ORIGINAL ARTICLE
Losartan Supports Liver Regrowth via Distinct Boost of PortalVein Pressure in Rodents with 90 % Portal Branch Ligation
Kezhou Li • Xiaohong Qi • Jiaying Yang •
Jianping Gong • Chunlu Tan • Qingjie Xia •
Jieran Long • Zhongdin Wang
Received: 27 February 2012 / Accepted: 27 March 2013 / Published online: 30 April 2013
� Springer Science+Business Media New York 2013
Abstract
Objectives The study used a model of 90 % portal branch
ligation (PBL) in rats to study the effect of losartan on
portal vein pressure (PVP) and liver regeneration in rats
after PBL.
Methods A total of 144 male Sprague–Dawley rats were
arbitrarily designated into three treatment method groups: a
sham operation group (Sham), a PBL treatment group
(PBL), and a PBL plus losartan treatment group
(PBL ? L). Losartan (2 mg/day) was intragastrically ga-
vaged 3 days before the PBL or sham operation to time
points of study.
Results Both the PBL and PBL ? L groups showed an
intense surge in PVP after PBL treatment, peaking at 12 h
postsurgery, then lessening progressively afterwards. PVP
was substantially greater in these two groups compared
with the Sham group at 6–72 h postsurgery (p \ 0.01).
Compared with the PBL group, the PBL ? L group
showed a noticeable reduction in PVP 6–48 h postsurgery
(p \ 0.05); the PBL group showed considerably raised
levels of plasma ALT and AST 6–72 h postsurgery
(p \ 0.01). Compared to the PBL group, the PBL ? L
group showed drastically reduced plasma ALT and AST
levels 12–72 h postsurgery (p \ 0.05).
Conclusions Losartan supports liver regeneration in 90 %
of rats that underwent PBL. The mechanism may be related
to losartan’s ability to regulate PVP and increase serum
hepatocyte growth factor levels.
Keywords Liver regeneration � Portal branch ligation �Hepatocyte growth factor � Losartan
Introduction
Extended hepatectomy is the recommended treatment for
large liver malignancies, hilar cholangiocarcinoma (CCA),
and colorectal liver metastasis [1]. Conversely, inadequate
functional remnant liver (FRL) volume can cause postop-
erative fatality by inducting hepatic complications, a
component that often restricts the scientific application of
this treatment [2, 3]. To decrease postoperative risk, some
investigators recommend using portal vein embolization
(PVE) as a preoperative measure to enhance the prognosis
for extended hepatectomies, with reassuring outcomes.
Functional remnant liver volume can be enhanced by
means of compensatory hypertrophy induced by preoper-
ative selective hepatic PVE. Subsequently, PVE may not
only improve the surgical safety of radical liver resection,
but also improve successful outcomes in some patients [4].
Even with PVE, however, radical liver resection may not
be suitable for 5–36 % of patients due to insufficient
contralateral hepatic hypertrophy [5]. Liver regeneration is
Kezhou Li and Xiaohong Qi contributed equally to this work.
K. Li � X. Qi � J. Yang (&) � C. Tan � Z. Wang
Department of Hepatobiliopancreatic Surgery, West China
Hospital, Sichuan University, Chengdu 610041, Sichuan
Province, China
e-mail: [email protected]
J. Gong
Hepatobiliary Surgery, Second Affiliated Hospital of Chongqing
Medical University, Chongqing, China
Q. Xia
Advanced Medical Center, West China Hospital, Sichuan
University, Chengdu, China
J. Long
Department of Oncology, West China Hospital, Sichuan
University, Chengdu, China
123
Dig Dis Sci (2013) 58:2205–2211
DOI 10.1007/s10620-013-2664-3
a sophisticated and stringently performed course of action,
influenced by the complicated network of signaling path-
ways that integrate extracellular signals, along with a
cascade of intracellular molecular events. Numerous
growth components and cytokines are involved during liver
regeneration in animal models; similar components may
also occur in human liver regeneration [6, 7]. Of the
acknowledged components, hepatocyte growth factor
(HGF) is the most essential proliferation revitalizing
component, along with mitogen, which could mature liver
cells. Liver regeneration can be promoted through esca-
lating serum HGF levels in several animal models for liver
regeneration [8–10].
