of Oxalate Induced Renal Tubular Epithelial Cell Injury and Inhibition
of Calcium Oxalate Crystallization in vitro by Aqueous Extract of Tribulus
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Basic and Translational Urology
S. Tandon, S. K. Singla, C. Tandon
Department of Biotechnology and Bioinformatics (AA, ST, CT), Jaypee University
of Information Technology, Waknaghat, Solan, India and Department of Biochemistry
(SKS), Panjab University, Chandigarh, India
Recurrence and persistent side effects of present day treatment for urolithiasis
restrict their use, so an alternate solution, using phytotherapy is being
sought. The present study attempted to evaluate the antilithiatic properties
of Tribulus terrestris commonly called as “gokhru” which is
often used in ayurveda to treat various urinary diseases including urolithiasis.
Materials and Methods: The activity of Tribulus
terrestris was investigated on nucleation and the growth of the calcium
oxalate (CaOx) crystals as well as on oxalate induced cell injury of NRK
52E renal epithelial cells.
Results: Tribulus terrestris extract exhibited
a concentration dependent inhibition of nucleation and the growth of CaOx
crystals. When NRK-52E cells were injured by exposure to oxalate for 72
h, Tribulus terrestris extract prevented the injury in a dose-dependent
manner. On treatment with the different concentrations of the plant, the
cell viability increased and lactate dehydrogenase release decreased in
a concentration dependent manner.
Conclusion: The current data suggests that
Tribulus terrestris extract not only has a potential to inhibit nucleation
and the growth of the CaOx crystals but also has a cytoprotective role.
Our results indicate that it could be a potential candidate for phytotherapy
words: phytotherapy; urolithiasis; calcium oxalate; NRK 52E,
Int Braz J Urol. 2010; 36: 480-9
is common, affecting up to 10% of the population at some point during
their lifetime (1). Calcium-containing stones are the most commonly occurring
to an extent of 75-90% followed by magnesium ammonium phosphate (Struvite)
to an extent of 10-15%, uric acid 3-10% and cystine 0.5-1% (2). Calcium
oxalate stones are found in two different varieties, calcium oxalate monohydrate
(COM) or Whewellite, and calcium oxalate dihydrate (COD) or Weddellite.
COM, the thermodynamically most stable form, is observed more frequently
in clinical stones than COD and it has a greater affinity for renal tubular
cells, thus responsible for the formation of stones in the kidney (3).
Various authors have suggested the role
of crystal induced cell injury in the development of kidney stones by
providing the sites for crystal attachment and retention within the kidneys
Oxalate, a metabolic end product and a major constituent of the majority
of renal stones, has been shown to be toxic to renal epithelial cells
of cortical origin (6). It has been observed that exposure of renal epithelial
cells to oxalate which is a constituent of most kidney stones leads to
a disruption of the normal activities of the renal epithelial cells such
as altered membrane surface properties and cellular lipids, changes in
gene expression, disruption of mitochondrial function, formation of reactive
oxygen species and decreased cell viability (7).
Various mechanisms have been proposed to
explain crystal retention (8). As a result of crystal growth and agglomeration,
particles may be formed that are too large to freely pass the renal tubules.
Alternatively, relatively small crystals could be retained by adhering
to the surface of the urothelial lining and then increase in size (8).
The surgical methods available to treat
kidney stones like extracorporeal shock wave lithotripsy have serious
side effects. Therefore, it is worthwhile to look for an alternative for
the management of urolithiasis. Many medicinal plants have been employed
during ages to treat urinary stones though the rationale behind their
use is not well established through systematic and pharmacological studies,
except for some composite herbal drugs and plants (9-12). Plant medicines
are in great demand both in the developed as well as developing countries
for primary health care because of their wide range of biological and
medicinal activities, higher safety margin and low cost.
Fruits of Tribulus terrestris (Zygophyllaceae)
locally named as “gokhru” in India are commonly used in folklore
to treat urolithiasis. So far, its diuretic properties have been documented
in literature and it is actively used in various drug formulations of
kidney stone treatments.
The present study aimed at investigating the efficacy of Tribulus terrestris
on calcium oxalate crystal nucleation and growth in vitro as well as further
examining the potency of Tribulus terrestris on oxalate induced injury
in NRK 52E (rat renal tubular epithelial) cells.
of the Tribulus terrestris Extract
dried and matured fruits of Tribulus terrestris were obtained from “Natural
Remedies Pvt. Ltd.” at Bangalore in India. A collection of voucher
specimens is available at the company.
