Article pubs.acs.org/JPCB
Dielectric Response of Cytoplasmic Water and Its Connection to the Vitality of Human Red Blood Cells: I. Glucose Concentration Influence Evgeniya Levy,† Gregory Barshtein,‡ Leonid Livshits,‡ Paul Ben Ishai,†,§ and Yuri Feldman*,†
J. Phys. Chem. B 2016.120:10214-10220. Downloaded from pubs.acs.org by EASTERN KENTUCKY UNIV on 08/24/18. For personal use only.
†
Department of Applied Physics, The Rachel and Selim Benin School of Engineering and Computer Science, The Hebrew University of Jerusalem, Edmond J. Safra Campus, Jerusalem 91904, Israel ‡ Department of Biochemistry & Molecular Biology, IMRIC, Faculty of Medicine, The Hebrew University of Jerusalem, Ein Kerem, Jerusalem 91120, Israel § Department of Physics, Ariel University, P.O.B. 3, Ariel 40700, Israel S Supporting Information *
ABSTRACT: The vitality of red blood cells depends on the process control of glucose homeostasis, including the membrane’s ability to “switch off” D-glucose uptake at the physiologically specific concentration of 10−12 mM. We present a comprehensive study of human erythrocytes suspended in buffer solutions with varying concentrations of D-glucose at room temperature, using microwave dielectric spectroscopy (0.5 GHz−50 GHz) and cell deformability characterization (the Elongation ratio). By use of mixture formulas the contribution of the cytoplasm to the dielectric spectra was isolated. It reveals a strong dependence on the concentration of buffer D-glucose. Tellingly, the concentration 10−12 mM is revealed as a critical point in the behavior. The dielectric response of cytoplasm depends on dipole-matrix interactions between water structures and moieties, like ATP, produced during glycolysis. Subsequently, it is a marker of cellular health. One would hope that this mechanism could provide a new vista on noninvasive glucose monitoring.
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INTRODUCTION Red blood cells (RBCs), also called erythrocytes, are the most common and abundant type of blood cells. They are nonspherical biconcave discs and consist of a cellular membrane and a cytoplasm that is rich in hemoglobin. Their task is to transport oxygen in and carbon dioxide out of the organism. The plasma membrane of erythrocytes is nonconductive compared to their cytoplasm, which results in charge accumulation and interfacial polarization. This leads to the well-known β-dispersion in RBC dielectric spectrum at the 0.l−10 MHz1. This dispersion has been studied intensively from the beginning of the twentieth century and has resulted in some intriguing conclusions. For example, using the dielectric properties of β-dispersion, the molecular thickness of plasma membrane was estimated.1 Since then, the electrical properties of RBC have been extensively investigated2−11 and the electrical parameters (the membrane permittivity and the membrane conductivity) can be considered to be well established. Glucose is essential for the function of erythrocytes.12 Recently, it was shown6,7,9 that the membrane capacitance (or the membrane permittivity) is altered by the presence of Dglucose and dependent on its concentration in the buffer. Furthermore, the membrane capacitance is also linked to the geometric shape of the cells. In the case of spherical cells (in hypotonic saline solution) this dependence is non monotonic in its behavior, with a critical point close to 12 mM D-glucose © 2016 American Chemical Society
concentration. Additionally, it has been reported that erythrocyte ghosts (the plasma membrane of an erythrocyte void of hemoglobin) in phosphate buffered saline (PBS) change back to a biconcave shape with increasing of adenosine triphosphate (ATP) concentration in the suspension.13 This indicates that ATP interaction with the cytoskeleton is responsible for cellular shape. In erythrocytes, ATP is mainly produced by anaerobic glycolysis, following the uptake of glucose through the membrane glucose transporter GLUT1.1,13,14 The key regulative processes of glucose penetration are also dependent on intracellular ATP and adenosine monophosphate (AMP) and how they bind to this membrane protein.13,14 Recently, microwave