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Janos Petipeterdi - One of the best experts on this subject based on the ideXlab platform.
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independent two photon measurements of albumin gsc give low values
American Journal of Physiology-renal Physiology, 2009Co-Authors: Janos PetipeterdiAbstract:two-photon microscopy is an advanced confocal laser-scanning fluorescence imaging technique that has been used in renal research for about a decade as a very powerful tool for the deep optical sectioning of the living kidney tissue (4, 6, 8, 9). Two-photon applications have changed a number of existing paradigms in renal (patho)physiology as summarized in a current review (10). Since two-photon imaging allows the direct visualization of the glomerular filtration barrier (GFB) with submicron resolution in the intact kidney in vivo, it was used recently for the reevaluation of albumin's glomerular sieving coefficient (GSC) (12). In this interesting work, Russo et al. (12) observed mass glomerular filtration of fluorophore-conjugated albumin in normal kidneys (GSC in the 0.02–0.04 range) and its rapid endocytosis in the proximal tubule. Based on these two-photon studies, the authors (12) concluded that the GFB normally leaks albumin at nephrotic levels and that this filtered albumin load is avidly bound and retrieved by cells of the proximal tubule. In the current issue of JASN, these same authors (13) report further two-photon evidence for the tubular origin of diabetic albuminuria. Since the value of albumin GSC measured by two-photon microscopy in these studies is 50 times greater than previously measured by micropuncture (17) or calculated (7) (GSC in the 0.0006 range), the two-photon studies generated heated debate in top renal journals (1, 2, 5, 11) and at the American Society of Nephrology's 2008 Annual Meeting. One of the recurring criticisms was the low signal-to-noise fluorescence and other technical aspects of two-photon microscopy. It became clear that further work is needed in this area with better controlled two-photon experiments which would confirm or refute the high albumin GSC values. It would be even better if this came from an independent laboratory. In the American Journal of Physiology-Renal Physiology, George Tanner (15) reports his own two-photon studies on the albumin GSC in the rat. It is important to note that although he used the same technology and imaging facility at the Indiana Center for Biological Microscopy as Russo et al. (12, 13), the brands of microscopes were different. In his independent work, Tanner (15) found that the albumin GSC was in the 0.002–0.004 range, much lower than previously reported (12, 13). He identified a number of factors that were likely responsible for the higher GSC values found by Russo et al. Several of these factors were unrelated to imaging and concerned the poor animal conditions such as hypothermia, dehydration, low blood pressure, and low glomerular filtration rate (GFR) (15). In fact, none of the Russo et al. papers measured or reported blood pressure data (12, 13) even if the perfusion pressure is the most important one of the Starling forces for filtration in the glomerular capillaries. Of the imaging related factors Tanner (15) identified the high laser outputs (high levels of illumination) and the use of external, instead of internal, photodetectors as possible further culprits which he believes resulted in the collection of significant out-of-focus fluorescence (noise and not albumin) in the Bowman's space. The principle of two-photon microscopy is that the simultaneous absorption of two photons of equally low energy (long wavelength) can cause excitation of a fluorophore equivalent to the absorption of a single photon of double the energy (half the wavelength) (3). Two-photon images are confocal solely by excitation (excitation normally happens only in the focus) and there is no need to filter the emitted fluorescence with pinholes as with conventional confocal microscopy. For this reason, two-photon microscopy most often uses external, so-called nondescanned detectors which are very efficient, collecting close to 100% of the emitted fluorescence. In contrast, internal detection (i.e., within the scanhead) is less efficient since it uses several mirrors and the pinholes which absorb or exclude a significant portion of the emitted light. However, when imaging with two-photon in inhomogeneous, highly scattering tissues (unfortunately the kidney is a great example), the images may not be “pure” confocal when using the external detectors. This is due to the scattered exciting laser giving rise to fluorescence emission out-of-focus, usually within the first few microns in the sample (16). The out-of-focus fluorescence could be significant when imaging very superficial glomeruli in the Munich-Wistar rats (within 50 μm from the surface). Tanner (15) claims that for this reason he found better signal-to-noise ratio, lower fluorescence in the