Chinese Medicine, 2011, 2, 109-114
doi:10.4236/cm.2011.23018 Published Online September 2011 (http://www.SciRP.org/journal/cm)
Study on the Expression of Organic Anion Transporting
Polypeptide (oatp2a1) in Rat with Spleen Deficiency
Syndrome and the Exploration of Clinical Significance*
Ai-Zhen Pan1, Yao-Kun Hao1, You-Wu Lin1, Ze-Xiong Chen1, Shi-Jun Zhang1#,
Xiao Dong1, Bin Hu2
1Department of Traditional Chinese Medicine, The First Affiliated Hospital of Sun Yat-Sen Universty,
Guangzhou, China
2DaAn Gene Co., Ltd. of Sun Yat-Sen University, Guangzhou, China
Received June 16, 2011; revised June 28, 2011; accepted July 1, 2011
Abstract
Objective: to explore the mechanism of transportation and transformation of dampness by the way of the
expression of organic anion transporting polypeptide (oatp) superfamily member 2a1 (oatp2a1) mRNA in rat
with spleen deficiency syndrome and the significance in transportation and transformation of dampness.
Methods: 32 wistar male rats were divided randomly into four groups: normal group (n = 6), normal + AA
group (n = 6), spleen deficiency group (n = 10), Spleen deficiency + AA group (n = 10). After reserpine-in-
duced spleen deficiency model was made, intragastric administration of aristolochic acid (AA) was adopted
for three days, the expression of oatp2a1 mRNA were detected in the tissues of lung, liver, kidney, stomach,
small intestine and large intestine in four groups by using Fluorescent Quantitative-Polymerase Chain Re-
action (FQ-PCR). Results: the expression of oatp2a1 mRNA in above six tissues could be detected. The ex-
pression of oatp2a1 mRNA in liver tissue of rat with spleen deficiency syndrome was up-regulated com-
pared to normal group (P = 0.035, P < 0.05), the expression of oatp2a1 mRNA in small intestinal tissue of
rat with spleen deficiency syndrome was down-regulated compared to normal group (P = 0.004, P < 0.01),
the expression of oatp2a1 in intestinal tissue in normal + AA group is down-regulated compared to normal
group (P = 0.032, P < 0.05). Conclusions: oatp2a1 might be one of the material basis involved in transporta-
tion and transformation of dampness. The changes of expression of oatp2a1 mRNA in small intestine, liver
tissue suggests that small intestine, liver might play an important role in the transportation and transforma-
tion of dampness in the state of spleen deficiency. We further concluded that the function of spleen’s gov-
erning transportation and transformation of dampness was not only including the function of the gastrointes-
tinal, but also part of the liver function in some degree, which needs to be further studied.
Keywords: Dampness, Spleen Deficiency Syndrome, oatp2a1
1. Introduction
Metabolism of body fluid includes the transportation and
transformation of water, essence of water and grain, and
dampness, the generation, distribution and excretion of
water involves coordination of various visceral functions.
especially the lung, spleen (stomach), kidney, and triple
energizer. In Jing Mai Bie Lu of Su Wen(Plain Ques-
tions), it is said that water enters the stomach, goes up-
ward to the spleen, which can distribute essence upwards
to the lung, which can regulate water passage to transport
water downwards to the bladder, through which water
and essence are distributed to the whole body. Currently,
more and more research has been carried out about
transportation and transformation of water as well as
essence of water and grain, but the research about damp-
*Source of support: this work was supported by the Major Special
Program of the “Eleventh Five-year Plan” for Sci & Tech Research o
f
China (No. 2009ZX10005-016), National Natural Science Foundation
of China (No. 81072806) and Natural Science Foundation of Guang-
don
g
Province
(
No. 9151008901000117
)
.

A.-Z. PAN ET AL. 110
ness mechanism is relative few, which holds back the
development of dampness metabolism theory. Many re-
searchers studied water liquid metabolism by the way of
Aquaporin and antidiuretic hormone (ADH), few of pre-
vious studies were carried out about the mechanism of
the dampness by the way of oatps.
