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Maastricht University, Department of Surgery, and * Anatomy and Embryology, Nutrition and Toxicology Research Institute Maastricht (NUTRIM), 6200 MD Maastricht, The Netherlands
3To whom correspondence should be addressed. E-mail: nep.deutz{at}ah.unimaas.nl.
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ABSTRACT |
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 TOP ABSTRACT MODELS TO STUDY INTERORGAN...RESULTSDISCUSSIONLITERATURE CITED |
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KEY WORDS: • arginine • gut • liver • muscle • kidney
Arginine metabolism involves various organs like the kidney, muscles, the intestines, and the liver, which cooperate in an interorgan axis. Arginine metabolism is highly compartmentalized, which is due to the fact that the enzymes involved in arginine metabolism are expressed to a different extent in the various organs involved (1). Arginine metabolism comprises both arginine production and arginine disposal. Major pathways for arginine production are protein breakdown and de novo arginine production from citrulline. Major disposal pathways are metabolism by the enzymes arginase and nitric oxide synthase (NOS)4 and incorporation of arginine in protein [for recent reviews, see (1–7)].
Kidney
The kidney is a major organ for endogenous arginine synthesis. Citrulline is taken up from the renal artery, and converted to arginine in the proximal renal tubule by the enzymes argininosuccinate synthetase and argininosuccinate lyase (8–14). Although it is generally believed that the kidney is the major site for de novo arginine synthesis in adult animals (14), the amount of arginine synthesized in this organ accounts for only about 10% of total plasma arginine flux, the remainder being derived from protein catabolism (15,16).
Intestine
Renal uptake of citrulline appears to be regulated by circulating citrulline levels (12). Citrulline is a nonessential amino acid, which is synthesized by intestinal conversion of arterial (mainly muscle-derived) and luminal glutamine (9,17,18). Because the liver does not take up citrulline in significant quantities, most citrulline synthesized by the bowel reaches the systemic circulation, and the kidney takes up about 83% of the intestinally released citrulline (9). Due to the arginase activity in the intestinal mucosa (both type I and II arginase), 
40% of arginine absorbed from the intestinal lumen is degraded in the intestine in the first pass (19,20), which leaves about 60% of the enterally administered arginine for delivery to the portal circulation.
Liver
The liver is a major arginine producer, but contains also high levels of the cytosolic enzyme arginase I, which breaks down arginine into urea and ornithine. As a consequence, the liver does not release significant amounts of arginine, and in the basal state only 5–15% of urea is derived from plasma arginine (15). Besides utilization of dietary arginine by the intestine, the liver also metabolizes arginine that is released in the portal circulation (21).
Muscle
Little is known about a direct role of muscle in arginine metabolism. However, as a source of protein, muscle protein breakdown will also involve arginine production, while muscle glutamine adds to intestinal citrulline production and therefore indirectly to arginine production.
Factors that may affect arginine metabolism under physiological conditions
Gender differences in arginine metabolism have been reported. NO synthesis, based on [15N]arginine to urinary [15N]nitrate conversion, appears to be on average 25% higher in women than in men (22), probably due to differences in estrogen (23). Moreover, testosterone increases arginase activity, at least when administered to rats (24). Also, gender-related differences in protein metabolism have been reported (25), which probably are related to sex hormones (26).
Arginine metabolism under pathophysiological conditions: sepsis
Arginine levels are markedly reduced in patients with sepsis (27–29), which suggests compromised endogenous synthesis and/or increased utilization of arginine. Metabolic data from a pig model of sepsis (30,31) confirm this suggestion.
Aim of the study
This paper aimed to further clarify whole body and organ arginine metabolism under physiological conditions and during endotoxemia, using multicatheterized in vivo mice models (32) and stable isotope techniques. Gender and strain differences were also studied.
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MODELS TO STUDY INTERORGAN METABOLISM |
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Mouse model
Mice. Male and female inbred FVB mice (17–28 g, 2–3 mo old) were bred at the Department of Anatomy and Embryology (Academic Medical Centre, Amsterdam, The Netherlands). Male and female inbred C57BL6/J mice (16–32 g, 2–3 mo old) were originally obtained from Jackson Laboratories and were bred at the Department of Anatomy and Embryology (AMC, Amsterdam, The Netherlands).
All animals were transported to the Centralized Animal Facilities of Maastricht University, and were adapted to the new environment for at least 1 week. The mice were fed standard lab nonpurified diet (Hope Pharms) and were subject to standard 12 h light-dark cycle periods (0730 h to 1930 h). Room temperature was maintained at 25°C. Unrestricted access to water was provided throughout the experiment.
