J. Phy8iol. (1976), 255, pp. 399- 414 With 4 text-figures Printed in Great Britain

399

LACTATE METABOLISM IN THE ISOLATED PERFUSED RAT KIDNEY: RELATIONS TO RENAL FUNCTION AND GLUCONEOGENESIS

By JULIUS J. COHEN AND JOHN R. LITTLE* From the Department of Physiology, University of Rochester, Rochester, New York 14642, U.S.A.

(Received 28 April 1975) SUMMARY

1. In the intact dog, decreases in both glomerular filtration rate and net renal Na+ reabsorption due to raised ureteral pressure were not associated with a decrease in renal lactate oxidation rate, although total -renal CO2 production decreased in proportion to the changes in net renal reabsorption of Nat and glomerular filtration rate. 2. In order to determine whether, in the absence of other added substrates, the metabolism of lactate supports only the 'basal' renal metabolism or can enhance renal function as well, the rate of lactate utilization and decarboxylation by the isolated perfused rat kidney have been quantified in relation to renal function and one measure of renal basal metabolism, glucose production. 3. The perfusate was Krebs-Ringer bicarbonate (pH 7 35-7 48) with Fraction V bovine serum albumin, 6g/100 ml. L-( + )-lactate was added to raise the lactate concentration from endogenous levels to 2-5, 5 0 or 10 mM. 4. We determined: net lactate utilization rate, lactate decarboxylation rate (14CO2 produced from L-(+)-[U-_4C]lactate), net glucose production rate, and net re-absorptive rate of Na+. 5. The apparent Km and Vm.a, for lactate oxidation were 241 mm and 1 29 #tmole.g-l.min-1 respectively. There was no apparent maximum for total lactate utilization rate due to continuing increases in glucose production rate as lactate concentration was raised. At ca. 10 mm lactate, glucose production accounted for about half of the total lactate utilized. Therefore the basal energy requirements of the kidney need not be constant since glucose production increases as lactate concentration is raised. 6. Both lactate oxidation rate and lactate utilization rate were significantly correlated with the net reabsorption of Na+ by the renal tubules, *

Present address: University of Maryland School of Medicine, Baltimore,

Maryland, U.S.A.

J. J. COHEN AND J. R. LITTLE with the percentage of filtered Na+ reabsorbed and with the glomerular filtration rate. The major fraction of the net renal reabsorption of Na+ was probably supported by the metabolism of substrates either bound to albumin or derived from renal tissue since the percentage of filtered Na+ reabsorbed increased from ca. 78 %, when no lactate was added, to 97 % when initial lactate concentration was 10 mm. Therefore, addition of lactate increased both the basal metabolism and tubular function. However, these observations do not permit us to conclude whether it was the presence of lactate, or its utilization by oxidative or by other pathways which enhanced net renal reabsorption of Na+ and the glomerular filtration rate. 400

INTRODUCTION

In the intact dog the rate of lactate oxidation by the kidney is not affected by 50 % decreases in both net Na+ reabsorptive rate (T!sa+) and glomerular filtration rate induced by raising ureteral pressure, although total renal CO2 production is reduced by a half (Brand, Cohen & Bignall, 1974). Thus, it is not clear whether the renal metabolism of lactate can provide support for reabsorption of Na+, or the basal metabolism of the kidney, or both. In the isolated perfused rat kidney preparation (Little & Cohen, 1974) the metabolism of a single substrate can be studied, independent of the metabolic activities of other organs, while simultaneously, renal function is quantified. Therefore, we have examined the above question by varying the lactate concentration available to the kidney while simultaneously determining the rates of lactate utilization and oxidation. These rates were correlated with changes in renal function, and as a measure of renal basal metabolism, glucose production rate. The observations show that addition of lactate enhances the net reabsorption of Na+ by the renal tubules, glomerular filtration rate and a portion of renal basal metabolism, as measured by glucose production. METHODS Perfusion apparatus. The previously described perfusion apparatus (Little & Cohen, 1974) was modified to prevent losses of 14CO2 from the perfusion circuit: the distal end of the venous cannula was joined to the venous reservoir by a ground glass joint; a Plexiglass cover was fitted tightly over the Plexiglass kidney support so as to cover the kidney and reduce loss of 14CO2 from the surface of the organ; the 14CO2trapping apparatus of Miller, Bly, Watson & Bale (1951) was used, so that the 14CO2 in the effluent gas from the membrane gas-exchanger (Kolobow & Bowman, 1963) was collected in 20 ml. ethanolamine and an aliquot counted as described by Jeffay & Alvarez (1961). When a second trap containing 20 ml. ethanolamine was placed in series with the first, it contained no measurable radioactivity. Perfusion medium. The perfusate solution was Krebs-Ringer bicarbonate