A number of organic anion transporters (human OATP/
SLCO, rodent (oatp/Slco) can efficiently transport a va-
riety of foreign organisms such as drugs, xenobiotics,
and endogenous substances so on, oatp2a1 is expressed
widely in human and rat tissues. During recent years, it
has become increasingly recognized that oatps play im-
portant roles in drug absorption and disposition and are
critically involved in the cellular uptake of drugs in tis-
sues important for pharmacokinetics, such as intestine,
liver and kidney. Although several members of multi
specific oatps that mediate the elimination of organic
anions in the liver and other organs have been identified.
few studies have been carried to elucidate the role of
oatp2a1 in elimination of AA or dampness. So our objec-
tive of study is to explore the mechanism of transporta-
tion and transformation of dampness by the way of the
expression of oatp2a1 in rat with spleen deficiency syn-
drome and the significance in transportation and trans-
formation of dampness. The findings of the report are as
follows.
2. Methods
2.1. Animals
32 six-week-old wistar male rats weighting to 150 - 180
g were purchased from the animals central of Guangdong
province, animals were housed in a temperature-, light-,
and humidity-controlled environment. License number is
SCXK2008-0002, Guangdong License number is 2008A
020.
2.2. Drugs and Reagents
2.3. Instruments
Sigma desktop high-speed refrigerated centrifuge ma-
chines, MJ gradient PCR instrument, MJ Opticon2 auto-
matic quantitative PCR instrument, sanyo ultra low tem-
perature refrigerator.
2.4. Animal Group
After being purchased, the rats were treated with free
diet，activity, sleep until weighting to 250 - 280 g dur-
ing the first two weeks. The rats were randomly divided
into 4 groups: normal group (n = 6), normal group + AA
group (n = 6), spleen deficiency group (n = 10), spleen
deficiency + AA group (n = 10).
2.5. Production of Spleen Deficiency Rat Model
10 rats were given reserpine 5mg/kg/d, subcutaneous in-
jection for continuous 15 days with normal feeding, which
references and improves the spleen deficiency rat model
documentation [1]. The criterion of spleen defi- ciency are
as follows: 1) listlessness, somnolence; 2) anorexia; 3)
loose stool (anal dirty); 4) abatement of drinking water.
2.6. Group Intervention Methods
After reserpine-induced spleen deficiency model was
made, intragastric administration of aristolochic acid (20
mg/kg/d) was adopted to the normal + AA group and
spleen deficiency + AA group of rats, continuously in-
tragastric administration of AA for 3 days [2]. The nor-
mal group was intragastricly administrated by 0.9% sa-
line (10 ml/kg) for 3 days. Each group of rats in the last 6
hours after administration were sampled.
2.7. Observation of General Symptoms
General symptoms were closely observed every day of
experiment, such as the quantity of diet and drinking
water, body weight, growth condition, excrement situa-
tion, the state of mind and activity, complexion and so
on.
Aristolochic acid (AA) was obtained from YI-ER-TA
Pharmaceutical Limited Company of Wu Huo, the purity
of AA was 99%, 20 mg/PC. Reserpine injection was pur-
chased from BANG-MING Pharmaceutical Limited
Company of guang dong, 1mg/pc. RNAiso™ Plus isola-
tion kit was purchased from TaKaRa (D9108A) 5 × RT
buffer, 5 × quantitative PCR buffer, dNTPs, MMLV, Taq
enzyme was purchased from Guangzhou Huayin Medical
Technology Co., Ltd., OligoT was purchased from Pro-
mega. Conventional sub-analytically pure chemical re-
agents.
2.8. Specimen Collection
The rats were anesthetized with 3% pentobarbital sodium
by the way of intraperitoneal injection 0.2 ml/100 g, each
piece of tissue was drew from lung, liver, kidney, stom-
ach, small intestine, large intestine, each size of sample
was about 5 mm * 5 mm, putted into the freezing tube;
all samples were preserved within 15 minutes into the
−80˚C refrigerator.

A.-Z. PAN ET AL.111
2.9. oatp2a1 Gene Expression
Total RNA extraction: total RNA extraction used differ-
ent hydroxyl guanidine chloride-chloroform method, to
test OD values.
Synthesis of primers: to find the target gene mRNA
sequence in GenBank, to design specific primers in the
CDS area, probes used for primer design were software
Primer express 2.0 software. The specimens were sent to
the British Biotechnology Co.Ltd. Shanghai for synthesis,
desktop equipment for the ABI 3900 High-throughput
DNA synthesizer. Protein gene sequences: upstream
5’-tccgaaacaggtacctgggcc-3’, downstream 5’-tccagctgat-
gaagaagagcagc-3’, fluorescent group sequence: 5’-FAM-
cagatggtctacaaggccttgggcacac-BHQ1-3’, reference pro-
tein β-acting gene sequences were as follows: upstream
5’-gaagctcatttcctggtatgacaatg-3’, downstream 5’-cttggag-
gccatgtaggccatg-3’, fluorescent group gene sequence: 5’-
FAM-tatggctacagcaacagggtggtggac-BHQ1-3’.