sensors attached to the skin have been used to measure blood glucose levels noninvasively. The dielectric response of these sensors, usually operating in the high GHz frequency region, has shown some sensitivity to the presence of glucose in the blood.15−23 Clearly, at these frequencies this is not related to any interfacial polarization effect, due to the cell membrane, but rather to the dielectric response of water. Consequently, the role of water in the monitoring of glucose by using microwave frequencies appears to be extremely important. The RBC cytoplasm can be Received: July 13, 2016 Revised: September 6, 2016 Published: September 12, 2016 10214
DOI: 10.1021/acs.jpcb.6b06996 J. Phys. Chem. B 2016, 120, 10214−10220
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Inc., USA). The washed and isolated erythrocytes were then resuspended in PBS and supplied with nine differing D-glucose (Sigma-Aldrich G5400) concentrations ranging from 0 to 20 mM (i.e., 0, 2, 5, 8, 10, 12, 15, 18, and 20 mM). In order to keep the final osmolarity of the suspensions constant, a correspondent concentration of L-glucose (Sigma-Aldrich G5500) had to be added to the PBS buffer for each concentration batch. L-Glucose is an optic enantiomer of Dglucose that is not transportable through the erythrocyte membrane and is frequently used as a control in glucose transport and kinetic studies.7 Dielectric Spectroscopy. Dielectric measurements were carried out in the frequency range from 500 MHz to 50 GHz using a microwave network analyzer (Keysight N5245A PNAX), together with a flexible cable and slim-form probe (Keysight N1501A Dielectric Probe Kit). The calibration of the system was performed with the aid of three references: air, a Keysight standard short circuit, and pure water at 25 °C. A special stand for the slim-form probe was designed and combined with a sample cell holder for liquids (total volume ∼7.8 mL). The holder was enveloped by a thermal jacket and attached to a Julabo CF 41 oil-based heat circulatory system. The cell was held at 25 °C by the circulator-thermostat with temperature fluctuations less than 0.1 °C. The whole measuring system was placed in an air-conditioned room maintained at 25 ± 1 °C. Each sample was measured at least six times. The real and imaginary parts ε′(ω) and ε′′(ω) were evaluated using the Keysight N1500A Materials Measurement Software with an accuracy of Δε′/ε′ = 0.05, Δε″/ε″ = 0.05.36 When D-glucose was added to the PBS, the cells were first incubated for 5 min at 25 °C before dielectric measurements were made. Determination of RBC Deformability. The present research employed the computerized cell flow-properties analyzer (CFA), designed and constructed in house.34 The CFA enables the monitoring of RBC hemodynamic characteristics as a function of shear stress, under conditions resembling those in microvessels, by a direct visualization of their dynamic organization in a narrow-gap flow-chamber that has been placed under a microscope.34,37,38 RBC deformability is determined by monitoring the elongation of RBCs, while they are stuck to a polystyrene slide, under flow-induced sheer stress.34 In brief, 50 μL of RBC suspension (1% hematocrit, in PBS) are inserted into the flow-chamber (adjusted to 200 μm gap) containing an uncoated slide (purchased from Electron Microscopy Science (Washington, PA)). The RBCs that adhere to the slide surface are then subjected to controllable flow-induced sheer stress (3.0 Pa), and their deformability is determined by the change in cell shape. This change is expressed by the elongation ratio: ER = a/b, where a is the major cellular axis and b is the minor cellular axis. ER = 1 reflects a round RBC, undeformed by the applied sheer stress. The CFA contains an image analysis program capable of automatically measuring the ER for individual cells. The deformability distribution of a large RBC population (at least 2500 ± 300 cells) is then provided as a function of shear stress.34 The accuracy of the axes measurement is about 10%. RBCs with ER ≤ 1.1 are defined as “undeformable” cells, namely the cells that do not deform under the high sheer stress, 3.0 Pa, used in this study.