Experiment. LPS [E. coli O55:B5, Sigma, 100 µg/200 mL saline/10 g bw (body weight)] was given by i.p. injection to mice (34) to study effects of endotoxemia. Control animals received a corresponding volume of saline to study metabolism under physiological conditions. After injection with LPS or saline, the mice were transferred to a clean cage and food was withheld. Intake of nutrients was therefore equal in the groups. Drinking water was provided without restriction.
Five hours after LPS or saline treatment, anesthesia was induced in the mice by an i.p. injection of a mixture of ketamine (62.5 mg/kg bw, Nimatek, AUV) and medetomidine (400 µg/kg bw, Domitor, Farmos) (32). Anesthesia was maintained with a continuous subcutaneous infusion of a mixture of ketamine (17.5 mg/kg bw/h) and medetomidine (112 µg/kg bw/h) (32). During the surgical procedures, the mice were kept at 37°C using a temperature controller (Technical Service, Maastricht University) and heat pads. The jugular vein, carotid artery, portal vein, and hepatic vein were catheterized in male mice to study portal-drained viscera (PDV; mainly gut) and liver metabolism. In female mice, the jugular vein, carotid artery, renal vein, and inferior caval vein (just above the bifurcation) were catheterized to study renal and muscle metabolism. A 30-gauge needle fixed in a silastic tube (Silastic Medical Grade tubing 0.40 mm ID, 0.84 mm OD, Dow Corning Corporation, Medical Products) was used for catheterization, and was fixed with cyano-acrylate (Cyanolit 201, Het Rubberhuis) (32). A normal saline infusion (0.9% NaCl) of 1 mL/10 g bw/h was given via the jugular vein to correct for fluid losses during measurements.
A 30-min primed-constant infusion of stable isotopes (Mass Trace) was given in the jugular vein (35), which was adequate to reach an isotopic steady state within 20 min. Plasma flow across the portal-drained viscera and liver (male mice), and across the kidney and hindquarter (female mice) was measured using an indicator-dilution technique with infusion of [glycyl-1-14C]-p-aminohippuric acid (14C-PAH, NEN Life Science Products) in the mesenteric vein of male mice and in the abdominal aorta of female mice (32).
Blood was collected from the carotid artery, portal vein, and hepatic vein in male mice and from the carotid artery, renal vein, and caval vein just above the bifurcation in female mice, as described (32). Amino acid concentrations and tracer-tracee ratios (TTR) were determined in plasma (36,37).
Calculations
Whole body rate of appearance (WB Ra) of arginine, citrulline, and phenylalanine in plasma were calculated from the arterial isotope TTR values of [15N2]arginine, [13C;2H2]citrulline, [2H5]phenylalanine, respectively, as described recently (35). NO production was calculated as plasma arginine to citrulline flux and de novo arginine production was calculated as plasma citrulline to arginine flux (15,35,38). Whole body protein breakdown and synthesis were calculated as described, using arterial isotope TTR values of [2H5]phenylalanine, [2H2]tyrosine, and [2H4]tyrosine (35). Whole body arginine clearance is defined as the amount of plasma that is completely cleared each minute from arginine, and was calculated as: Wb Ra (arginine)/arterial concentration (arginine).
Substrate metabolism across the organs was calculated in a 2-compartmental model (39). Organ substrate fluxes (net balances) were calculated by multiplying the venous-arterial concentration difference across the organ with the mean plasma flow across the organ of the group and are expressed in nmol · 10 g bw–1 · min–1. A positive flux indicates net release and a negative flux reflects net uptake.
The portal-drained organs are thought to mainly represent the intestinal tract including pancreas, stomach, and spleen. Liver values were calculated by subtracting PDV from splanchnic values.
Arginine disposal and production rates of PDV, liver, hindquarter, and kidney were calculated by multiplying TTR with substrate fluxes as described (35,40). For comparison between muscle and renal arginine metabolism, hindquarter metabolic data were multiplied by 2 to correct for total muscle mass.
Statistical analysis
Results are presented as means ± SEM. Data were analyzed by 2-way ANOVA to assess strain and gender differences. Effects of LPS were tested by univariate analysis with LPS, strain, and gender as factors. One-way ANOVA was used to test strain differences in organ flow. A repeated measures ANOVA was used for comparing interorgan differences in flow and arginine metabolism between strains. Significance was defined as a 2-tailed P < 0.05.