Reverse transcriptase polymerase chain reaction (RT-
PCR) 10 μl RNA template reverse transcription reaction,
apparatus for the MJ gradient PCR instrument (United
States Bio-Rad Company), the reaction system as fol-
lows: 5 × Buffer 4 μL, dNTP 1μL, RNase Free water, 2
μl, Oligo dT18 1 μl, MMLV enzyme 2 μl.
2.10. Quantitative PCR Reactions
Positive standard and its gradient pre-trial preparation
positive product of pre-trial preparation was electro-
phored by 2% low melting agarose gel after PCR ampli-
fication (containing ethidium bromide, prepared with
TAE buffer), target band was cut in the long-wave UV,
Determination of OD 260/280 > 1.8, which show the
purity is up to grade . Measured with OD260 values and
fragment length data conversion from the concentration
(copy/μl), as the positive standard. Take positive stan-
dard 5 μl diluted by 10 times (45 μl water and adequate
mixing), followed by dilution continues, the positive
quantitative standard was prepared gradient.
positive standard samples under test and the following
reaction system (25 μl system): Slco2a1 and gapdh fol-
low the same system of 10X PCR Buffer 2.5 μl, 2.5 mM
dNTP 2 μl, H2O 16μl, 15 pmol/μl primer 1 + 1 μl, 10
pmol/μl probe, 0.3 μl, 5 U/μl Taq 0.2 μl, Template 2 μl.
94˚C 2 min; 94˚C 5 sec, 60˚C, 30 sec, reading FAM fluo-
rescence values, 40 cycle; 30˚C 5 sec.
2.11. Statistical Analysis
Quantitative Instrument aMJ Opticon2 automatic quanti-
tative PCR instrument (United States Bio-Rad company).
After reaction, the computer automatically analyzed and
calculated results. The results were shown by the table
under the Copies value (i.e. copy number) analysis, with
B, i.e. B = copy number/μl cDNA. Taking into account
the total RNA concentration of each sample differences,
the final results are translated by the following formula:
A = B (target gene) ÷ B (internal reference gene). A sta-
tistical value is required when the final value.
Application of statistical methods statistical software
SPSS 13.0 for windows, using analysis of variance
(ANOVA, homogeneity of variance) on the results of
statistical analysis.
3. Results
3.1. Comparison of General Symptoms
After reserpine-induced spleen deficiency model was
made, the rats had those symptoms such as loss of appe-
tite, listlessness, somnolence, anorexia, Loose stool (anal
dirty), thin, swallow complexion, and so on. There was
significant difference between the normal group and the
spleen deficiency syndrome group.
3.2. Expression of oatp2a1 mRNA
The expression of oatp2a1 mRNA was detected in the
tissues of lung, liver, kidney, stomach, small intestinal
and large intestine in four groups by using Fluorescent
Quantitative-Polymerase Chain Reaction (FQ-PCR).
Oatp2a1 mRNA was expressed in lung, liver, kidney,
stomach, small intestine and large intestine tissues in
normal group, oatp2a1 mRNA expression analysis of
variance had statistic significant (P = 0, P < 0.01); Pair-
wise comparison results were as follows: the expression
of oatp2a1 mRNA in lung tissue was higher than that in
liver tissue (P = 0.03, P < 0.05), the expression of
oatp2a1 mRNA in lung tissue was lower than that in
kidney tissue (P = 0, P < 0.01), the expression of oatp2a1
mRNA in lung was lower than that in gastric tissues (P =
0.03, P < 0.05), the expression of oatp2a1 mRNA in lung
tissue is lower than that in small intestine (P = 0, P <
0.01), the expression of oatp2a1 mRNA in liver tissue
was lower than that in kidney tissue (P = 0, P < 0.01),
the expression of oatp2a1 mRNA in liver tissue was
lower than that in small intestinal tissues (P = 0.006, P <
0.01), the expression of oatp2a1 mRNA in stomach tis-
sue was lower than that in kidney tissue (P = 0, P < 0.01),
the expression of oatp2a1 mRNA in large intestine tissue
was lower than that in the kidney (P = 0, P < 0.01), the
expression of oatp2a1 mRNA in stomach tissues was
lower than that in small intestinal tissues (P = 0.006, P <
0.01), the expression of oatp2a1 mRNA in large intestine
tissues was lower than that of small intestinal tissues (P

A.-Z. PAN ET AL. 112
= 0, P < 0.01). In summary, the oatp2a1 mRNA expres-
sion was the highest in kidney and small intestine tissue
of 6 groups, followed by the liver, stomach, large intes-
tine, the expression of oatp2a1 mRNA is least in lung
tissue. While, there was no significant difference be-
tween the kidney and small intestine tissues. There was
no statistic- cal significance among the three tissues of
liver, stomach, and large intestine.