considered as a concentrated aqueous solution with its main relaxation peak at dozens of gigahertz. It is well-known that over a wide temperature range and at frequencies up to 40 GHz, the experimental complex permittivity spectra of the bulk water can be described by the simple Debye function.24,25 However, whenever water interacts with another dipolar or charged entity, a symmetrical broadening of its dispersion peak and a change in the attendant relaxation time26−30 is induced. The origin of the alteration of the dielectric loss peak is defined by the dynamics of H-bond network rearrangements in the vicinity of the different solute molecules. The modification of water’s relaxation peak can be described by the phenomenological Cole−Cole (CC) function:31 ε*(f ) = ε′(ω) − iε″(ω) = εh +
Δε 1 + (iωτ )α
(1)
Here ε′ and ε″ are the real and the imaginary parts of the complex permittivity, ω = 2πf is the cyclic frequency, and i2 = −1. The parameter εh denotes the extrapolated high-frequency permittivity and Δε = εl − εh, is the relaxation amplitude (with the low frequency permittivity limit denoted by εl). The exponent α (0 < α ≤ 1) is a measure of the symmetrical broadening. It was shown that the relationship between the parameters of the main peak of water in aqueous solutions is linked to the type of the solute and can be combined in a new phenomenological approach26,32 to describe the dynamics of the water/solute interaction. There exists a fundamental connection between the relaxation time, τ, the broadening parameter, α, and the Kirkwood-Froehlich correlation function B, itself dependent on Δε (see Appendix A). This approach has been applied to some simple aqueous solutions27−30 where the solute was either dipolar or ionic. In these systems we were able to verify the specific mechanism of solute (matrix) interaction with water dipoles and illuminate the differences between events that are controlled by either dipole−dipole or ion-dipole interactions. These findings shed light on the mechanism of hydration shell formation in each case. The CC parameters of the main water peak can be considered as markers that can help to clarify the type (ion-dipole or dipole−dipole) and the rate at which water interacts with a solute.33 Here we will study the microwave dielectric response of water in the cytoplasm of erythrocytes subjected to a wide range of glucose concentrations in the buffer. These results will be supplemented by direct measurements of cell deformability.34,35 The approach described above will then be used to offer new insights to the metabolism of RBC.
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MATERIALS AND METHODS Cells Preparation. The cells preparation protocol was based on the protocol detailed in ref 7. Three human blood samples were collected from healthy donors (upon their consent under the Helsinki Ethics Committee (#0568−12HMO), Hadassah Hospital, Israel). These samples were drained to plastic vacutainer (BD Vacutainer PST) with lithium heparin (68 IU). RBC were isolated from the blood by centrifugation, washed (twice) from their plasma, once again by centrifugation (500g for 10 min), in PBS, and resuspended at a hematocrit of about 15% in PBS (pH 7.4). This routine preserves the biconcave shape of the cells. The concentration of RBC in suspension was controlled by a complete blood counter (Automated Hematology Analyzer, XP-300, Symex America,
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RESULTS AND DISCUSSION An example of typical dielectric loss spectra for a RBC suspension and pure water at 25 °C are presented in the Figure 10215
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Figure 1. In panel (a) are shown the dielectric loss spectra at 25 °C of an RBC suspension in PBS with 0 mM D-glucose (red triangles) compared to water (black line). dc conductivity has been removed. In panel (b) are shown the derived losses of cellular cytoplasm for 0 mM D-glucose (red triangles) and 10 mM D-glucose (blue circles). The lines are the fitting curves.
Figure 2. In panel (a) is shown the experimental relaxation times for one cell in the presence of varying buffer concentrations of D-glucose. In panel (b) α(lnτ) is shown dependence for one cell at 25 °C. Solid lines are the fitting curves using eq A2.