RENAL LACTATE METABOLISM AND FUNCTION

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containing (mm): Na+, 122; K+, 5; Ca2+ 2-5; Mg2+, 1; Cl-1, 104; HCO3r, 25; S042-, 1; phosphate, 2. To this solution was added: inulin, 250-300 ,ug/ml.; urea, 7 mM; and bovine serum albumin, 6 g/100 ml. (Fraction V powder, Miles Laboratories, Kankakee, Illinois). The albumin was dissolved in ca. 50 ml. glass-distilled water and its pH adjusted to 7-4 with dilute NaOH. It was then added to the gassed (5 % C0295 % 02) medium and made up to final volume (200 ml.) with distilled water. This solution was promptly placed in the perfusion circuit within the thermostated chamber (38-390 C) and recirculation was begun through the membrane gas-exchanger (gassed with 5 % CO2-95 % 02). Approximately 20 min were required for the perfusate to reach 380 C. Three experiments were done at each of four initial nominal lactate concentrations: endogenous (028 + 0.04), 2-5, 5 or 10 mm. Stock lactate solution (see below) was added to the perfusate to achieve lactate concentrations above endogenous levels. The mean perfusate Na+ concentration was 143-1 + 0 7 m-equiv/l. and its pH was between 7-35 and 7-48 throughout the course of the perfusion. Preparation of stock lactate solution and purity of [14C]lactate. Each stock lactate solution consisted of sodium L-( + )-[U-14C]lactate (International Chemical and Nuclear, Cleveland, Ohio) and ca. 20% sodium L-( + )-lactate, except for the experiments done at the endogenous level of lactate where only [14C]lactate was added. The sodium lactate solution was prepared by adjusting the pH of 30 % (wlv) L-( + )-lactic acid (Miles Laboratories, Kankakee, Illinois), to 7-4 with dilute NaOH. The radioactivity due to [14C]lactate and the lactate concentration of the stock and perfusate solutions were measured in each experiment. The specific activity (,tc/,zmole) of lactate in the perfusate at the beginning of each experiment was calculated as follows: total L-( + )-[U-'4C]lactate in perfusate = (14C-radioactivity of stock solution, ,uc/ml.) x (vol. added, ml.) E([lactate] in control sample, mM)1 F([lactate] in stock solution, mM)1 x (vol. stock added, ml.)] J+L x (perfusate vol., ml.) It was assumed that this initial lactate specific activity did not change significantly throughout each experiment. This assumption is consistent with the linear 14CO2 production rate throughout the experiments (Fig. 1 B). The purity of the [U-14C]lactate used was confirmed by chromatography: 5 or 10 yul. stock lactate solution was placed on Whatman No. 1 filter paper and run by ascending chromatography using Solvent D described by Stark, Goodban & Owens (1951) followed by spraying with 0-05 % bromphenol blue in absolute ethanol. Single spots were obtained containing 97-3 and 97-7 % of the total added "4C-radioactivity which was similar in position to the spot produced by a lithium lactate solution. Procedure. Male Long-Evans rats weighing ca. 400 g (Blue Spruce Farms, Altamont, New York) were fed on Purina rat chow and water ad libitum; they were not starved before use. The preparation of the animals, the cannulation of the vessels and transfer of the kidney to the thermostated perfusion chamber have been described (Little & Cohen, 1974). In brief, the kidney perfusion was accomplished as follows: with the kidney in situ, a perforated glass cannula (Weiss, Passow & Rothstein, 1959) with a ground-glass joint at its distal end was placed in the inferior vena cava. The right renal artery was cannulated via the superior mesenteric artery by the method of Nishiitsutsuji-Uwo, Ross & Krebs (1967); renal perfusion was never interrupted. While renal perfusion continued, the kidney was extirpated and transferred to a holder and placed inside the humidified, thermostated chamber. The kidney was suspended from the two cannulae which were clamped in the holder (Weiss et al. 1959). The cannula in the vena cava was connected to the venous reservoir by a ground glass joint so that the renal