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RESULTS |
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Arterial concentrations of arginine, citrulline, and ornithine are listed in Table 1 for healthy mice. Plasma arginine levels were not significantly different between male and female mice, although they tended to be higher in female mice (P = 0.09). Moreover, protein breakdown and synthesis were also higher in female mice (P < 0.01 vs. male mice). Plasma citrulline and ornithine levels were both higher in FVB mice than in C57BL6/J mice (P < 0.001). Although differences were not all statistically significant, whole body arginine production tended to be higher in C57BL6/J mice (P = 0.07), while citrulline (P = 0.05), NO (P = 0.08) and de novo arginine (P < 0.01) production were higher in FVB mice. Protein breakdown was higher in FVB mice than in C57BL6/J mice (P < 0.01) (Table 1). Whole body arginine clearance tended to be higher in C57BL6/J mice than in FVB mice, although the differences were not statistically significant (P = 0.10; Fig. 1A).
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Portal flow was higher in FVB mice (0.74 ± 0.14 mL/10 g bw/min) than in C57BL6/J mice (0.32 ± 0.12 mL/10 g bw/min: P < 0.05), but no differences between FVB and C57BL6/J mice were present for liver, hindquarter, or renal flow. LPS reduced liver plasma flow (from 0.97 ± 0.15 to 0.44 mL/10 g bw/min; P < 0.05), but had no effect on portal, hindquarter, or renal flow (not shown).
Organ arginine metabolism (net flux, disposal, and production of arginine) is shown in Figure 2. The PDV and liver showed net uptake of arginine, while the kidney released arginine, although we have to be careful in the interpretation because the organs were studied in different genders. Significant strain differences were present for PDV arginine disposal and production (P < 0.05) and, although not statistically significant, a tendency towards strain differences was present for PDV net flux (P = 0.08). Also, liver and muscle net flux differed between FVB and C57BL6/J mice (P < 0.05). Whereas PDV arginine disposal and production were both higher than liver arginine disposal and production in FVB mice, C57BL6/J mice showed lower PDV arginine metabolism (P < 0.01 for interaction). Significant differences in arginine disposal, production, and net flux between muscle and kidney (P < 0.01) were observed for the 2 strains.
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DISCUSSION |
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TOPABSTRACTMODELS TO STUDY INTERORGAN...RESULTSDISCUSSIONLITERATURE CITED |
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Gender and strain differences in whole body arginine metabolism
Plasma arginine concentrations and protein turnover were higher or tended to be higher in female than in male mice. These gender differences cannot be explained by differences in body composition between males and females. When data were expressed by weight of fat-free mass, differences between males and females would only enlarge. Therefore, sex hormones (e.g., estrogen and testosterone) may play an important role, as was suggested previously for gender differences in protein metabolism (26). Arginase activity is stimulated by testosterone (24), which might explain lowered arginine levels in male mice.
Whole body arginine metabolism differs between FVB and C57BL6/J mice, with (a tendency towards) higher levels of citrulline production, de novo arginine production, NO production, and protein breakdown, and higher plasma citrulline and ornithine levels in FVB mice. Whole body arginine clearance, which indicates arginine consumption capacity, is also strain related and tends to be lower in FVB mice. Since whole body protein synthesis is equal in FVB and C57BL6/J mice, arginase activity, as another major route of arginine catabolism, may be higher in C57BL6/J mice. This suggested higher arginase activity in C57BL6/J mice, however, did not result in a higher plasma ornithine level in these mice, which suggests that whole body plasma ornithine clearance is also higher in C57BL6/J mice. Increased whole body ornithine clearance could result from elevated polyamine production and glutamate production via ornithine aminotransferase (OAT) in this strain, but we have no further data to confirm this suggestion.
