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Am J Physiol Cell Physiol 293: C1296-C1301, 2007. First published August 8, 2007; doi:10.1152/ajpcell.00393.2006
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CELLULAR METABOLISM

Polyamine homeostasis in arginase knockout mice

Joshua L. Deignan,1,5 Justin C. Livesay,5 Lisa M. Shantz,6 Anthony E. Pegg,6 William E. O'Brien,7 Ramaswamy K. Iyer,1,5 Stephen D. Cederbaum,2,3,4,5 and Wayne W. Grody1,3,4,5

Departments of 1Pathology and Laboratory Medicine, 2Psychiatry, 3Pediatrics and 4Human Genetics and 5The Mental Retardation Research Center, David Geffen School of Medicine at the University of California, Los Angeles, California; 6Department of Cellular and Molecular Physiology, Pennsylvania State University, Hershey, Pennsylvania; and 7Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas

Submitted 19 July 2006 ; accepted in final form 7 August 2007


   ABSTRACT
TOP
 ABSTRACT
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
The role of ornithine decarboxylase (ODC) in polyamine metabolism has long been established, but the exact source of ornithine has always been unclear. The arginase enzymes are capable of producing ornithine for the production of polyamines and may hold important regulatory functions in the maintenance of this pathway. Utilizing our unique set of arginase single and double knockout mice, we analyzed polyamine levels in the livers, brains, kidneys, and small intestines of the mice at 2 wk of age, the latest timepoint at which all of them are still alive, to determine whether tissue polyamine levels were altered in response to a disruption of arginase I (AI) and II (AII) enzymatic activity. Whereas putrescine was minimally increased in the liver and kidneys from the AII knockout mice, spermidine and spermine were maintained. ODC activity was not greatly altered in the knockout animals and did not correlate with the fluctuations in putrescine. mRNA levels of ornithine aminotransferase (OAT), antizyme 1 (AZ1), and spermidine/spermine-N1-acetyltransferase (SSAT) were also measured and only minor alterations were seen, most notably an increase in OAT expression seen in the liver of AI knockout and double knockout mice. It appears that putrescine catabolism may be affected in the liver when AI is disrupted and ornithine levels are highly reduced. These results suggest that endogenous arginase-derived ornithine may not directly contribute to polyamine homeostasis in mice. Alternate sources such as diet may provide sufficient polyamines for maintenance in mammalian tissues.

ornithine; putrescine; spermidine; spermine; decarboxylase

ARGINASE CONVERTS ARGININE to ornithine with the concurrent production of urea (36). There are two isoforms of arginase, namely arginase I (AI) and arginase II (AII), that are similar in their enzymatic properties but differ with regard to their subcellular localizations and tissue distributions (11). AI is most highly expressed in the cytosol of the liver but is also expressed in red blood cells, the gastrointestinal tract, thymus, skin, uterus, and sympathetic ganglion (48, 50). AII, encoded by a separate gene with an overall 53% amino acid similarity to AI, is localized to mitochondria, has a leader sequence cleaved during processing, and has a radically different pI than AI (9, 43). It is most highly expressed in the kidney and prostate and is also in the brain, gastrointestinal tract, and lactating mammary gland (50).

The polyamines putrescine, spermidine, and spermine are organic cations that have a wide tissue distribution (44). They are essential for cell proliferation and differentiation in many mammalian cellular systems and are produced when ornithine is decarboxylated by ornithine decarboxylase (ODC) to yield putrescine (41). Putrescine is further converted to spermidine and spermine by the actions of spermidine synthase and spermine synthase, respectively (30). Spermidine can also be converted back into putrescine and spermine can be converted back into spermidine through the sequential actions of spermidine/spermine-N1-acetyltransferase (SSAT) and polyamine oxidase (PAO) (3). Microorganisms have an alternate pathway for polyamine production whereby arginine is first converted to agmatine by arginine decarboxylase (ADC) and agmatine is then converted to putrescine by agmatinase (16, 24), whereas the existence of a mammalian agmatinase enzyme has been experimentally determined in mice and humans, the existence of a mammalian ADC is controversial at the moment (5). What was thought to be the putative murine ADC was recently shown to be an antizyme inhibitor lacking decarboxylase activity (21).