Bowman's capsule (translating to lower albumin GSC) when he used internal detectors with the classical confocal pinhole method. Of course the price one pays when using internal as opposed to external detectors is the much reduced fluorescence levels. But there may be additional imaging-related reasons for the previously measured high GSC values by Russo et al. (12, 13), independent of the two-photon technology. Since the previous micropuncture-based albumin GSC is 0.0006 (17), performing fluorescence intensity measurements with 8-bit depth resolution (used by Russo et al. and most studies by Tanner as well) may not provide the necessary dynamic range. With 8-bit depth resolution the pixel intensities (gray scale) are in the 0–255 range, far less than what the predicted, more than 1,000-fold difference in fluorescence intensities in the two compartments would require. Most advanced imaging systems allow 12-bit depth imaging (0–4,095 gray intensity scale), which seems absolutely necessary for correct fluorescence-based GSC measurements. Consistent with the better dynamic range with 12-bit imaging, Tanner (15) found even lower albumin GSC values with an Olympus system (uses 12-bit) compared with a Zeiss system (uses 8-bit). Low average fluorescence intensities in the Bowman's capsule (values between 0 and 1) are hardly distinguishable from background under in vivo conditions. This can explain the high standard deviation in Tanner's work (15) when using 8-bit resolution (GSC was 0.004 ± 0.004) which suggests that the “real” albumin GSC is even lower. Since my laboratory at the University of Southern California routinely uses the two-photon technology for imaging the mouse and rat kidney in vivo, including function of the GFB (14), we decided to provide experimental support for the above issues. Figure 1 shows an experiment similar to those reported by Russo et al. (12, 13) and Tanner (15). A 70-kDa dextran-rhodamin B conjugate (slightly larger than albumin) was injected intravenously and fluorescence intensities in the Bowman's space and in the glomerular capillaries were detected using 8-bit depth resolution. Mean arterial blood pressure was measured during imaging as described before (6) and it was normal. The fluorescence intensity of dextran-rhodamine in the Bowman's space was low (in the 10–20 range) but distinguishable from background, and it showed regular oscillations (Fig. 1C), similar to what we reported earlier (6). These oscillations are normal and are due to two important renal physiological Mechanisms that control GFR and renal hemodynamics: 1) tubuloglomerular feedback and 2) the Myogenic Mechanism (6). The oscillatory pattern of fluorescence actually provided assurance that we in fact measured the function of GFB. However, under the same imaging conditions and in the same glomerulus, the plasma fluorescence was saturated (Fig. 1D), meaning that the 70-kDa dextran GSC value was much lower than 0.04 (10/255). When we reduced detector sensitivity so the fluorescence intensity in the Bowman's space was around 1, a line scan of the capillary plasma (Fig. 1B) found still saturated plasma fluorescence (dextran GSC is lower than 1/255 = 0.004). The rationale for performing a line scan is that it is very fast (1,000 Hz) and it can separate the cell and plasma fractions of capillary blood much better compared with a single xy scan (6). The streaming unlabeled red blood cells can significantly scatter, absorb, and reduce dextran fluorescence in the capillaries during full-frame xy scanning, leading to the underestimation of “pure” plasma fluorescence (overestimation of albumin GSC). This was likely an additional factor in the Russo et al. studies (12, 13). Fig. 1. Two-photon imaging of glomerular permeability to macromolecules in the intact Munich-Wistar rat kidney in vivo. A: circulating plasma was labeled with 70-kDa dextran-rhodamine B (red), and proximal (PT) and distal (DT) renal tubules with quinacrine (green). ... Even if imaging a perfectly maintained animal with 12-bit depth resolution, a number of physiological Mechanisms cause normal variations in Bowman's space fluorescence, like the regular oscillations in single-nephron GFR shown in Fig. 1C and in our previous study (6). Also, the concentration of plasma (fluorescence) is higher at the efferent vs. afferent end of glomerular capillaries. Depending on the timing (Fig. 1C) and location of fluorescence GSC measurements, the results can be highly variable due to the many significant inherent errors. In summary, two-photon microscopy is a powerful imaging tool that can detect very low levels of macromolecules (fluorescence) in the Bowman's space and at the brush-border membrane of the proximal tubule. The GSC of albumin is very low (lower than 0.004) even when fluorescence tools are used for its determination. Well-controlled systemic parameters and animal techniques (blood pressure monitoring, infusion) and adequate imaging methods (12-bit depth resolution, line scans) are absolutely required.
