal blood flow (RBF) autoregulation studies. In eight SAD and six baroreceptor-intact rats, AP and RBF were recorded (1-h periods) before and after furosemide (10 mg/kg followed by 10 mg · kg−1 · h−1 iv)administration. In control conditions, AP variability was markedly enhanced in SAD rats (coefficient of variation: 16.0 ± 1.2 vs. 5.4 ± 0.5% in intact rats), whereas RBF variability was only slightly increased (8.7 ± 0.6 vs. 6.1 ± 0.5% in intact rats), suggesting buffering by autoregulatory mechanisms. In SAD rats, but not in intact rats, the AP-RBF relationships could be modeled with a four-parameter sigmoid Weibull equation ( r 2 = 0.24 ± 0.07, 3,600 data pairs/rat), allowing for estimation of an autoregulatory plateau (10.1 ± 0.7 ml/min) and a lower limit of RBF autoregulation (PLL = 93 ± 6 mmHg, defined as AP at RBF 5% below the plateau). After furosemide treatment, autoregulation curves ( r 2 = 0.49 ± 0.07) in SAD rats were shifted downward (plateau = 8.6 ± 0.8 ml/min) and rightward (PLL = 102 ± 5 mmHg). In five of six intact rats, PLL became measurable (104 ± 1 mmHg), albeit with limited accuracy ( r 2 = 0.09 ± 0.03). In conclusion, the conscious SAD rat offers the possibility of describing RBF autoregulation curves under dynamic, unforced conditions. The tubuloglomerular feedback and myogenic mechanisms cooperate in setting PLL and thus in stabilizing RBF during spontaneous depressor episodes.

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Time-Dependent Autoregulation of Renal Blood Flow in Conscious Rats

Journal of the American Society of Nephrology ◽

10.1681/asn.v12112253 ◽

2001 ◽

Vol 12 (11) ◽

pp. 2253-2262

Author(s):

BERT FLEMMING ◽

NICOLE ARENZ ◽

ERDMANN SEELIGER ◽

THOMAS WRONSKI ◽

KATHARINA STEER ◽

...

Keyword(s):

Blood Flow ◽

Renal Blood Flow ◽

Dynamic Properties ◽

Rate Of Change ◽

Tubuloglomerular Feedback ◽

Operating Pressure ◽

Renal Vasculature ◽

Pressure Flow ◽

Conscious Rats ◽

Maximum Conductance

Abstract. Response of renal vasculature to changes in renal perfusion pressure (RPP) involves mechanisms with different frequency characteristics. Autoregulation of renal blood flow is mediated by a rapid myogenic response and a slower tubuloglomerular feedback mechanism. In 25 male conscious rats, ramp-shaped changes in RPP were induced to quantify dynamic properties of autoregulation. Decremental RPP ramps immediately followed by incremental ramps were made for four different rates of change, ranging from 0.118 to 1.056 mmHg/s. Renal blood flow and cortical and medullary fluxes were assessed, and the corresponding relative conductance values were calculated continuously. During RPP decrements, conductance increased. With increasing rate of change of RPP decrements, maximum conductance increased from 10% to 80%, as compared with control. This response, which indicates the magnitude of autoregulation, was more pronounced in cortical versus medullary vasculature. Pressure at maximum conductance decreased with increasing rate of change of RPP decrements from 88 to 72 mmHg. During RPP increments, dependence of maximum conductance changes on the rate of change was enhanced (-20 to 110% of control). Thus, a hysteresis-like asymmetry between RPP decrements and increments, a resetting of autoregulation, was observed, which in direction and magnitude depended on the rate of change and duration of RPP changes. In conclusion, renal vascular responses to changes in RPP are highly dependent on the dynamics of the error signal. Furthermore, the method presented allows differentiated stimulation of various static and dynamic components of pressure-flow relationship and, thus, a direct assessment of the magnitudes and operating pressure range of active mechanisms of pressure-flow relationships.

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Aging Impairs Renal Autoregulation in Mice

Hypertension ◽

10.1161/hypertensionaha.119.13588 ◽

2020 ◽

Vol 75 (2) ◽

pp. 405-412 ◽

Cited By ~ 2

Author(s):

Jin Wei ◽

Jinxiu Zhu ◽

Jie Zhang ◽

Shan Jiang ◽

Larry Qu ◽

...

Keyword(s):

Blood Pressure ◽

Blood Flow ◽

Renal Blood Flow ◽

Tubuloglomerular Feedback ◽

Myogenic Response ◽

Renal Autoregulation ◽

Integrin Α5 ◽

Aging Kidney

Impaired renal autoregulation permits more transmission of disturbance in systemic blood pressure, which initiates barotrauma in intrarenal microvasculatures such as glomerular and tubulointerstitial capillaries, contributing to the development of kidney damage and deterioration in renal function, especially under the conditions with high blood pressure. Although it has been postulated that autoregulatory efficiency is attenuated in the aging kidney, direct evidence remains lacking. In the present study, we measured the autoregulation of renal blood flow, myogenic response of afferent arteriole (Af-Art), tubuloglomerular feedback in vivo with micropuncture, as well as tubuloglomerular feedback in vitro in isolated perfused juxtaglomerular apparatus in young and aged C57BL/6 mice. We found that renal blood flow was not significantly changed in response to a defined elevation of renal arterial pressure in young mice but significantly increased in aged mice. Additionally, myogenic response of Af-Art measured by microperfusion with a stepwise increase in perfusion pressure was significantly blunted in the aging kidney, which is associated with the attenuation of intraluminal pressure-induced intracellular calcium increases, as well as the reduced expression of integrin α5 (Itga5) in Af-Art. Moreover, both tubuloglomerular feedback in vivo and in vitro were nearly inactive in the aging kidney, which is associated with the significantly reduced expression of adenosine A1 receptor (A1AR) and suppressed vasoconstrictor response to adenosine in Af-Art. In conclusion, this study demonstrates that aging impairs renal autoregulation with blunted myogenic response and inhibited tubuloglomerular feedback response. The underlying mechanisms involve the downregulations of integrin α5 and A1AR in the Af-Art.

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