ODC is highly controlled at both the transcriptional and translational levels and has a very short half-life (18, 51). ODC activity is mainly controlled through the induction of ornithine decarboxylase antizyme 1 (AZ1), which after being associated with ODC, directs it to the proteasome for degradation (4, 12, 19, 22). Antizyme-2 and antizyme-3 also exist and are known to inhibit ODC activity; however, antizyme-2 is much less abundant (14) and expression of antizyme-3 is restricted to the testis germ cells (15). Antizyme induction is also known to block polyamine transport (4, 12, 22). High polyamine levels increase synthesis of antizyme, and spermidine and spermine are more effective than putrescine at stimulating its translation (19, 27). SSAT is also induced by increased polyamine levels through transcriptional mechanisms (29).

Polyamines are maintained by a balance between synthesis, interconversion, and transport (45), and because of their respective roles as the substrate and product of the arginase reaction, arginine and ornithine have been proposed as participants in the regulation of polyamine metabolism in various organs. For example, in tumor cell lines that have become resistant to the ODC inhibitor difluoromethylornithine (DFMO), arginase activity is greatly increased, supplying the cells with sufficient ornithine to compete with the inhibitor (13, 28). Furthermore, in the small intestines of neonatal animals, polyamine synthesis is very low (1, 2); however, in the intestines of adults, polyamine levels increase at the same time that arginase and ODC are induced (47).

We previously created an AI knockout mouse as a model of human arginase deficiency (OMIM 207800 [OMIM] ); the mouse is born normally and thrives for 10–12 days before succumbing to hyperammonemia, with only moderate hyperargininemia (17). An AII knockout mouse was generated by O'Brien's group (39), and we bred them together and produced an arginase double knockout mouse last year (8). We wanted to test the hypothesis that AI and AII contribute to the regulation of polyamines in mouse tissues through the production of ornithine, the precursor for putrescine. Putrescine formation from ornithine via ODC occurs in the cytosol, whereas ornithine can theoretically be produced from both AI in the cytosol and AII in the mitochondria. We analyzed polyamine levels in our arginase single and double knockout animals at 2 wk of age, the latest timepoint at which all of the mice are alive (8). If endogenous arginase-derived ornithine is important for polyamine homeostasis, the disruption of one or both arginase isoforms should result in altered polyamine levels. However, if there is little or no involvement of the arginases, polyamine levels should be relatively unaltered in the knockout mice, and this would suggest that compensatory homeostatic mechanisms or alternate sources may be involved.


   MATERIALS AND METHODS
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 ABSTRACT
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Animals. C57BL/6J AI+/– heterozygote mice were previously developed in our laboratory (17), and C57BL/6J AII–/– homozygote knockout mice were kindly supplied by William O'Brien at Baylor College of Medicine (39). The AI–/–/AII–/– double knockouts were created as described previously (8). For genotyping, genomic DNA was extracted from tail or toe snip samples of 6- to 10-day-old pups using standard techniques, and PCR was performed using previously published primer sets (17, 39). Animals were maintained on normal 12-h/12-h light:dark cycles, were maintained at room temperature, and were fed a standard chow diet. Mice were euthanized by CO2 asphyxiation. Experiments involving mice were approved by the Chancellor's Animal Research Committee.

Polyamine analysis. Each tissue was weighed, homogenized, and deproteinized overnight. Samples were filtered and analyzed by HPLC using an ion-pair reverse-phase HPLC separation method with postcolumn derivatization using o-phthalaldehyde as described previously (31). All tissue samples were taken from nonfasted mice at postnatal days 12 to 14. Results are reported in nanomoles per gram of tissue as means ± SD. Normalization to milligram protein per sample yielded similar results.