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independent two photon measurements of albumin gsc give low values
American Journal of Physiology-renal Physiology, 2009Co-Authors: Janos PetipeterdiAbstract:two-photon microscopy is an advanced confocal laser-scanning fluorescence imaging technique that has been used in renal research for about a decade as a very powerful tool for the deep optical sectioning of the living kidney tissue (4, 6, 8, 9). Two-photon applications have changed a number of existing paradigms in renal (patho)physiology as summarized in a current review (10). Since two-photon imaging allows the direct visualization of the glomerular filtration barrier (GFB) with submicron resolution in the intact kidney in vivo, it was used recently for the reevaluation of albumin's glomerular sieving coefficient (GSC) (12). In this interesting work, Russo et al. (12) observed mass glomerular filtration of fluorophore-conjugated albumin in normal kidneys (GSC in the 0.02–0.04 range) and its rapid endocytosis in the proximal tubule. Based on these two-photon studies, the authors (12) concluded that the GFB normally leaks albumin at nephrotic levels and that this filtered albumin load is avidly bound and retrieved by cells of the proximal tubule. In the current issue of JASN, these same authors (13) report further two-photon evidence for the tubular origin of diabetic albuminuria. Since the value of albumin GSC measured by two-photon microscopy in these studies is 50 times greater than previously measured by micropuncture (17) or calculated (7) (GSC in the 0.0006 range), the two-photon studies generated heated debate in top renal journals (1, 2, 5, 11) and at the American Society of Nephrology's 2008 Annual Meeting. One of the recurring criticisms was the low signal-to-noise fluorescence and other technical aspects of two-photon microscopy. It became clear that further work is needed in this area with better controlled two-photon experiments which would confirm or refute the high albumin GSC values. It would be even better if this came from an independent laboratory. In the American Journal of Physiology-Renal Physiology, George Tanner (15) reports his own two-photon studies on the albumin GSC in the rat. It is important to note that although he used the same technology and imaging facility at the Indiana Center for Biological Microscopy as Russo et al. (12, 13), the brands of microscopes were different. In his independent work, Tanner (15) found that the albumin GSC was in the 0.002–0.004 range, much lower than previously reported (12, 13). He identified a number of factors that were likely responsible for the higher GSC values found by Russo et al. Several of these factors were unrelated to imaging and concerned the poor animal conditions such as hypothermia, dehydration, low blood pressure, and low glomerular filtration rate (GFR) (15). In fact, none of the Russo et al. papers measured or reported blood pressure data (12, 13) even if the perfusion pressure is the most important one of the Starling forces for filtration in the glomerular capillaries. Of the imaging related factors Tanner (15) identified the high laser outputs (high levels of illumination) and the use of external, instead of internal, photodetectors as possible further culprits which he believes resulted in the collection of significant out-of-focus fluorescence (noise and not albumin) in the Bowman's space. The principle of two-photon microscopy is that the simultaneous absorption of two photons of equally low energy (long wavelength) can cause excitation of a fluorophore equivalent to the absorption of a single photon of double the energy (half the wavelength) (3). Two-photon images are confocal solely by excitation (excitation normally happens only in the focus) and there is no need to filter the emitted fluorescence with pinholes as with conventional confocal microscopy. For this reason, two-photon microscopy most often uses external, so-called nondescanned detectors which are very efficient, collecting close to 100% of the emitted fluorescence. In contrast, internal detection (i.e., within the scanhead) is less efficient since it uses several mirrors and the pinholes which absorb or exclude a significant portion of the emitted light. However, when imaging with two-photon in inhomogeneous, highly scattering tissues (unfortunately the kidney is a great example), the images may not be “pure” confocal when using the external detectors. This is due to the scattered exciting laser giving rise to fluorescence emission out-of-focus, usually within the first few microns in the sample (16). The out-of-focus fluorescence could be significant when imaging very superficial glomeruli in the Munich-Wistar rats (within 50 μm from the surface). Tanner (15) claims that for this reason he found better signal-to-noise ratio, lower fluorescence in the Bowman's capsule (translating to lower albumin GSC) when he used internal