Scientific studies propose that angiotensin II is actually a
highly effective inhibitor of HGF. Implementing angio-
tensin II receptor 1 (AT1) antagonist also has been proven
to minimize lesions of the cardiovascular and pulmonary
systems by increasing serum HGF levels in animal models
of diabetes and pulmonary fibrosis [11, 12]. However, the
results of AT1 antagonist on serum HGF levels and liver
regeneration in 90 % of PBL rats have not been docu-
mented. Research has shown that, as a possible AT1
antagonist, losartan can minimize portal vein pressure
(PVP) in patients with portal hypertension in liver cirrho-
sis. The consequence of losartan on PVP, however, as a
result of stages after PVE has not yet been shown. For this
reason, our research addresses the consequences of losartan
on PVP, serum HGF levels, and liver regeneration in rats
after 90 % PBL.
Materials and Methods
Animal Experiments
A total of 144 male Sprague–Dawley rats (8 weeks old),
weighing 180–220 g, obtained from the Laboratory Animal
Center, West China Center of Medical Science, were used in
our study. The rats consumed conventional water and food
under controlled temperature and moisture and a 12-h light/
dark cycle. All rats in the study were observed for 1 week,
then randomized into three groups: the sham operation group
(Sham group); the model group (PBL only), and the treat-
ment group (PBL ? losartan 2 mg/kg 9 day). The rats were
anesthetized by injection of 1.5 % sodium pentobarbital
(40 mg/kg) into the abdominal cavity. Under the micro-
scopic lense, portal vein branches, which provide to the
median, left, and right lateral lobes of the liver, were sepa-
rated and ligated carefully. Only portal vein branch supply to
the caudate lobe was preserved. During this process, proper
care was taken to not damage the hepatic artery and bile
ducts. The ligated liver lobes comprised 90 % of the liver
weight. All PBL surgeries were performed between 9:00 and
12:00 a.m. In the sham operation group, the portal vein
branches were dissociated but not ligated, and the abdominal
cavity was then closed immediately. Daily for 3 days before
surgery until the end of the experiment, the sham operation
group and the PBL group received physiological saline,
whereas the PBL ? L group was given losartan.
Portal Vein Pressure, Blood Samples, and Liver
Samples
To measure PVP, the abdomen was opened along the ori-
ginal incision under anesthetization at 6, 12, 24, 48, 72,
120, or 168 h after surgery for each of the groups. An
electronic manometer (Nihon Kohden, Tokyo, Japan) with
a heparinized 22-gauge needle was inserted directly into
the portal vein to measure PVP. The zero graduation line
was defined by the anatomical position of portal vein, and
results were indicated in millimeters of mercury. All blood
samples were taken directly from the heart immediately
after liver extraction and centrifuged. The levels of ALT
and AST in the sera were detected with a standard clinical
automatic analyzer (Arkray, Kyoto, Japan). The complete
livers were surgically removed, blood was blotted with
filter paper, and the tissue was observed for color and
texture. The unligated liver lobes were maintained in 20 %
buffered formalin. The mass of unligated liver lobes and
total liver were weighed (accurate to 0.01 g), and LW/TW
index was calculated.
Histology and Immunohistochemistry
The unligated liver lobes taken from each time point were
fixed with 10 % formaldehyde, embedded in paraffin, and
sliced into 4-lm sections. Hepatic tissue sections were
routinely dewaxed and stained with hematoxylin and
eosin (H&E) to observe the pathological changes in liver
structures. Proliferating cell nuclear antigen (PCNA) in
unligated liver lobes was assayed immunohistochemically
using the S–P method, then incubated at 1:100 dilution
for 60 min with polyclonal antibody against mouse PCNA
(Santa Cruz Biotechnology, Santa Cruz, CA, USA). After
washing with Tris-buffered saline, sections were incu-
bated with the secondary antibody and immunostained by
the EnVision (Dako A/S, Grostup, Denmark) method
according to instructions. The criterion for immunohisto-
chemical-positive cells in terms of PCNA index was
brown-yellow stained nucleus with a distinct boundary.
Each section was counted for PCNA-positive nuclei in at
least five random areas, at 2009 magnification ([300
cells), and the percentages of labeled nuclei were
calculated.
2206 Dig Dis Sci (2013) 58:2205–2211
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Assays of HGF in Plasma
The plasma concentration of HGF was detected using the
ELISA method (HGF Assay Kit, Institute of Immunology,
Tokyo, Japan). The value of A492 was determined by
WellscanMK-3 type. Based on different concentrations of
standard serum A value, the specification curve and HGF
concentrations were attained.