Measurement of ODC activity. Tissue ODC activity was analyzed for each sample using a standard assay (6). Tissues were homogenized in 2–5 volumes of 100 mM Tris·HCl (pH 7.5), 2.5 mM dithiothreitol, and 0.1 mM EDTA and centrifuged at 15,000 g or more for 20 min to remove nuclei and mitochondria. Reactions contained 20 µM L-[1-14C]ornithine (47.70 mCi/mmol; NEN Life Science Products, Boston, MA), and activity is expressed as picomole CO2 liberated per 30 min per milligram protein extract.

cDNA preparation. Total RNA was harvested from 50 mg of a mouse liver, brain, kidney, and small intestine for each sample using the RNeasy Midi Kit (Qiagen). cDNA synthesis was carried out with 2 µg of total RNA per tissue using the ThermoScript RT-PCR System with oligo dT primers (Invitrogen). When RT-PCR primers did not amplify from separate exons, DNase-treated RNA was used for cDNA synthesis.

Quantitative RT-PCR. Gene-specific RT-PCR primers were designed to obtain predicted PCR products of 100–150 bases. PCR reactions were performed in triplicate with IQ SYBR Green Supermix (Bio-Rad, Hercules, CA) and a 25-µl reaction volume. PCR assays were performed with a Bio-Rad ICycler IQ. The PCR protocol consisted of initial enzyme activation at 95°C for 3 min, followed by 40 cycles at 95°C for 15 s, 61°C for 30 s, and 72°C for 30 s. With the use of the same protocol, standard curves were generated from serial dilutions of purified PCR products to determine primer efficiency. To confirm the specificity of PCR products, a melting curve was obtained at the end of each run going from 55°C to 95°C, with fluorescence detected at 0.5°C intervals. Data were also normalized with the quantity of beta-actin in individual samples to correct for sample variability and were analyzed using relative expression ratios. Primers used for RT-PCR were as follows: ornithine aminotranferase (OAT), 5'-GGAGTCCACACCTCAGTCG-3', 5'-CCACATCCCACATATAAATGCCT-3'; SSAT, 5'-GAGAACACCCCTTCTACCACT-3', 5'-GCCTCTGTAATCACTCATCACGA-3'; AZ1, 5'-GTGGTGGCCTCTACATCGAG-3', 5'-AGCAGATGAAAACGTGGTCAG-3'; DAO, 5'-TGGGGCTGGAGTCATCCAA-3', 5'-TCCCGGACAGGACTTTTTCTT-3'; beta-actin, 5'-GGCTGTATTCCCCTCCATCG-3', 5'-CCAGTTGGTAACAATGCCATGT-3'.

Statistical analysis. Measurements of all studied groups were originally compared with wild-type levels using an unpaired Student's t-test. When the normality test of data distribution failed, a Kruskal-Wallis test was used followed by a Mann-Whitney rank sum test. Results were considered significant if P < 0.05 and highly significant if P < 0.01.


   RESULTS
TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Putrescine is increased in the AII knockout mice. The polyamines were originally measured in several tissues from the AII knockout mice at 8 to 10 wk of age, and no significant deviations from wild-type values were found (39); however, at 2 wk of age, putrescine was elevated three- to fourfold above normal levels in the liver and small intestines (P = 0.004 for both) in the AII knockout mice (Table 1). Putrescine was also increased two- to threefold in the kidneys of the double knockout mice compared with wild-type controls (P = 0.01) but was not altered in the kidneys in either of the single knockout animals (Table 1). A minor elevation in spermidine was also seen in the brains from the AI knockouts (P = 0.019) compared with controls (Table 1). Spermine levels were unaltered in all tissues.