The air-dried fine powdered plant fruits were boiled in distilled water.
The extract was then filtered using Whatman No. 1 filter paper and the
filtrate was evaporated in vacuum and dried using a rotary evaporator
at 60° C (13). The final dried samples were stored in labeled sterile
bottles and kept at -20° C. The various concentrations of the plant
sample tested for their inhibitory potency were 25 µg/mL, 50 µg/mL,
100 µg/mL, 200 µg/mL, 400 µg/mL and 1000 µg/mL,
which were prepared at the time of experiment and were referred to as
aqueous extract of Tribulus terrestris.
For cell culture studies a stock solution of the dried aqueous Tribulus
terrestris extract was dissolved in dimethyl sulfoxide (DMSO) [final concentration
of the DMSO in the highest concentration of plant extract tested did not
exceed 0.4% (v/v) and did not affect the cell proliferation]. Further
dilutions of the stock were done using serum free DMEM (Dulbecco’s
Modified Eagle’s Media) and filtered by 0.3 mm syringe filter (14).
method used was similar to that described by Hennequin et al. with some
minor modifications (15). Solutions of calcium chloride and sodium oxalate
were prepared at the final concentration of 3 mmoL/L and 0.5 mmoL/L, respectively,
in a buffer containing Tris 0.05 moL/L and NaCl 0.15 moL/L at pH 6.5.
Both solutions were filtered through a 0.22 µm filter; 33 mL of
calcium chloride solution was mixed with 3.3 mL of the aqueous extract
at different concentrations. Crystallization was started by adding 33
mL of sodium oxalate solution. The final solution was magnetically stirred
at 800 rpm using a PTFE-coated stirring bar. The temperature was maintained
at 37o C. The absorbance of the solution was monitored at 620 nm after
every 1 min. The percentage inhibition produced by the herb extract was
calculated as [1-(Tsi/Tsc)] X 100, where Tsc was the turbidity slope of
the control and Tsi the turbidity slope in the presence of the inhibitor.
activity against CaOx crystal growth was measured using the seeded, solution-depletion
assay described previously by Nakagawa and colleagues (16). Briefly, an
aqueous solution of 10 mM Tris-HCl containing 90 mM NaCI was adjusted
to pH 7.2 with 4 N HC1. Stone slurry (1.5 mg/mL) was prepared in 50 mM
sodium acetate buffer (pH 5.7). CaOx monohydrate crystal seed was added
to a solution containing 1 mM CaCl2 and 1 mM sodium oxalate (Na2C2O4).
The reaction of CaCl2 and Na2C2O4 with crystal seed led to deposition
of CaOx (CaC2O4) on the crystal surfaces, thereby decreasing free oxalate
that is detectable by spectrophotometry at ?214 nm. When aqueous extract
is added into this solution, depletion of free oxalate ions will decrease
if the test sample inhibits CaOx crystal growth. Rate of reduction of
free oxalate was calculated using the baseline value and the value after
30-second incubation with or without test sample. The relative inhibitory
activity was calculated as follows: % Relative inhibitory activity = [(C-S)/C]
× 100, where C is the rate of reduction of free oxalate without
any test sample and S is the rate of reduction of free oxalate with a
rat epithelial derived renal tubular epithelial (NRK 52E) cells were obtained
from National Centre of Cell Sciences (NCCS, Pune). The cells were maintained
as monolayers in Dulbecco’s Modified Eagle’s Medium (DMEM)
with 2.0 mM L-glutamine adjusted to contain 3.7 g/L sodium bicarbonate,
4.5 g/L glucose. Media was supplemented with 1% Penicillin (100 units/mL)-Streptomycin
(10,000 µg/mL) and 10% fetal bovine serum. Cells were cultured in
25 cm2 tissue-culture treated flasks at 37o C and 5% CO2 in humidified
52E cells were incubated in DMEM containing 1 mM sodium oxalate in the
presence of different concentrations of the aqueous extract of the test
sample (10 µg/mL, 25 µg/mL and 50 µg/mL) for 72 hours
(14,17). Cell injury was assessed by measuring the cell viability through
trypan blue and monitoring the lactate dehydrogenase (LDH) leakage into
- Trypan Blue Assay
cytotoxicity of the aqueous extract of T. terrestris was assessed by cell
viability using trypan blue exclusion method. For the determination of
cell viability, cells were plated at the density of 4 × 104 cells/well
and cultured for 72 h. The medium was replaced with serum-free medium
and the cells were treated with various concentrations of the plant extracts
(10 µg/mL, 25 µg/mL and 50 µg/mL) for a further 72 h.