The expression of oatp2a1 mRNA in liver tissue of rat
with spleen deficiency syndrome was up-regulated com-
pared to normal group (P = 0.035, P < 0.05), the expres-
sion of oatp2a1 mRNA in small intestinal tissue of rat
with spleen deficiency syndrome was down-regulated
compared to normal group (P = 0.004, P < 0.01), the
expression of oatp2a1 mRNA in intestinal tissue in nor-
mal + AA group is down-regulated compared to normal
group (P = 0.032, P < 0.05).The results were shown in
Table 1.
4. Discussion
Water is the main component of the human body, in any
individual, the body water content stays remarkably con-
stant from day to day. Water as solute liquid carrier, its
contents includes essence of water and grain, water,
dampness (food metabolites, drug metabolites, endoge-
nous and exogenous toxins, etc.) [4-6].The generation,
distribution and excretion of water is a complicated
physiological process involving functions of various
viscera, especially the lung, spleen, and kidneys, and
spleen’s function is the most important.
In present studies of water metabolism concerning
lung, spleen and kidney. Li Shuweng, etc., studied water
liquid metabolism from the Aquaporin-2 (AQP2) and
antidiuretic hormone (ADH) approach of the lung dys-
function , Li-Qun, Aquaporin 1 (AQP1) explored water
metabolism on the basis of rat models of the kidney
Yang and Qi deficiency [7,8]. Lao Shaoxian etc., used
water Aquaporin as a point index to carry out the study
of water liquid metabolism of splenic heat and humidity
syndrome type, they found spleen’s governing transpor-
tation and transformation function is closely related to
water AQP, the disorder of water AQP-mediated trans-
portation can lead to splenic dysfunction of transporta-
tion and transformation water liquid. Internal water re-
tention resulted in a range of water fluid pathological
changes such as absorption, distribution, metabolism
disorder [9-11]. These studies mainly concentrated on
the water and the essence of water and grain metabolism,
however, few of previous studies were carried out about
the mechanism of the dampness.
Body produces a large number of dampness including
food, metabolites, endogenous and exogenous toxins,
drug metabolites, etc. and foreign organisms in metabo-
lism. Current research shows that oatps can efficiently
transfer a variety of foreign organisms and play a key
role in transit dampness [12,13]. Members of the organic
anion transporter family functio n as uptake transporters
of a wide variety of drugs, xenobiotics and endogenous
substances. In humans and mice, 11 and 15 family mem-
bers, respectively, have thus far been identified. Previous
studies have considered only transport of organic anions
oatp, but recent research confirms oatp has a wide range
of substrates, including cationic, anionic, gender and
anion complex, if oatps dysfunction, will cause damp-
ness of the absorption, distribution and excretion of ob-
stacles, a partial or whole body fluid balance disorders,
leading to diseases [14-16].
The study found that oatp2a1 mRNA was expressed in
the lung, liver, kidney, stomach, small intestine and large
intestine tissues in the spleen deficiency model group
and normal group, suggested that oatp2a1 mRNA ex-
pression might be one of the foundation of the three vis-
cerals (lung, spleen and kidney) as center in the co-
regulation of dampness. The expression of oatp2a1
mRNA in liver tissue of rat with spleen deficiency syn-
drome was up-regulated compared to normal group, the
expression of oatp2a1 mRNA in small intestinal tissue of
Table 1. oatp2a1mRNA expression levels in 6 tissues of each group (x ± s).