402

J. J. COHEN AND J. R. LITTLE

venous effluent was not exposed to the atmosphere. After transferring the kidney to the chamber, the mean pressure in the renal artery, distal to the end of the cannula, was adjusted and maintained at ca. 100 mmHg by varying the perfusate flow rate. Samples of 'arterial' perfusate were obtained from a stopcock placed between the arterial reservoir and the pulsatile arterial pump so that no change in pressure or flow occurred in the renal arterial circuit, between pump and kidney, during sampling. Since the resistance of the membrane gas-exchanger is too great to permit perfusate to pass through it by gravity, as can be done with a film oxygenator (Miller et al. 1951), the level of perfusate in the venous reservoir was regulated by a second pump which passed the venous perfusate through the silicone rubber membrane gas-exchanger and then on to the arterial reservoir. The gas mixture leaving the exchanger (5 % C02:95% 02, 300 ml./min) was bubbled through ethanolamine for collection of 14CO2 and 12CO2. The use of a membrane gas-exchanger, rather than a film gasexchanger, has been shown to reduce the denaturation of lipoprotein (Zapol, Levy, Kolobow, Spragg & Bowman, 1969) and perhaps of albumin as well (Lee, Krumhaar, Fonkalsrud, Schjeide & Maloney, 1961). Although no lipoprotein was added to the perfusate in the present experiments, the use of a membrane gas-exchanger would permit future incorporation of lipoprotein in the perfusate without a change in design of the apparatus. The albumin concentration 6 g/100 mil. was chosen as a result of an earlier study (Little & Cohen, 1974) in which the smallest increase in water content (ca. 10 %o) of the kidney and the maximal % Na+ reabsorption was obtained at this concentration of albumin. The mean perfusion pressure of 100 mmHg is that used in our previous study (Little & Cohen, 1974) and is similar to or higher than the pressure used by others (Bowman, 1970; Nishiitsutsuji-Uwo et al. 1967; Franke, Huland & Weiss, 1971), although less than the perfusion pressure used by Ross, Epstein & Leaf (1973). The range of mean arterial pressure for the rat is from 80 to 130 mmHg (Gertz, Mangos, Braun & Pagel, 1966; Brenner, Troy & Daugharty, 1971 ; Andreucci, HerreraAcosta, Rector & Seldin, 1971); the low renal vascular resistance of the perfused kidney suggests that the decrement in pressure from renal artery to glomerular capillary may be less than occurs in vivo. Hence, the pressure in the glomerular capillary bed at a mean arterial pressure of 100 mmHg may be similar to that of the kidney in vivo. There was no prior or in-line filtration of the perfusate as has been recently reported by Ross et al. (1973) to have improved the function and the stability of the isolated perfused rat kidney. The albumin was not dialysed before use. Following a 20 min equilibration period during which the renal vascular resistance stabilized, three consecutive 20 min urine collections were made. At the beginning of each 20 min observation period (and at the end of the final observation), the testtube for urine collection was changed; the perfusate flow rate was measured; a 4 ml. perfusate sample was removed for analysis; the 20 ml. ethanolamine, containing all the 14C02 in the gaseous effluent from the membrane gas exchanger, was collected and simultaneously replaced by a fresh 20 ml. ethanolamine to maintain continuous trapping of.14C02. Urine volume was determined by weighing the tared urine collection tube. The mid-period values for perfusate flow rate and the concentrations of inulin and cations were estimated by averaging the values from the beginning and end of each 20 min observation period. Toward the end of the equilibration period and after the final observation, 0 5 ml. perfusate was removed under anaerobic conditions for measurement with a Radiometer pH meter. At the end of each experiment the wet and dry weights of the perfused and control kidneys were determined (Little & Cohen, 1974). Analytical. Inulin, Na+ and K+ concentrations in the perfusate and urine were measured as previously described (Little & Cohen, 1974). L-( + )-lactate and D-( + )-