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  		Table 1. Polyamines in mouse tissues

 
ODC enzyme activity is maintained in arginase knockout mice. To determine whether an upregulation of ODC activity could account for the observed alterations in putrescine in the AII knockout and double knockout animals as well as the maintenance of polyamines in the liver from the AI knockout and double knockout animals where ornithine levels are already known to be greatly reduced (8), we measured ODC activity in several tissues. ODC activity was only marginally reduced (P = 0.026) in livers from the AII knockout animals compared with wild-type controls, but otherwise, no alterations were found (Table 2). No major differences were found in ODC activity between male and female mice (data not shown).


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  		Table 2. Ornithine decarboxlase activity in mouse tissues

 
OAT, AZ1, and SSAT expression are altered in the livers of AI-deficient mice. To determine whether the altered expression of other enzymes involved in ornithine production and in the polyamine biosynthetic pathway (OAT, AZ1, SSAT) may contribute to the observed alterations or maintenance of polyamines in the liver, mRNA levels of these genes were analyzed. OAT, a mitochondrial enzyme that can reversibly convert ornithine and {alpha}-ketoglutarate to glutamic-{gamma}-semialdehyde and glutamate, functions in arginine metabolism through production of glutamate and proline or the synthesis of ornithine (23, 32, 46). OAT expression was increased in the AI knockout and double knockout livers (P < 0.001 for each) compared with wild-type controls (Fig. 1A), whereas AZ1 expression was increased in the AI knockout livers but was decreased in the double knockout livers (P < 0.001 for each) compared with that of the wild-type controls (Fig. 1B). SSAT expression was also increased in the livers from the AI knockout animals but was decreased in the double knockouts compared with that of the wild-type controls (P < 0.01 for each) (Fig. 1C).


Figure 1
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  		Fig. 1. Liver mRNA levels. Ornithine aminotransferase (OAT, A), antizyme 1 (AZ1, B), and spermidine/spermine-N1-acetyltransferase (SSAT, C) were measured in the livers of arginase knockout mice (AI, arginase I; AII, arginase II). Results are reported as means ± SD. For AI+/+/AII+/+, n = 10 animals (6 males, 4 females). For AI–/–/AII+/+, n = 12 animals (8 males, 4 females). For AI+/+/AII–/–, n = 14 animals (6 males, 8 females). For AI–/–/AII–/–, n = 14 animals (8 males, 6 females). Average ages are as follows (in days): AI+/+/AII+/+: 14.0; AI–/–/AII+/+: 12.3; AI+/+/AII–/–: 12.6. AI–/–/AII–/–: 13.6. ***P < 0.001.

 
OAT expression is altered in the kidneys and small intestine of double knockout mice. Putrescine was minimally increased in the kidneys from the double knockout animals compared with controls (Table 1). To determine whether increased expression of OAT in the kidneys could account for the increased putrescine levels via production of ornithine, we measured OAT mRNA levels and found that OAT expression was actually decreased compared with that of wild-type controls (P < 0.01) (Fig. 2A). OAT expression was also decreased in the small intestines from the double knockout animals (Fig. 2B), though no alterations in polyamines in this tissue in the double knockouts were previously seen, so the significance of this decrease is unknown (Table 1). OAT expression was unaltered in the kidneys and small intestines from the single knockout mice, and SSAT and AZ1 expression were unaltered in all of the mice in those tissues (data not shown). Protein levels of OAT, SSAT, and AZ1 also appear unaltered or below the limit of detection by immunoblot in the brains, kidneys, and small intestines from the arginase knockout mice, even when several hundred micrograms of protein were used per well (J. Deignan, unpublished observations).


Figure 2
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  		Fig. 2. Kidney and small intestine OAT mRNA levels. OAT was measured in the kidneys (A) and small intestines (B) of wild-type and double knockout mice. Results are reported as means ± SD. For AI+/+/AII+/+, n = 10 animals (6 males, 4 females). For AI–/–/AII–/–, n = 14 animals (8 males, 6 females). Average ages are as follows (in days): AI+/+/AII+/+: 14.0; AI–/–/AII–/–: 13.6. **P < 0.01.