function (eq 1) and the solid lines of Figure 1b show the quality of the obtained fit. The fitting parameters are presented in Table 1 (Supporting Information). The relaxation times of the cytoplasm are presented in Figure 2a. The dominant feature here is the decrease of the relaxation time as the concentration of D-glucose increases from 0−10 mM and then a dramatic reverse, as the concentrations continue to increase. A similar glucose dependent phenomena was observed for the membrane permittivity of the β-dispersion of spherical RBC under similar circumstances.6 The initial behavior is relatively straightforward to explain. When glucose uptake by the cell begins, the consequent water influx affects the cellular interior electrolyte distribution: first causing electrolyte dilution in submembrane and cytosolic compartments and further activating ion-dependent processes in order to release water excess.43−45 Additionally, glucose utilization has been associated with a temporal appearance of charged glycolytic metabolites (such as ATP) and further related electrolyte reorganization.43,46−50 The decrease of relaxation times as a function of increasing electrolyte concentration has been previously explored in refs 28 and 29, where it was further demonstrated that there is a fundamental dependence between the relaxation time and the broadening parameter: α(lnτ). The details of the model are presented in Appendix A and the results are plotted in Figure 2b. The curvature of the α(lnτ) dependence for c < 10 mM is indicative of an -dipole-ion interaction (see Table 2 of
1a. The dc conductivity contribution has been removed from the spectra. At the frequencies measured, the plasma membrane of the cell is transparent, and therefore the relative permittivity of the cytoplasm can be obtained from those of the cell suspension using an appropriate mixture equation.39,40 The optimal model in this case was first presented by Kraszewski,41 who considered the microwave propagation in a heterogeneous medium. The underlying assumption is that a biphasic suspension can be considered as a sum of an infinite number of thin water and substance layers, each of thickness δt ≪ λ, where λ is the freespace wavelength. Consequently the permittivity of the cellular interior can be represented as ε*cell
⎛ (ε* )1/2 − (ε* )1/2 (1 − φ) ⎞2 mix buff = ⎜⎜ ⎟⎟ φ ⎝ ⎠
(2)
Here, ε*mix, ε*cell, and ε*buff are the dielectric permittivity of the mixture, the interior of the cell and the buffer, respectively. The volume fraction of the RBC (hematocrit) is represented by φ. Examples of the derived loss spectra of the cytoplasm for 2 different glucose concentrations are shown in Figure 1b. The recalculated spectra were fitted using an in-house software, Datama,42 capable of simultaneously modeling both the real and imaginary components of the measured permittivity. The model function used was based on the CC 10216
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shells of ATP,29 leaving relatively fewer defined water structures in the interior, or (2) more speculatively it could also point to reorganization and correlation of those same water structures as the cell struggles to maintain integrity in the face of increasing glucose uptake, a conflict clearly evidenced in the elongation ratio (see Figure 4).
Supporting Information), an expected result, if one follows the accepted sequence of biochemical reactions known as glycolysis.13,32 In that case, τc, the asymptotic value of the relaxation time, is equal to 10.1 ps, significantly slower than the relaxation of bulk water at the same temperature. For purely ionic solutions28,29 at the same temperature τc is nearly on par with the relaxation time of bulk water. The discrepancy between its value in pure solutions and that of the cytoplasm points toward new structures of water, different from those of traditional bulk water, yet not those of the traditional hydration shell. A similar situation has been proposed and observed by the group of Havenith51−54 when investigating the hydration shells in electrolyte solutions using THz spectroscopy. Additionally, like in ionic solutions N0, the density of relaxation acts during τc tend toward 1. However, in our case the values of τc are closer to those found in high concentrations of AMP/ ATP in solution.29 The implication here is that during the biochemical process of glycolysis the dominant factor regulating the relaxation of these water structures is the exchange of a water molecule with the hydrations shells around ATP. As has been noted above, the situation radically changes around the D-glucose concentration of 10−12 mM. The dependences of α(lnτ) move to the first quadrant of the schematic of the hyperbole branch scheme (see Figure A.1). The fitting parameters are τc equal to 7.42 ps and N0 still tends toward 1. One could be induced to considering the nature of the relaxation as becoming dominated by a dipole−dipole interaction. However, such a direct analogy to previous work on simple saccharide solutions27 may not be wholly justified. At a D-glucose concentration equal to 10−12 mM the majority of ATP molecules concentrate near the membrane and interact with the GLUT1 transports, effectively regulating their activity. While buffer D-glucose concentrations increase outside the cell, extracellular Na + is pumped in to maintain osmotic pressure.46,50 Concurrently, the relaxation times increase with increasing concentration, suggesting that the effective length scales that dictate these water structures grow. Possibly this suggests that in the competition for water between membrane ATP and incoming Na+ water moves back toward the interior. At the same time the B function in Figure 3 demonstrates a monotonic decay with the growth of D-glucose concentration. This could be due to a number of reasons: (1) as the process of glycolysis persists, water is increasingly bound in hydration
Figure 4. Elongation ratio in the presence of varying concentrations of D-glucose (blue triangles).