RENAL LACTATE METABOLISM AND FUNCTION

403

glucose concentrations in urine and perfusate were determined on perchloric acid protein-free filtrates by the methods of Hohorst (1963) and a modification of the procedure described by Bergmeyer & Bernt (1963), respectively. The recovery of lactate (lithium salt) added to samples of the perfusate was 93-6 + 0-67 0/ (mean + S.E. of mean, n = 8); the recovery of D-( + )-glucose was 95-8 + 0-67 00 (mean + s.E. of mean, n = 8). The assayed perfusate and urine concentrations of L-( + )-lactate and D-( + )-glucose were corrected for these incomplete recoveries. The total 14CO2 production for any observation period was determined from the algebraic sum of the 14CO2 collected in the ethanolamine trap plus the net change in 14CO2 in the perfusate volume. The 14CO2 content of the perfusate was measured by the diffusion flask method (Passman, Radin & Cooper, 1956) with two modifications: hyamine solution was placed in a plastic centre well permitting a single Erlenmeyer flask to be used; and 1-0 M phosphate buffer (pH = 5.5) was used to release the 14CO2 as described by Anderson & Snyder (1969). The mean recovery of 14CO2 added to the flask as sodium [14C]bicarbonate was 99 3 % ± 0-24 0/O (mean + S.E. of mean, n = 8); urinary 14C02 was not measured. To estimate the loss of 14CO2 from the entire system during kidney perfusion, four experiments were performed in which sodium [L4C]bicarbonate, instead of stock lactate solution, was added to the perfusate. After equilibration, the radioactivity recovered in the trap was compared with the decrease in perfusate 14CO2 content for three 20 min observation periods in each experiment. The ethanolamine trap contained 94-4 + 3-6 00 (mean ± S.E. of mean, n = 12 periods from four experiments) of the counts disappearing from the perfusate for which correction was made. Calculations. The inulin clearance was considered to be equal to the glomerular filtration rate. The renal tubular reabsorption of Na+ was calculated from the difference between the rate of Na+ filtered (glomerular filtration rate multiplied by the Na+ concentration in the perfusion fluid) and the rate of lNa+ excreted (rate of flow of urine multiplied by the Na+ concentration in the urine). Metabolic rates (+ indicates net production; - indicates net utilization) were calculated from the change in perfusate content between two consecutive samples (taken at 20 min intervals) and the urinary excretion of the substrate. The rate of lactate decarboxylation was calculated from the relationship: 14CO2 produced Specific activity of lactate in perfusate (/ac/pmole) All data are reported per gram wet weight of the contralateral (unperfused) kidney (Little & Cohen, 1974). The mean ratio of the we& weights (perfused kidney/contralateral kidney) was 1-116+ 0-014 (mean+s.E. of mean, n = 12) while the ratio of the dry weights was 0-952 + 0-018 (mean + S.E. of mean, n = 12). Statistical treatment and graphic analysis. The relationship between the simultaneous rates of lactate metabolism and either lactate concentration or renal function was evaluated by determining whether there is a significant linear regression between pairs of variables. Each regression line was calculated by the least squares technique and the difference of the mean slope from zero was tested.