 
Putrescine catabolism is decreased in ornithine-deficient liver. Finally, to determine a possible mechanism for the maintenance of putrescine levels in AI knockout and double knockout livers where ornithine levels are extremely low (8), we analyzed the expression of the putative mouse diamine oxidase (DAO), also known as amiloride-binding protein (Abp1). DAO participates in polyamine catabolism through the oxidative deamination of putrescine to {gamma}-aminobutyraldehyde, which is then oxidized to GABA (26, 37, 38). AI knockout and double knockout mice exhibited reduced levels of DAO mRNA compared with their wild-type counterparts (P = 0.004 and 0.002, respectively) (Fig. 3). DAO expression in the AII knockout animals was unaltered.


Figure 3
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  		Fig. 3. Diamine oxidase (DAO) mRNA levels in the liver. Results are reported as means ± SD. For each genotype, n = 6 mice (3 males, 3 females). Average ages are as follows (in days): AI+/+/AII+/+: 14.0; AI–/–/AII+/+: 12.3; AI+/+/AII–/–: 12.6; AI–/–/AII–/–: 13.6. **P < 0.01.

 

   DISCUSSION
TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
The role of the arginases in polyamine biosynthesis has been difficult to resolve. The initial discovery of the gene for AII opened up the possibility of independent but overlapping roles for the two isoforms (9, 25, 43) since cytosolic AI was already known to be one of the main participants in the urea cycle, allowing ornithine to be recycled back into the cycle for the continued removal of excess ammonia. Upon its discovery, mitochondrial AII was thought to synthesize ornithine for the production of polyamines, proline, and glutamate, mostly due to the more restricted tissue distribution of AI at the time. However, studies in our lab showed that AI was also highly expressed in most mouse tissues (50) and was also widely expressed in developing embryos and brain (48, 49). This suggested for the first time that cytosolic AI-derived ornithine may play a role outside of the urea cycle.

One logical role proposed for AI was the production of ornithine for polyamine synthesis, since AI functions in the cytosol alongside ODC, which produces putrescine from ornithine. However, from the results in this study, neither AI nor AII appears necessary for the production of ornithine for polyamines (as evidenced by the general maintenance of polyamine levels in all tissues examined) nor does the absence of either isoform greatly affect total ornithine levels in most tissues at 2 wk of age, except for the highly reduced ornithine levels previously seen in the AI knockout and double knockout livers where large amounts of ornithine are required for the urea cycle (8). Moreover, the minor elevations that are seen in the levels of putrescine surprisingly occur when arginase expression is decreased, not increased as one might expect. This challenges the longstanding belief that endogenous arginase is necessary for polyamine production through the synthesis of ornithine.

The increased putrescine seen in the AII knockout and double knockout animals are not likely due to the catabolism of spermidine by SSAT because no significant decreases in spermidine are seen in any tissue and SSAT expression is unaltered when putrescine is increased (Table 1; Fig. 1C). One could also suggest that the ornithine for polyamines results from glutamate and glutamine breakdown via OAT. Whereas glutamine and glutamate were previously shown to be decreased in several tissues in the AI knockout animals, they were mostly unaltered (except for brain) in the double knockout tissues compared with wild-type controls (8). Therefore, this pathway does not likely contribute. Even though OAT expression was increased in both the AI knockout and double knockout livers compared with wild-type levels (Fig. 1A, P < 0.001 for each), the increased expression may in fact cause the enzymatic reaction to proceed toward glutamate and glutamine production rather than toward ornithine production to maintain glutamate and glutamine if ornithine levels are highly reduced. This hypothesis, however, remains to be tested.