detectors with the classical confocal pinhole method. Of course the price one pays when using internal as opposed to external detectors is the much reduced fluorescence levels. But there may be additional imaging-related reasons for the previously measured high GSC values by Russo et al. (12, 13), independent of the two-photon technology. Since the previous micropuncture-based albumin GSC is 0.0006 (17), performing fluorescence intensity measurements with 8-bit depth resolution (used by Russo et al. and most studies by Tanner as well) may not provide the necessary dynamic range. With 8-bit depth resolution the pixel intensities (gray scale) are in the 0–255 range, far less than what the predicted, more than 1,000-fold difference in fluorescence intensities in the two compartments would require. Most advanced imaging systems allow 12-bit depth imaging (0–4,095 gray intensity scale), which seems absolutely necessary for correct fluorescence-based GSC measurements. Consistent with the better dynamic range with 12-bit imaging, Tanner (15) found even lower albumin GSC values with an Olympus system (uses 12-bit) compared with a Zeiss system (uses 8-bit). Low average fluorescence intensities in the Bowman's capsule (values between 0 and 1) are hardly distinguishable from background under in vivo conditions. This can explain the high standard deviation in Tanner's work (15) when using 8-bit resolution (GSC was 0.004 ± 0.004) which suggests that the “real” albumin GSC is even lower. Since my laboratory at the University of Southern California routinely uses the two-photon technology for imaging the mouse and rat kidney in vivo, including function of the GFB (14), we decided to provide experimental support for the above issues. Figure 1 shows an experiment similar to those reported by Russo et al. (12, 13) and Tanner (15). A 70-kDa dextran-rhodamin B conjugate (slightly larger than albumin) was injected intravenously and fluorescence intensities in the Bowman's space and in the glomerular capillaries were detected using 8-bit depth resolution. Mean arterial blood pressure was measured during imaging as described before (6) and it was normal. The fluorescence intensity of dextran-rhodamine in the Bowman's space was low (in the 10–20 range) but distinguishable from background, and it showed regular oscillations (Fig. 1C), similar to what we reported earlier (6). These oscillations are normal and are due to two important renal physiological Mechanisms that control GFR and renal hemodynamics: 1) tubuloglomerular feedback and 2) the Myogenic Mechanism (6). The oscillatory pattern of fluorescence actually provided assurance that we in fact measured the function of GFB. However, under the same imaging conditions and in the same glomerulus, the plasma fluorescence was saturated (Fig. 1D), meaning that the 70-kDa dextran GSC value was much lower than 0.04 (10/255). When we reduced detector sensitivity so the fluorescence intensity in the Bowman's space was around 1, a line scan of the capillary plasma (Fig. 1B) found still saturated plasma fluorescence (dextran GSC is lower than 1/255 = 0.004). The rationale for performing a line scan is that it is very fast (1,000 Hz) and it can separate the cell and plasma fractions of capillary blood much better compared with a single xy scan (6). The streaming unlabeled red blood cells can significantly scatter, absorb, and reduce dextran fluorescence in the capillaries during full-frame xy scanning, leading to the underestimation of “pure” plasma fluorescence (overestimation of albumin GSC). This was likely an additional factor in the Russo et al. studies (12, 13). Fig. 1. Two-photon imaging of glomerular permeability to macromolecules in the intact Munich-Wistar rat kidney in vivo. A: circulating plasma was labeled with 70-kDa dextran-rhodamine B (red), and proximal (PT) and distal (DT) renal tubules with quinacrine (green). ... Even if imaging a perfectly maintained animal with 12-bit depth resolution, a number of physiological Mechanisms cause normal variations in Bowman's space fluorescence, like the regular oscillations in single-nephron GFR shown in Fig. 1C and in our previous study (6). Also, the concentration of plasma (fluorescence) is higher at the efferent vs. afferent end of glomerular capillaries. Depending on the timing (Fig. 1C) and location of fluorescence GSC measurements, the results can be highly variable due to the many significant inherent errors. In summary, two-photon microscopy is a powerful imaging tool that can detect very low levels of macromolecules (fluorescence) in the Bowman's space and at the brush-border membrane of the proximal tubule. The GSC of albumin is very low (lower than 0.004) even when fluorescence tools are used for its determination. Well-controlled systemic parameters and animal techniques (blood pressure monitoring, infusion) and adequate imaging methods (12-bit depth resolution, line scans) are absolutely required.