The elongation ratio curve (Figure 4) has a maximum at the same concentration point as that of the minimum of the cytoplasm relaxation times: 10−12 mM. The RBC deformability is regulated by several inter-related mechanisms, which involve numerous membrane and cytosolic proteins. Specifically, spectrin (a cytosolic protein and a key molecule in these mechanisms) undergoes reversible conformational changes (folding/unfolding), thus modifying the erythrocyte’s structure. These structural processes are directly affected by glucose55,56 and also must be effected by the action of ATP on the GLUT1 transporters at the critical concentration.35,57
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CONCLUSIONS
The above results demonstrate the connection of the cytoplasm water to the vitality, or alternately the functionality as reflected by the membrane integrity, of RBC. While the cascade of biochemical reactions is complex, the dielectric response of water is straightforward and governed by the final product of glycolysis. As such, it can act as an efficient marker for the health of the cell. One would hope that this mechanism could provide a new vista on noninvasive glucose monitoring.
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APPENDIX A: THE MODELOF DIPOLE-MATRIX INTERACTION26
The Froehlich’s function B58 is a function of the averaged dipole moment involved, the concentration of dipoles, the correlation between them, and the temperature of the system. At the same time, this function is proportional to Δε. As such, it also reflects to some degree the structure involved with the relaxation in question. It was shown26,32 that α is a time fractal dimension, which is controlled by macroscopic physical quantities, and reflects the rate of interactions of the dipole relaxation units with their surroundings:
Figure 3. D-Glucose concentration dependence of the B function. 10217
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2εl(T ) + εh 1 T= ⟨M ⟩2 ; 3εl(T ) 3ε0kV
ln(Nτ /N0τ ) ln(τ /τc)
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(A1)
G x − x0
*E-mail:
[email protected]; Telephone: +972-2-658-6187. Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS We would like to thank Keysight Technologies Israel Ltd. for the loan of Vector Network Analyzer Agilent N5245A PNA-X. The authors are grateful to Drs. Andreas Caduff and Mark Talary for their suggestions that stimulated this work. We are grateful also to Mr. Daniel Agranovich for helpful discussion.
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(A2)
where A (0 < A ≤ 1) is the asymptotic value of α. The parameters of function eq A2 are connected to the fractal model eq A1 by the relationships: N0τ = exp(G), τc = exp(x0)
REFERENCES
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(A3)
The constant A, representing the asymptotic value of the parameter α, divides the plane into two hemispheres (α > A and α < A). Recalling the definition of α as the fractal dimension relating the density of elemental relaxation acts happening, to the time frame within which they happen26 (eq A1), A should be viewed as the static limit of that dimensionality; when τ → ∞ for quadrants I and IV and τ → 0 for quadrants II and III. The parameter x0 refers to the asymptotic value of x that divides the plane along the x-axis into two half-planes: x > x0 and x < x0 (i.e., correspondently τ > τc and τ < τc) (see Figure A.1).
Figure A.1. Four hyperbolic branches of the function defined by eq A2. Reprinted with permission from ref 26 (Copyright 2010, American Institute of Physics).
Thus, eq A2 describes four hyperbolic curves bounded by two asymptotes.
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AUTHOR INFORMATION
Corresponding Author
Here Nτ is the number of interactions occurring in the minimum mesoscopic region of the sample in the time frame of τ. N0τ, occurs during the fractional time scaling τc. In the expression for B, M is the thermally averaged macroscopic dipole moment, V is the sample volume, k is Boltzman’s constant, and ε0 is the permittivity of free space. All experimental dependences of α versus the variable x = lnτ can be summarized in one function as follows:26−28 α=A+
Fitting parameters for RBC cytoplasm with various Dglucose concentrations (PDF)
ASSOCIATED CONTENT
S Supporting Information *
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.jpcb.6b06996. 10218
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