The percentage viability for the cells was calculated as (live cells/total
cells) x 100.
LDH Leakage Assay
leakage assay was performed by the method described by Wagner et al. (18).
Briefly, 6.6 mM NADH and 30 mM sodium pyruvate were prepared in Tris (0.2M,
pH 7.3). Reaction was initiated with the addition of 50 µL of the
test sample and the disappearance of NADH was monitored at 340 nm, for
5 min at an interval of 1 min. The percentage of LDH release was calculated
by dividing the activity of LDH in the supernatant by the LDH activity
measured after complete cell lysis achieved by sonication.
were expressed as mean values of three independent experiments (each in
triplicate) and analyzed by the analysis of variance (p < 0.05) to
estimate the differences between values of extracts tested.
of Nucleation of CaOx Crystals by Tribulus terrestris Extract
displays the effect of the different concentration of the aqueous extract
of Tribulus terrestris on the nucleation of calcium oxalate crystals.
As regards control (with no plant sample), the percentage inhibition was
constant at 71.4 ± 0.001 with increase in the concentration of
Tribulus terrestris extract of 25 µg/mL, 50 µg/mL and 100
µg/mL. As the concentration of Tribulus terrestris extract was increased
to 200 µg/mL, the percentage inhibition increased to 100 ±
0.001 but was reduced to 85.7 ± 0.002 for 400 µg/mL. The
percentage inhibition was restored to 100 ± 0.001 with 1000 µg/mL
of the extract.
of CaOx Crystal Growth by Tribulus terrestris Extract
demonstrates the percentage inhibition shown by Tribulus terrestris on
the calcium oxalate crystal growth. Tribulus terrestris extract showed
inhibition in a concentration dependent manner. The percentage inhibition
with 25 µg/mL of plant sample was 17.6 ± 0.004. With 50 µg/mL,
100 µg/mL and 200 µg/mL, the inhibition was almost constant
in the range of 65-70% but inhibition increased significantly with 400
µg/mL and 1000 µg/mL of Tribulus terrestris extract to 126.4
± 0.001 and 169.2 ± 0.001 respectively.
Diminution of Oxalate-induced Renal Tubular Epithelial Cell Injury by
Tribulus terrestris Extract
depicts the protective effect of the aqueous extract of Tribulus terrestris
towards the renal tubular epithelial cells. The oxalate induced a significant
injury to the cells which could be ascertained by a decrease in viability
from 100% in the controls (untreated cells) to 73.9%. However, the injury
due to oxalate was significantly reduced in those cells treated with the
Tribulus terrestris extracts. As the concentration of the extract increased
from 10 µg/mL to 50 µg/mL, the percentage viability improved
showing that the plant has an inhibitory activity towards the oxalate
which caused injury to the renal cells in a concentration dependent manner.
The plant extract alone (50 µg/mL, containing 0.4% DMSO) had no
effect on the cell injury in the absence of oxalate indicating that even
at the highest concentration of DMSO used there was no cytotoxicity to
the cells. The percentage viability with 10 µg/mL, 25 µg/mL
and 50 µg/mL was 81.6 ± 6.9, 84.9 ± 1.9 and 89.1 ±
dehydrogenase is a stable cytosolic enzyme that is released when the cell
is lysed or there is any injury on the cell membrane. A significant increase
in LDH release was seen when the NRK 52E cells were exposed to oxalate
alone. When NRK 52E cells were treated with the plant extract at varying
concentrations(10, 25 and 50 µg/mL) along with oxalate (1 mM) for
72 h, a reduction in oxalate-induced cell injury was observed as assessed
by a decreased LDH release (Figure-4), Again it was seen that the plant
extract alone had no significant effect on the measures of cell injury
in the absence of oxalate. The percentage LDH release for 10 µg/mL,
25 µg/mL and 50 µg/mL was observed to be 126.5 ± 4.2,
112.6 ± 5.2 and 109.8 ± 1.0 respectively after treatment
with oxalate and the plant extract with respect to control.
is growing evidence that CaOx nephrolithiasis is associated with renal
injury. Hyperoxaluria is a major risk factor for calcium oxalate nephrolithiasis,
and calcium oxalate urinary stones are the most common type of urinary
stone. High level of oxalate produced a variety of changes in the renal
epithelial cells, such as an increase in free radical production and a
decrease in antioxidant status, followed by cell injury and cell death.