When we further compare arginine metabolism between the 2 strains by using whole body phenylalanine production as a measure of protein breakdown, and whole body arginine production as the sum of arginine appearance in plasma by protein breakdown and de novo arginine production, we could consider arginine transport capacity. For example, phenylalanine appearance in plasma is 39 nmol · 10 g bw–1 · min–1 in male FVB mice, which is about 78 nmol · 10 g bw–1 · min–1 arginine release [when assuming a 1:2 ratio between presence of phenylalanine and arginine in, for example, myofibrillar proteins (data for calculation ratio from SWISS-PROT/TrEMBL (41)]. Since measured arginine appearance in plasma is only 39 nmol · 10 g bw–1 · min–1, of which 12 nmol · 10 g bw–1 · min–1 is from de novo arginine production, 51 nmol · 10 g bw–1 · min–1 arginine [calculated as 78 – (39 – 12)] does not appear in plasma and therefore probably is not transported out of the cell. A similar calculation for C57BL6/J mice indicates that [25*2 – (46 – 5) =] 9 nmol · 10 g bw–1 · min–1 arginine is not transported out of the cell. This might indicate that C57BL6/J mice have a higher activity for arginine transport to the extracellular space compared with FVB mice. Although inward arginine transport and arginase activity have been linked (42), no data are available on a potential link between arginase activity and outward cellular arginine transport. Data on intracellular arginine concentrations could give more information to confirm the above calculations. Little is known from the literature, however, about strain differences in arginine metabolism. The FVB strain is known to originate from Swiss (white) mice, while the C57BL6/J strain originates from the black subline 6 (black) mice (43). These original mice strains are genealogically far apart.
Whole body arginine metabolism during endotoxemia
Although endotoxemia causes a general increase in plasma ornithine levels and whole body NO production, gender and strain differences in arginine and protein metabolism in response to LPS also exist. Female mice respond to LPS with smaller changes in plasma arginine and citrulline production than male mice. Whether this is related to the higher susceptibility of males to sepsis, as has been described for patients, and the gender difference in immune response (44–47) needs further investigation. An obvious strain difference is present in the response of whole body arginine clearance during endotoxemia. While FVB mice increased their whole body arginine clearance, C57BL6/J mice lowered their whole body arginine clearance. This may indicate increased arginase activity in FVB mice in response to LPS, but lowered arginase activity in C57BL6/J mice. FVB mice therefore show a T-helper 2 (Th2) response (humoral/anti-inflammatory) to endotoxemia, which is mainly through arginase 1 upregulation (42,48). In contrast, C57BL6/J mice seem Th1 responders (cellular/pro-inflammatory) to endotoxemia, which should be mainly through NOS2 induction (42,48). Although NO production was increased in C57BL6/J mice after LPS, the increase was not greater than in FVB mice. The change in protein breakdown after LPS also tends to be different between the 2 strains, with greater protein breakdown in FVB mice. This could be linked to the higher arginine production in FVB mice after LPS and the concomitant arginase need for arginine.
Interorgan arginine metabolism
Net arginine uptake occurs in the PDV and liver under normal conditions, while the kidney is an organ of net arginine release. Muscle arginine metabolism is in general greater than renal arginine metabolism. However, for the PDV and liver these differences were strain dependent. FVB mice showed a higher PDV than liver arginine metabolism, whereas C57BL6/J mice had a more pronounced liver arginine metabolism.
After endotoxemia, a general decrease in liver metabolism occurred, while changes in PDV, muscle and renal arginine metabolism were largely strain dependent. FVB mice lowered arginine metabolism in PDV and muscle with no change in renal arginine metabolism, whereas C57BL6/J mice increased muscle and renal arginine metabolism with no change in PDV arginine metabolism. The significance of these findings will need further investigation.
In conclusion, strain and gender differences are present in arginine metabolism under physiological conditions and during endotoxemia. Whole body metabolism indicates that arginase activity probably is higher in C57BL/6 mice than in FVB mice, while in response to endotoxemia FVB mice seem to act according to a Th2 response and C57BL6/J mice are Th1 responders. Interorgan arginine metabolism indicates net arginine uptake in PDV and liver, with net arginine release from the kidney under physiological conditions. FVB mice have a more pronounced PDV arginine metabolism, while C57BL7/J mice have a higher liver arginine metabolism. During endotoxemia, liver arginine metabolism decreases while changes in PDV, renal and muscle metabolism are strain-dependent.
Therefore, strain and gender differences are important to consider when arginine metabolism is compared between groups. Moreover, investigation of the underlying mechanism of strain and gender differences in arginine metabolism could be useful to understand changes in arginine metabolism during metabolic challenges.
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FOOTNOTES |
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2 Grant support: Grants 902-23-098 and 902-23-239 from the Dutch Organization for Scientific Research (NWO).
4 Abbreviations used: bw, body weight; LPS, lipopolysaccharide; NO, nitric oxide; NOS; nitric oxide synthase; PDV, portal-drained viscera; Ra, rate of appearance; TTR, tracer/tracee ratio.
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