Statistical Analysis
Data were expressed as mean ± SEM and analyzed by
t test or Pearson correlative analysis with SPSS II.5 soft-
ware. p values B0.05 were considered statistically
significant.
Results
Losartan Inhibits Rise of PVP
The normal value of PVP in rats is approximately
10.56 ± 0.75 mmHg. Compared with that in the sham
operation group, the PVP of rats in the PBL group and the
PBL ? L group increased sharply after PBL. For these two
groups, postsurgery PVP peaked at 12 h and then gradually
decreased to normal levels approximately 120 h after sur-
gery. The average PVP of the PBL group was significantly
higher than that of the sham operation group between 6 and
72 h (p \ 0.01), whereas the PVP of the PBL ? L group
decreased significantly at 6–48 h after surgery (p \ 0.05)
(Fig. 1).
Losartan Inhibits the Increase of ALT and AST Levels
The typical ALT level in rats is approximately
40.33 ± 7.09. The ALT levels in the PBL group increased
rapidly after PBL, peaking (488.83 ± 41.80) at 24 h after
surgery, then decreased gradually. Compared with ALT
levels in the sham operation group, ALT levels in the PBL
group increased dramatically between 6 and 72 h
(p \ 0.01). The ALT levels in the PBL ? L group were
significantly higher than those in the sham operation group,
yet significantly lower than those in the PBL group
between 12 and 72 h postsurgery (p \ 0.01 or p \ 0.05)
(Fig. 2).
The AST levels in rats are typically approximately
75.00 ± 17.09. After PBL, AST levels in the PBL group
peaked (806.16 ± 59.56) at 12 h, and then dropped grad-
ually. The AST levels in the PBL group were significantly
higher than those in the sham operation group at 6–72 h
postsurgery (p \ 0.01). In comparison with the PBL group,
AST levels in the PBL ? L group decreased gradually
after 12 h and reached a normal level at 72 h. Between 6
and 72 h, AST levels in the PBL ? L group were signifi-
cantly lower than those in the PBL group (p \ 0.01 or
p \ 0.05) (Fig. 3).
Fig. 1 PVP values at the various time points after surgical treatment
(millimeters of mercury ±s). PVP values are clearly higher in both
the PBL and PBL ? losartan groups compared with the sham-
operation group; however, PVP in PBL ? losartan group is lower
than that in the PBL group. *p \ 0.01 versus sham-operation group;
**p \ 0.01 or p \ 0.05 versus the PBL group
Fig. 2 Serum ALT value after 90 % PBL at different time points
(U/L, ±s). ALT values were clearly higher in both the PBL and the
PBL ? losartan groups compared with the sham-operation group;
however, ALT in the PBL ? losartan group was lower than that in the
PBL group. *p \ 0.01 versus sham operation group; **p \ 0.01 or
p \ 0.05 versus PBL group
Dig Dis Sci (2013) 58:2205–2211 2207
123
Losartan Increases the Plasma Concentration of HGF
Portal branch ligation resulted in a rise in plasma HGF
concentrations in both the PBL group and the PBL ? L
group. After PBL, HGF levels in the PBL group reached
seven times their initial preoperative values. HGF
concentrations then decreased gradually, finally maintain-
ing a level of approximately 2.0 ng/ml after 168 h. Com-
pared with HGF levels in the PBL group, HGF levels in the
PBL ? L group were notably higher between 6 and 168 h
postsurgery and remained significantly higher at 168 h
postsurgery (p \ 0.01) (Fig. 4).
Losartan Increases the PCNA Index
The PCNA index was used to evaluate cell proliferation
in vivo in the regenerating liver after PBL. The basic value
of the PCNA index is 5.55 % in rat liver tissue. In the PBL
group, the PCNA index was significantly elevated by 12 h
after PBL, and peaked at 120 h. Compared with that in the
sham operation group, the PCNA index was significantly
higher between 12 and 168 h (p \ 0.01). For the PBL ? L
group, the PCNA index peaked at 72 h. Compared with
that in the PBL group, the PCNA index for the PBL ? L
group was significantly elevated at 12–168 h postsurgery
(p \ 0.01 or p \ 0.05) (Figs. 5, 6a–c).