These changes are significant predisposing factors for the facilitation
of crystal adherence and retention (5,14).
to significant side effects and failure to prevent recurrence by the present
day treatment procedures for urolithiasis, alternative treatment modalities
using herbal products have assumed importance. A dramatic advancement
in using phytotherapy for urolithiasis treatments has been observed in
recent years and many investigators have proposed to further scientific
study on its efficacy. Many medicinal plants have been employed for centuries
to treat urinary stones though the rationale behind their use is not well
the present study, the anticalcifying properties of Tribulus terrestris
commonly called “gokhru” were explored in vitro. The inhibitory
potency of the plant was tested on the nucleation and growth of the most
commonly occurring kidney stones, calcium oxalate monohydrate. A concentration
dependent trend of inhibition was observed using Tribulus terrestris extract
with maximum inhibition of 100% and 170% for CaOx nucleation and the growth
assay respectively with 1000 µg/mL of the extract.
our study with NRK 52E, Tribulus terrestris proved to have a protective
effect towards the renal epithelial cells again in a concentration dependent
manner. When NRK-52E cells were injured by exposure to oxalate for 72
h, the plant extract prevented the injury in a dose-dependent manner.
The mechanism of inhibition /reduction in the injury needs to be studied
further. Studies have shown that inhibition of the inflammatory response
induced by injury due to crystal formation helps in restoring normalcy.
et al. (19) have suggested in studies using certain Algerian medicinal
plants that the herb extract may contain substances that inhibit the growth
of COM crystals. This property of plant extracts could be important in
preventing kidney stone formation; the agglomeration of particles is a
critical step in urinary stone formation, as larger crystals are less
likely to pass spontaneously in the urinary tract (8,20). They (19) further
postulated that the plant extracts may contain substances that inhibit
CaOx crystal aggregation and also the binding of the crystals to the renal
epithelial surface. This could explain a decrease in LDH release as seen
in the cells treated with the plant extract compared to those treated
with oxalate alone.
studies are in agreement with the studies previously reported as regards
the anti-urolithiatic potency of Tribulus terrestris on the growth COM
crystals using double diffusion gel growth technique (21). The anti-urolithiatic
ability of the plant is also currently being evaluated in animal models
and has exhibited dose-dependent anti-urolithiatic activity and almost
completely inhibited stone formation further supporting our results (22,23).
Recently several plants including Herniaria hirsuta (24), Phyllanthus
niruri (25) and Bergenia linguata (26) are being explored for their anti-urolithiatic
properties on the basis of their usage in the traditional medicine. Herniaria
hirsuta, a plant from Morocco is also known to exhibit the antilithiatic
activity. The adhesion of the radioactive COM crystals to the Madin Darby
canine kidney cells was studied in the presence and the absence of the
aqueous extract. COM crystal binding to the cells was inhibited by the
extract in a concentration dependent manner (24). In vitro effect of an
aqueous extract of Phyllanthus niruri L., a plant used in Brazilian folk
medicine for the treatment of urolithiasis, on a model of CaOx crystal
endocytosis by Madin-Darby canine kidney cells was investigated by Campos
and Schor. The extract exhibited a potent and effective non-concentration-dependent
inhibitory effect on the CaOx crystal internalization. This response was
present even at very high (pathologic) CaOx concentrations and no Phyllanthus
niruri L.-induced toxic effect could be detected (25). Bergenia ligulata
is a widely used plant in South Asia, mainly India and Pakistan, as a
traditional medicine for treatment of urolithiasis. The crude aqueous-methanolic
extract of Bergenia ligulata rhizome was studied using in vitro and in
vivo methods and the extract showed the anti-urolithic activity through
CaOx crystal inhibition, diuretic, hypermagneseuric and antioxidant effects
(26). Also in our laboratory, antilithiatic potency of Dolichos biflorus
(27) and Trachyspermum ammi (28) has been evaluated in vitro and in vivo.