(flc/min.g)

RESULTS

The metabolism of lactate during perfusion Lactate utilization (Fig. 1 A) was approximately linear during the entire period of perfusion except at 10 mm lactate where it decreased after 60 min of perfusion. By contrast, the lactate oxidation rate was linear with time

J. J. COHEN AND J. R. LITTLE 404 at all lactate concentrations above the endogenous level (Fig. 1 B). As noted earlier, this suggests that the specific activity of the lactate remained constant during the time the observations were made. The mean lactate oxidation rates (each mean is based on nine observations in three experiments) at 5 mM (0.83 + 0'08 flmole.g-1.min-') and 10 mm (0.98 + 008 I

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1. A-C, cumulative fates of lactate in the perfused rat kidney. Each point is the mean of three observations made with three kidneys at a single initial perfusate lactate concentration, in mM: endogenous (0-28 + 0 04), 0; 2-5, 0; 5 0, A; and 10, A. D, summary of the metabolic fates of lactate as a function of lactate concentration, [lactate] The data for the rates of product formation used in this figure were obtained from the means of the cumulative metabolism of lactate after 60 min perfusion for three kidneys at each initial perfusate lactate concentration. .

RENAL LACTATE METABOLISM AND FUNCTION 405 u-moles . g-1. min-') lactate concentrations were not significantly different from each other. The small increase in net lactate utilization which occurs between lactate concentrations of 5 (1 25 + 014 #mole. g-1. min-') and 10mM (1.54+0*43 #mole.g-1.min-1) (Fig. 1A) is accounted for principally by a significant increment (P < 0-01) in gluconeogenesis (Figs. 1 C and 2D). In all experiments, mean net glucose production rate (Fig. 1 C) decreased during the 60 min perfusion period, as Bowman (1970) also has observed. Fig. 1 D shows that the sum of the glucose produced (in lactate equivalents) and the lactate oxidized are within 10 % of the total lactate c

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Fig. 2. A, correlation between lactate utilization, QLAC9 and perfusate lactate concentration, [lactate]P; from the graph QLAC = - 039-0- 14 [lactate]p (r = 0-60, P < 0.0001). B, correlation between lactate oxidation rate, Q~OL, and lactate concentration; the graph gave the values for (a) QLXc= -0.22-0-15 [lactate]p (r = 0-86, P < 0.0001) and for (b) QLC = -0-69-0-003 [lactate]p (r = 0 37, P = 0.13). C, Lineweaver-Burke (double-reciprocal) plot for 1/lactate oxidation v8. 1/[lactate]p: the values Kn. = 1-3 smole.g-l min-, kM = 2-1 mm (r = 0-84; P < 0-0001, n = 36) were taken from the graph. D, correlation between net glucose production rate, QOGLU, and lactate concentration; the values QGLU = 0-041 + 0 06 [lactate]p (r = 0-62, P < 0.0001, n = 36) were given.

12

J. J. COHEN AND J. R. LITTLE 406 utilized when the initial lactate concentration was 2.5 or 5 mm. At 10 mM lactate, the sum was greater than the net lactate disappearance by ca. 37 %. This suggests that a high lactate concentration stimulated gluconeogenesis from substrates derived either from the kidney or from the perfusate (Nishiitsutsuji-Uwo et al. 1967). Note that at the endogenous lactate levels, lactate oxidation rate did decrease with time; here, substrate availability must have limited oxidative metabolism.