Losartan’s Effects on the LW/TW Ratio
After PBL, the ligated liver lobes atrophied and darkened,
whereas the unligated liver lobes underwent hypertrophy.
In the sham operation group, the caudate lobe accounted
for 10 % of the liver weight. Compared with the LW/TW
ratio in the sham operation group, the LW/TW ratio in the
PBL group increased significantly from 24 h (p \ 0.01),
increasing gradually, reaching 27.83 % by 168 h
Fig. 3 Serum AST value after 90 % PBL at different time points (U/
l, ±s). AST values were obviously higher in both the PBL and
PBL ? losartan groups compared with the sham operation group;
however, AST in the PBL ? losartan group is lower than that in the
PBL group. *p \ 0.01 versus sham operation group; **p \ 0.01
versus PBL group
Fig. 4 HGF levels after PBL at different time points (ng/ml, ±s).
HGF values are higher in both the PBL and PBL ? losartan groups
compared with the sham operation group; however, HGF in the
PBL ? losartan group is higher than that in the PBL group. *p \ 0.01
versus sham operation group; **p \ 0.01 or p \ 0.05 versus PBL
group
Fig. 5 PCNA indexes after PBL at different time points. *p \ 0.01
versus sham operation group. PCNA values clearly higher in both the
PBL and the PBL ? losartan groups compared with the sham
operation group; however, PCNA in the PBL ? losartan group is
higher than that in the PBL group. **p \ 0.01 versus PBL group
2208 Dig Dis Sci (2013) 58:2205–2211
123
postsurgery. The LW/TW ratio for the PBL ? L group
reached 31.15 % by 168 h postsurgery. In the PBL ? L
group, the LW/TW ratio was higher than that in the PBL
group between 24 and 168 h postsurgery (p \ 0.01)
(Fig. 7).
Pathologic Changes in Hepatic Tissue
In the sham operation group, the hepatic cells arrayed
radially around the central vein. After PBL, cells of unli-
gated liver lobes showed slight edema and hepatic sinu-
soids dilated significantly by 24 h. Hepatic lobules were
severely distorted by 72 h. Thereafter, the hepatic tissue
gradually returned to normal. In the PBL ? L group,
hepatocyte edema and dilation of hepatic sinusoids were
less severe than in the PBL group, and took less time to
return to normal. In both the PBL group and the PBL ? L
group, the number of mitotic-phase hepatocytes were
significantly higher than in the sham operation group
(Fig. 8a–c).
Discussion
Significant hepatectomy is the recommended treatment for
patients with enormous liver tumor, CCA, or hepatocellular
carcinoma (HCC). Although this course of action is carried
out to extend life expectations, it also offers the probability
of resulting in hepatic malfunction due to the substantial
removals of hepatic tissue. Consequently, numerous
affected patients are regarded as not suitable candidates for
this surgical treatment because of inadequate liver remnant
volume [13]. There is considerable agreement at numerous
hepatic surgical centers that when future liver remnant
(FLR) is B20 % of the standardized total liver volume,
both the postoperative mortality rate and the incidence of
complications after hepatic resection increase appreciably.
For patients with cirrhosis or having received large-dose
chemotherapy, this percentage should be to B40 and
B30 %, respectively [14]. Preoperative PVE is actually a
contrasting technological innovation currently in use to
enhance the degree and performance for the FLR in an
effort to reduce the probability of complications from
major hepatectomy for HCC or CCA. Embolization of the
portal vein branches feeding the liver segment which
would be resected makes it possible for redistribution of
the portal circulation of blood toward the branches for the
FRL. Consequently, the effective use of PVE before
expanded hepatectomy not only adds to the applicability of
the course of action, but additionally allows for surgical-
safe practices [15, 16]. Recently, the use of PVE to manage
inadequate FLR in patients requiring major hepatectomy
has become more common.