The most active protein fraction was isolated from these plants and thus
adds a new perspective to study plant fractions for their therapeutic
use as antilithiatic proteins.
conclusion, the aqueous extract of Tribulus terrestris has been shown
to possess an ability to inhibit CaOx crystallization in vitro. In addition
this extract has also shown cytoprotective properties towards the NRK
52E cells by lowering LDH leakage and increasing the cell viability. Our
study suggests the possibility of using Tribulus terrestris as a therapeutic
agent to treat urolithiasis and further characterization of its active
compound(s) could lead to a new candidate drug for patients with urolithiasis.
Department of Biotechnology, Government of India, provided funds for this
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October 29, 2009
Dr. C. Tandon
Biotechnology and Bioinformatics
Jaypee University of Information Technology
Waknaghat, 173215, Solan, India
Kidney stone disease is a major health problem in modern
societies. As technology evolved, surgical options have gained more acceptance
as they provide less invasive approaches, more efficacious results and
lesser collateral effects. However, the costs involved are significant
and an increasing effort should be continuously made in order to optimize
prevention. The article presented by Aggarwal et al. clarifies the efficacy
of the herbal Tribulus terrestris on the inhibition of calcium oxalate
calculi formation. Herbal medicine has been long used to treat different
health conditions including stone disease. However, only more recently
efforts began to be made to determine the mechanisms involved and their
objective efficacy. In the present evidence-based medicine era this is
of utter importance. Herbal medicines may be an alternative to the currently
existing medicines providing the additional advantage of minimal or inexistent
collateral effects. Other herbal medicines should undergo evaluations
in vitro to amplify the urologist’s clinical armamentarium to combat
Department of Urologic Surgery
University of Minnesota
Minneapolis, MN, USA
In this paper, the authors addressed the potential use
of Tribulus terrestris as the therapeutic agent to treat urolithiasis.
Urolithiasis is characterized by high recurrence rate and among the treatments
used are extracorporeal shock wave lithotripsy and drug treatment, although
there is no satisfactory drug to use in clinical therapy. Thus the prevention
of this disease or its recurrence would be of great interest. Phytotherapy
is a common method used in folk medicine as an alternative for primary
health care in many countries and particularly the potential effect of
many plants to treat urolithiasis has been reported over the past years.
The precipitation of calcium oxalate (CaOx) inside the renal tubules and
the interaction between CaOx crystals and tubular epithelium plays an
important role in the genesis and evolution of urolithiasis, since renal
tubular cells selectively bind and uptake CaOx crystals, a phenomenon
followed by a series of intracellular events that culminate in a cell
damage and death. It was shown that aqueous extract of Tribulus terrestris
was able to inhibit CaOx crystallization in vitro and showed cytoprotective
properties increasing the cell viability.
The extract of plants with antilithiatic properties (Tribulus terrestris,
Phyllanthus niruri, Herniaria hirsute, etc.) has been shown effective
to prevent calculi development in the experimental models in vivo and
in vitro, showing significant effects on many stages of stone formation
including crystallization, aggregation, cellular adherence and adsorption
of macromolecules into the calculi, however, its effects in lithiatic
patients are much less clear. Many reasons can be raised for this difference
such as the treatment onset, number of patients, time of treatment, adhesion
to the treatment, etc. Moreover, it was previously shown (1) that rats
with already formed vesical calculi, the administration of Phyllanthus
niruri had no effect on the calculi size or elimination rate but it induced
a shift in the calculi shape toward a smoother surface and probably more
fragile form, which could contribute to elimination and/or dissolution
of calculi. Overall the available data point to a useful therapeutic application
of these plants, including Tribulus terrestris in lithiatic patients,
mainly as prophylactic agent in those persons who are at high risk to
develop stones since they can potentially interfere with the pathogenesis
of urolithiasis and may represent an attractive alternative for the prevention
of lithiasis of the urinary tract.
1. Barros ME, Lima R, Mercuri LP, Matos JR, Schor N, Boim
MA: Effect of extract of Phyllanthus niruri on crystal deposition in experimental
urolithiasis. Urol Res. 2006; 34: 351-7.
Associate Researcher, Renal Division
Federal University of São Paulo
São Paulo, SP, Brazil