Arginine:glycine amidinotransferase (AGAT) catalyzes a reaction converting arginine and glycine into guanidinoacetate and ornithine and could also contribute to the ornithine pool for polyamines (35); however, AGAT mRNA levels appear unaltered in tissues from arginase single and double knockout animals (J. Deignan, unpublished observations). Whereas the maintenance of putrescine could also be due to a defect in its catabolism to acetylputrescine and GABA by DAO, given the slow turnover rate of DAO and the efficacy of the present polyamine interconversion and transport systems, a regulatory role for DAO was thought to be unlikely (37). However, the reduced DAO expression in the livers from the AI knockout and double knockout animals indicates that it could be a potential mechanism for putrescine maintenance when ornithine is greatly reduced (Fig. 5). We previously showed that GABA (4-aminobutyric acid) levels were not significantly altered in the liver, brain, or kidneys in 2-wk-old arginase knockout animals (8), so whether this reflects a lack of DAO involvement remains to be seen.

The age of the animals must also be taken into account. Mothers of the AI knockout and double knockout mice are heterozygotes and have one normal copy of the AI gene; therefore, by continuing to produce half of the normal amount of enzyme, they may be able to provide sufficient ornithine or polyamines in their milk to sustain their progeny. Homozygous AII knockouts have no apparent breeding difficulties, and ornithine or polyamines derived from AII in the mothers would not be a factor in the pups (39). As mentioned in RESULTS, polyamines were previously measured in tissues from the AII knockout mice at 8 to 10 wk of age, and no significant deviations were found (39). It is important to remember at that age, the animals are no longer nursing and are consuming solid mouse chow, therefore only dietary (from chow) or endogenously produced polyamines can exist.

It has been shown in nursing rats that dietary supplementation of putrescine or ornithine does not affect tissue levels of polyamines, in contrast to supplementation with spermidine and spermine (10). Furthermore, neither the supplementation nor the deprivation of dietary arginine greatly affects blood and tissue polyamine levels (40, 42). Putrescine levels in rodent milk are known to be much lower than those of spermidine or spermine, whereas putrescine levels in commercial rodent diet fed to weaned animals are much higher (10, 34). Spermidine and spermine levels are also much greater than putrescine levels in human breast milk but are much lower in infant formulas (33). Therefore, in rodents and humans, dietary polyamines, specifically spermidine and spermine, may be necessary and sufficient for many important biological processes; for example, supplementation of human infant formulas with polyamines is currently being investigated as a way to prevent food allergies, which have a high probability of developing if infant formula is relied upon too heavily (7, 20).

In the future we would like to use defined rodent diets to restrict or eliminate polyamines and test the relative contribution of exogenous versus endogenous polyamine sources; however, to study this using the AI knockout and double knockout animals, it will require successful adenoviral or pharmacological rescue to keep them alive beyond 2 wk, both of which are being investigated at this time. We also would like to pursue ex vivo cell culture studies to further assess the contribution of DAO to polyamine flux, which may be crucial for the maintenance of putrescine and polyamine synthetic gene regulation in the liver.

In conclusion, mice deficient in AII had minimally increased putrescine in the liver and small intestines at 2 wk of age, whereas the other polyamines (spermidine and spermine) were generally maintained. The general lack of regulatory enzyme and polyamine alterations in tissues from the arginase knockout mice suggests that only a minimal amount of ornithine is necessary for endogenous polyamine synthesis. Sufficient ornithine may be provided by other, as of yet unknown, enzymes, or sufficient polyamines may in fact come directly from dietary sources (20). The contribution of endogenous versus exogenous sources of polyamines requires further exploration.


   ACKNOWLEDGMENTS
 
This work was supported at University of California, Los Angelos (UCLA) by National Institutes of Health Grant HD-06576, by the Department of Defense Grant PC020651, by the Mental Retardation Research Center at UCLA, and at Pennsylvania State University by Grant CA-018138.


   FOOTNOTES
 

Address for reprint requests and other correspondence: W. W. Grody, David Geffen School of Medicine at UCLA, 10833 Le Conte Ave., Los Angeles, CA 90095-1732 (e-mail: wgrody{at}mednet.ucla.edu)

The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.


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