The adjustment of portal vein blood circulation hemo-
dynamics is an additional prospective reason for hepatic
failure after extensive hepatectomy. With substantial
hepatic resection, the portal vein blood flow offering the
remnant hepatic tissue increases dramatically. Subse-
quently, PVP results in being enhanced, which enables it to
Fig. 6 a PCNA expression in normal rat liver tissue (9200). b PCNA expression at 72 h after PBL in the PBL group (9200). c PCNA
expression at 72 h after PBL in the PBL ? L group (9200)
Fig. 7 LW/TW ratios after PBL at different time points. LW/TW
ratios are clearly higher in both the PBL and the PBL ? losartan
groups compared with the sham operation group; however, LW/TW
ratios in the PBL ? losartan group are higher than those in the PBL
group. **P \ .01 versus PBL group
Dig Dis Sci (2013) 58:2205–2211 2209
123
skimp on the dwelling with the remaining hepatic sinusoids
and thus triggering hepatic injury and inhibition of liver
regeneration [17–21]. This stress represents sinusoidal
endothelial cell injury, which results in future hepatocel-
lular damage and death [22, 23]. In the same manner,
injury to nonembolized segments accompanies the steep
surge in PVP in patients undergoing PVE. In our research,
transient portal hypertension and excessive hepatic blood
flow were observed after PBL. Our research also showed
that substantial amounts of serum ALT and AST comple-
mented the portal hypertension after PBL, which suggests
liver dysfunction. In the mean time, the phenomenon of
liver organ injuries (e.g., hepatic sinusoids dilation and
hepatocellular edema) was seen during the early phases
after PBL. We found, however, that PVP, ALT, and AST
were clearly lower in the PBL ? losartan group than in the
PBL group.
Conversely, resulting from insufficient FLR regrowth,
not every patient who undergoes PVE is able to undergo
significant hepatectomy [23, 24]. To overcome this obsta-
cle, we try to enhance liver regeneration after PBL with the
administration of specified drugs such as losartan. In the
course of liver regrowth after PBL, ordinarily quiescent
hepatocytes require models of reproduction to revive the
liver mass by means of hyperplasia. Liver regeneration is
actually a complicated and highly regulated course of
action, manipulating a complicated network of signaling
pathways that integrates extracellular signals in addition to
a cascade of intracellular molecular events.
Many advanced components and cytokines are essential
to the process of liver regrowth in animal models. In
addition, the expression of such components also occurs
during human liver organ regrowth. Furthermore, TNF-a,
TGF-a, and IL-6, HGF is regarded as essentially the most
significantly proliferative revitalizing component, along
with mitogen, to the mature liver cells, for its role in pro-
moting liver regeneration and as protection of liver tissue
via decreasing apoptosis of hepatic cells. HGF can be
considered a morphogenic, motogenic, or mitogenic
substance, depending on its variety of activities. Study
results propose that escalating serum HGF levels promote
liver regeneration. Numerous studies have also shown that
angiotensin is actually an efficient inhibitor of HGF, rec-
ognizing that use of AT1 antagonists can maximize serum
HGF levels [25–27]. Losartan clearly is this type of AT1
antagonist; it blocks various endogenous and exogenous
pharmacological results of angiotensin.
Our research established that plasma HGF levels began
to increase at 6–168 h after PBL, peaking at 6 h, and
progressively lessening. Compared with the PBL group,
serum HGF quantities in the PBL ? L group enhanced
significantly and maintained an advanced level even at
168 h postsurgery. The PCNA labeling index is undoubt-
edly a gauge capable of appraising liver organ regrowth.
With simplex PBL, PCNA labeling indexes progressively
enhanced and peaked at 120 h, and the quantity of positive
cells visibly increased within the liver tissue. With the use
of losartan, PCNA indexes for the PBL ? L group were
substantially higher than those within the PBL group,
starting 12 h after PBL. Consequently, we consider that the
effective use of losartan may possibly encourage hepato-
cyte proliferation within our 90 % PBL rat model. The
ratio of LW/TW is yet another essential indicator to
appraise liver regeneration. In our study, we observed that
the LW/TW ratio for the PBL ? L group was significantly
higher than that in the PBL group, starting at 24 h after
PBL. With this finding, we could consider that losartan
supports substantial recuperation of liver organ volume
level. The existing research also supports our speculation
that mechanisms through which losartan promotes liver
regeneration are most likely associated with its ability to
assist in the details about serum HGF.
Conclusions
Administration of losartan can hinder the increase in PVP
as a result of phases following PBL, liver organ damage,
Fig. 8 a Normal rat liver tissue HE 9200. b Pathological changes at 24 h after PBL in the PBL group HE 9200. c Pathological changes at 24 h
after PBL in the PBL ? L group HE 9200
2210 Dig Dis Sci (2013) 58:2205–2211
123
and thus indirectly encourage liver organ regrowth. Human
studies might be necessary to investigate the efficacy and
safety of this technique in the medical setting.
Conflict of interest None.
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