Nielshenrik Holsteinrathlou - One of the best experts on this subject based on the ideXlab platform.
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nonlinear interactions in renal blood flow regulation
American Journal of Physiology-regulatory Integrative and Comparative Physiology, 2005Co-Authors: Donald J Marsh, Olga Sosnovtseva, Ki H Chon, Nielshenrik HolsteinrathlouAbstract:We have developed a model of tubuloglomerular feedback (TGF) and the Myogenic Mechanism in afferent arterioles to understand how the two Mechanisms are coupled. This paper presents the model. The t...
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frequency encoding in renal blood flow regulation
American Journal of Physiology-regulatory Integrative and Comparative Physiology, 2005Co-Authors: Donald J Marsh, Olga Sosnovtseva, Alexey N Pavlov, Kaypong Yip, Nielshenrik HolsteinrathlouAbstract: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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renal blood flow regulation and arterial pressure fluctuations a case study in nonlinear dynamics
Physiological Reviews, 1994Co-Authors: Nielshenrik Holsteinrathlou, Donald J MarshAbstract:The arterial blood pressure, a physiological variable on which all renal excretory processes depend, fluctuates over a wide range of amplitudes and frequencies. Much of this variation originates in nonrenal vascular beds to support nonrenal tasks, and the fluctuations provide a noisy environment in which the kidney is obliged to operate. Were it not for renal blood flow autoregulation, it would be difficult to regulate renal excretory processes so as to maintain whole body variables within narrow bounds. Autoregulation is the noise filter on which other renal processes depend for maintaining a relatively noise-free environment in which to work. Because of the time-varying nature of the blood pressure, we have concentrated in this review on the now substantial body of work on the dynamics of renal blood flow regulation and the underlying Mechanisms. Renal vascular control Mechanisms are not simply reactive but have their own spontaneous dynamics. Both TGF and the Myogenic Mechanism oscillate autonomously. The TGF oscillation is the better understood of the two. There is an oscillation of tubular pressure, proximal tubular flow, early distal Cl- concentration, and efferent arteriolar blood flow at approximately 35 mHz; all these variables are synchronized when the measurements are made in a single tubule. The autonomous nature of the oscillation is supported by simulations of the nephron and its vasculature, which show that for a reasonable representation of the dynamics of these structures and of the parameters that govern their behavior, the solutions of the equation set are periodic at the frequency of the observed oscillation, and with the same phase relationships among its variables. The simulations also show that the critical variables for the development of the oscillation are the open-loop gain of the feedback system, and the various delays in the system of which convective transport in the axis of the thick ascending limb and signal transmission between the macula densa and the afferent arteriole are the most important. The oscillation in TGF is an example of nonlinear dynamical behavior and is yet another in a long list of oscillations and related dynamics arising in the inherently nonlinear properties of living systems. Some nonlinear systems can bifurcate to states known collectively as deterministic chaos, and TGF is a clear example of such a system. Rats with two different and unrelated forms of experimental hypertension provide tubular pressure records that pass statistical tests for ordered structure and sensitive dependence on initial conditions in the reconstructed state space, two of the hallmarks of deterministic chaos. These records also pass recent more stringent tests for chaos. The significance of deterministic chaos in the context of renal blood flow regulation is that the system regulating blood flow undergoes a physical change to a different dynamical state, and because the change is deterministic, there is every expectation that the critical change will yield itself to experimental discovery.(ABSTRACT TRUNCATED AT 400 WORDS)
Donald J Marsh - One of the best experts on this subject based on the ideXlab platform.