tissue normal (n = 6) normal + AA (n = 6) reserpine (n = 10) reserpine + AA (n = 10)
lung 1.49E−02 ± 1.22E−03 2.08E−02 ± 4.18E−03 1.80E−02 ± 6.62E−03 2.07E−02 ± 5.74E−03
liver 2.34E−02 ± 2.56E−03 2.07E−02 ± 5.35E−03 3.15E−02 ± 1.10E−02* 3.42E−02 ± 3.58E−03
kidney 3.88E−02 ± 8.24E−03 3.83E−02 ± 1.61E−02 3.92E−02 ± 1.09E−02 3.86E−02 ± 9.00E−03
stomach 2.33E−02 ± 8.50E−03 3.08E−02 ± 8.67E−03 2.35E−02 ± 9.10E−03 2.90E−02 ± 1.04E−02
small intestine 3.47E−02 ± 9.58E−03 2.33E−02 ± 8.49E−03▲ 2.04E−02 ± 6.23E−03△△ 2.78E−02 ± 1.03E−02
large intestine 1.65E−02 ± 4.37E−03 1.83E−02 ± 5.91E−03 2.05E−02 ± 1.01E−02 2.32E−02 ± 1.11E−02
Note: compared with normal group, * P < 0.05, ** P < 0.01; compared with the normal group, △ P < 0.05, △△ P < 0.01. Compared with normal group, ▲ P
0.05, ▲▲ P < 0.01. <

A.-Z. PAN ET AL. 113
rat with spleen deficiency syndrome was down-regulated
compared to normal group, the expression of oatp2a1
mRNA in intestinal tissue in normal + AA group was
down-regulated compared to normal group, while there
was no difference in the other four kinds of tissues be-
tween two groups. According to Chinese medicine the-
ory, the failure of spleen qi in the transportation and
transformation water fluids results in retention of damp-
ness, retenting in the gastrointestinal system, obstructing
in the meridians, or remaining in the organs. As a bidi-
rectional transfer protein [17], oatp2a1 mRNA was down-
regulated in the small intestine tissue of rat with spleen
deficiency syndrome, which means a self-protective re-
action of the body to reduce the absorption of dampness
in small intestine. In the same time, it was interesting to
find that the rats with spleen deficiency syndrome had
loose stool, which might indicate that the body evacuated
dampness by loose stool. oatp2a1 mRNA expression in
liver tissue of rat with spleen deficiency syndrome was
higher than that of normal rat, which suggested the en-
hanced ability in transporting dampness. This indicates
that the liver and small intestine play an important role in
the transportation and transformation of dampness, fur-
thermore, it reminds us that the function of spleen’s gov-
erning transportation and transformation of dampness
was not only including the functions of the gastrointesti-
nal, but also part of the liver function in some degree.
After intragastric administration of aristolochic acid,
oatp2a1 mRNA expression in mall intestine tissue of rat
in the normal + AA group model rats was significantly
down-regulated compared to the normal group. As we all
known, the small intestine is the main absorbing organ.
The decreased expression of oatp2a1 mRNA in the intes-
tinal tissue when stimulated by external organic anions
indicated that the small intestine reduced the absorption
of dampness, it might be the body self-protective re-
sponse to exogenous dampness.
Under exogenous dampness stimulation, the expres-
sion of oatp2a1 mRNA showed no significant reduction
or elevation, which might suggest that the exogenous
dampness makes an important difference in oatp2a1
mRNA expression, while this was not obvious in state of
spleen deficiency syndrome. This is perhaps a response
of body to transporting and transforming dampness.
In summary, oatp2a1 might be one of material basis
involved in transportation and transformation of damp-
ness, the changes of oatp2a1 mRNA expression in small
intestine and liver tissue suggested that small intestine
and liver might play an important role in the transporta-
tion and transformation of dampness in the state of
spleen deficiency. We further concluded that the function
of spleen’s governing transportation and transformation
of dampness was not only related to the functions of the
gastrointestinal, but also to the function of the liver in
some degree, which needs further study.
5. Acknowledgements
The authors would like to thank DA-AN GENE com-
pany for assistance with gene testing and we also thank
Feng WANG professor, director of central research
laboratories. YI-ER-TA Pharmaceutical Limited Com-
pany of wuhuo for providing drugs and reagents. This
work was supported by the major special program of the
“Eleventh Five-Year Plan” for Sci & Tech Research of
China, the National Natural Science Foundation of China
and the Natural Science Foundation of Guangdong
province.
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