Rates of lactate metabolism in relation to concentration of lactate in the perfusate Since there was continuous lactate utilization during the perfusion and no exogenous lactate was being added, the perfusate lactate concentration fell progressively during each experiment. Therefore we determined whether there was a significant linear correlation between simultaneous perfusate lactate concentrations and rates of metabolism. Net lactate utilization increased as lactate concentration was raised (Fig. 2A) from endogenous levels to 10 mm. The wide variation in lactate utilization rate at high lactate concentration is due to the inherent absolute errors in measuring lactate content of the perfusate. A LineweaverBurk plot (1/lactate utilization rate against 1/lactate concentration) revealed a slope which was not significantly different from zero (r = 0-23, P = 0.2) whether the observations made at the endogenous lactate concentrations were included or excluded. Hence no maximal rate for lactate utilization is apparent. In contrast, while lactate oxidation rate (Fig. 2B) increased rapidly as lactate concentration was raised above the endogenous level (Fig. 2B, a), the lactate oxidation rate plateaued (b) between lactate concentrations 4 and 5 mM. That a maximal lactate oxidation rate occurs is consistent with the linear Lineweaver-Burk plot shown in Fig. 2 C. The maximal lactate oxidation rate (1 -29 j#mole. g-1. min-') would require an 02 uptake of ca. 3 9 #mole . g-1 . min-I, which is approximately 75 % of the total in vivo renal 02 consumption rate (Knox, Fleming & Rennie, 1966). Thus, lactate oxidation rate reaches a maximum at ca. 4-2 mm lactate concentration, whilst net utilization of lactate does not reach a maximum even when the initial lactate concentration is 10 mm. The difference between the rate of lactate oxidation and total lactate utilization is largely accounted for by glucose production (Fig. 2D), which also does not show a maximum rate. Renal function in relation to lactate metabolism Mean rates of renal function and lactate oxidation Mean net reabsorption of Na+ by the kidney was highest throughout the perfusion period when the initial lactate concentration was 5 or 10 mM

RENAL LACTATE METABOLISM AND FUNCTION 407 and lowest when no lactate was added to the perfusate. At all lactate concentrations the net renal reabsorption of Na+ fell with time of perfusion (Fig. 3A), due to, in part, the decreases in glomerular filtration rate (Fig. 3C). Although mean rate of flow of perfusion fluid through the kidney also decreased with time (Fig. 3C), the lowest mean of renal perfusate flow observed in these experiments was at least fourfold greater 22 21 20

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Fig. 3. Mean rates of renal function and lactate oxidation during perfusion. Each point is the mean of three observations made with three kidneys at a single perfusate lactate concentration, in mM: endogenous (0.28 ± 0.04), 0; 2-5, *; 5 0, A; and 10, A. A shows the total Na+ re-absorbed by the kidney; B, the percentage of filtered Na+ which is reabsorbed, %, TN.+; C, the glomerular filtration rate, GFR, and the rate of flow of perfusate through the kidney, RPF; and D, the rate of production of carbon dioxide from the decarboxylation of lactate, QOm.

than the renal blood flow rates in vivo and hence should not limit proximal tubular reabsorptive rate (Buentig & Early, 1971). The decreases in the mean rates of glomerular filtration, flow of perfusion fluid through the kidney and net renal reabsorption of Na+ with time, are in contrast to the relatively constant mean lactate oxidation rates at each exogenous lactate

408 J. J. COHEN AND J. R. LITTLE concentration (Figs. 1 B, 3D): indeed, there was no significant change in mean lactate oxidation rate over the time course of the observations at each lactate concentration. Thus, in this present isolated perfused kidney preparation, some function of the concentration of the added substrate appears to establish the level of renal function, as well as the extent of the decrement in renal function with time.

Correlations between lactate metabolism and renal function The significant linear regressions which were obtained between renal function and lactate metabolism are consistent with the above inferences concerning level of renal function in relation to lactate concentration or rates of metabolism. Thus, there are significant correlations between the glomerular filtration rate, GFR, and both lactate oxidation rate, QLAC (GFR = 215-102 LAO; r = 040; P < 0.025) and lactate utilization

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QLAC(mOIe . g' . min-') QLAC (#qmole. g- . min-) Fig. 4. A, correlation of the percentage of filtered Na+ which is reabsorbed, % T'Na+, with net lactate utilization rate, QCC: % TN.+ = 77 7-5 9 QLAC (r = 0 37, P = 0.03); and fi, with lactate oxidation rate, QLAC; % TN = 71-7-18-2 Q~O (r = 0x46, P < 0.005). The S.D. of the intercepts are + 13'1 % (A) and +12.50% (B).

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Lactate metabolism in the isolated perfused rat kidney: relations to renal function and gluconeogenesis.

In the intact dog, decreases in both glomerular filtration rate and net renal Na+ reabsorption due to raised ureteral pressure were not associated wit...
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