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nonlinear interactions in renal blood flow regulation
American Journal of Physiology-regulatory Integrative and Comparative Physiology, 2005Co-Authors: Donald J Marsh, Olga Sosnovtseva, Ki H Chon, Nielshenrik HolsteinrathlouAbstract:We have developed a model of tubuloglomerular feedback (TGF) and the Myogenic Mechanism in afferent arterioles to understand how the two Mechanisms are coupled. This paper presents the model. The t...
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frequency encoding in renal blood flow regulation
American Journal of Physiology-regulatory Integrative and Comparative Physiology, 2005Co-Authors: Donald J Marsh, Olga Sosnovtseva, Alexey N Pavlov, Kaypong Yip, Nielshenrik HolsteinrathlouAbstract: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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Niels-Henrik Holstein-Rathlou. Nonlinear interactions in renal
2005Co-Authors: Donald J Marsh, Ki H Chon, Olga V. Sosnovtseva, Niels-henrik Holstein-rathlou, Department Of Molecular Pharmacology, Donald JAbstract:doi:10.1152/ajpregu.00539.2004.—We have developed a model of tubuloglomerular feedback (TGF) and the Myogenic Mechanism in afferent arterioles to understand how the two Mechanisms are coupled. This paper presents the model. The tubular model predicts pressure, flow, and NaCl concentration as functions of time and tubular length in a compliant tubule that reabsorbs NaCl and water; boundary conditions are glomerular filtration rate (GFR), a nonlinear outflow resistance, and initial NaCl concentration. The glomerular model calculates GFR from a change in protein concentration using esti-mates of capillary hydrostatic pressure, tubular hydrostatic pressure, and plasma flow rate. The arteriolar model predicts fraction of open K channels, intracellular Ca concentration (Cai), potential difference, rate of actin–myosin cross bridge formation, force of contraction, and length of elastic elements, and was solved for two arteriolar segments, identical except for the strength of TGF input, with a third, fixe
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renal blood flow regulation and arterial pressure fluctuations a case study in nonlinear dynamics
Physiological Reviews, 1994Co-Authors: Nielshenrik Holsteinrathlou, Donald J MarshAbstract:The arterial blood pressure, a physiological variable on which all renal excretory processes depend, fluctuates over a wide range of amplitudes and frequencies. Much of this variation originates in nonrenal vascular beds to support nonrenal tasks, and the fluctuations provide a noisy environment in which the kidney is obliged to operate. Were it not for renal blood flow autoregulation, it would be difficult to regulate renal excretory processes so as to maintain whole body variables within narrow bounds. Autoregulation is the noise filter on which other renal processes depend for maintaining a relatively noise-free environment in which to work. Because of the time-varying nature of the blood pressure, we have concentrated in this review on the now substantial body of work on the dynamics of renal blood flow regulation and the underlying Mechanisms. Renal vascular control Mechanisms are not simply reactive but have their own spontaneous dynamics. Both TGF and the Myogenic Mechanism oscillate autonomously. The TGF oscillation is the better understood of the two. There is an oscillation of tubular pressure, proximal tubular flow, early distal Cl- concentration, and efferent arteriolar blood flow at approximately 35 mHz; all these variables are synchronized when the measurements are made in a single tubule. The autonomous nature of the oscillation is supported by simulations of the nephron and its vasculature, which show that for a reasonable representation of the dynamics of these structures and of the parameters that govern their behavior, the solutions of the equation set are periodic at the frequency of the observed oscillation, and with the same phase relationships among its variables. The simulations also show that the critical variables for the development of the oscillation are the open-loop gain of the feedback system, and the various delays in the system of which convective transport in the axis of the thick ascending limb and signal transmission between the macula densa and the afferent arteriole are the most important. The oscillation in TGF is an example of nonlinear dynamical behavior and is yet another in a long list of oscillations and related dynamics arising in the inherently nonlinear properties of living systems. Some nonlinear systems can bifurcate to states known collectively as deterministic chaos, and TGF is a clear example of such a system. Rats with two different and unrelated forms of experimental hypertension provide tubular pressure records that pass statistical tests for ordered structure and sensitive dependence on initial conditions in the reconstructed state space, two of the hallmarks of deterministic chaos. These records also pass recent more stringent tests for chaos. The significance of deterministic chaos in the context of renal blood flow regulation is that the system regulating blood flow undergoes a physical change to a different dynamical state, and because the change is deterministic, there is every expectation that the critical change will yield itself to experimental discovery.(ABSTRACT TRUNCATED AT 400 WORDS)
Olga Sosnovtseva - One of the best experts on this subject based on the ideXlab platform.
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nonlinear interactions in renal blood flow regulation
American Journal of Physiology-regulatory Integrative and Comparative Physiology, 2005Co-Authors: Donald J Marsh, Olga Sosnovtseva, Ki H Chon, Nielshenrik HolsteinrathlouAbstract:We have developed a model of tubuloglomerular feedback (TGF) and the Myogenic Mechanism in afferent arterioles to understand how the two Mechanisms are coupled. This paper presents the model. The t...
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frequency encoding in renal blood flow regulation
American Journal of Physiology-regulatory Integrative and Comparative Physiology, 2005Co-Authors: Donald J Marsh, Olga Sosnovtseva, Alexey N Pavlov, Kaypong Yip, Nielshenrik HolsteinrathlouAbstract: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.
Anita T. Layton - One of the best experts on this subject based on the ideXlab platform.
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a mathematical model of the Myogenic response to systolic pressure in the afferent arteriole
American Journal of Physiology-renal Physiology, 2011Co-Authors: Jing Chen, Ioannis Sgouralis, Leon C Moore, Harold E Layton, Anita T. LaytonAbstract:Elevations in systolic blood pressure are believed to be closely linked to the pathogenesis and progression of renal diseases. It has been hypothesized that the afferent arteriole (AA) protects the glomerulus from the damaging effects of hypertension by sensing increases in systolic blood pressure and responding with a compensatory vasoconstriction (Loutzenhiser R, Bidani A, Chilton L. Circ Res 90: 1316–1324, 2002). To investigate this hypothesis, we developed a mathematical model of the Myogenic response of an AA wall, based on an arteriole model (Gonzalez-Fernandez JM, Ermentrout B. Math Biosci 119: 127–167, 1994). The model incorporates ionic transport, cell membrane potential, contraction of the AA smooth muscle cell, and the mechanics of a thick-walled cylinder. The model represents a Myogenic response based on a pressure-induced shift in the voltage dependence of calcium channel openings: with increasing transmural pressure, model vessel diameter decreases; and with decreasing pressure, vessel diameter increases. Furthermore, the model Myogenic Mechanism includes a rate-sensitive component that yields constriction and dilation kinetics similar to behaviors observed in vitro. A parameter set is identified based on physical dimensions of an AA in a rat kidney. Model results suggest that the interaction of Ca2+ and K+ fluxes mediated by voltage-gated and voltage-calcium-gated channels, respectively, gives rise to periodicity in the transport of the two ions. This results in a time-periodic cytoplasmic calcium concentration, myosin light chain phosphorylation, and cross-bridge formation with the attending muscle stress. Furthermore, the model predicts Myogenic responses that agree with experimental observations, most notably those which demonstrate that the renal AA constricts in response to increases in both steady and systolic blood pressures. The Myogenic model captures these essential functions of the renal AA, and it may prove useful as a fundamental component in a multiscale model of the renal microvasculature suitable for investigations of the pathogenesis of hypertensive renal diseases.
