L-arginine Exposure Improves Renal Function Markers of Metabolic Syndrome in Female Rats
A.C. Cemaluk Egbuonu
Female gender is an independent risk factor for the development of metabolic
syndrome (MES) (a cluster of features indicating metabolic disorders), that
is associated with kidney damage, insulin resistance and a significant reduction
in Nitric Oxide (NO), a major metabolite of L-arginine (ARG). This study aimed
to ascertain the effect of ARG on selected markers of MES related to kidney
damage in female Wistar albino rats. Two groups of rats were given 3 mL kg-1
body weight (b.wt.) of distilled water, DW and 60 mg kg-1 b.wt. of
ARG, respectively as control and treated groups. Exposing the female rats to
ARG caused a significant decrease (p<0.01) in the concentration of urea (6.34±0.23
mg/100 mL), creatinine (4.41±0.50 mg/100 mL) and albumin (14.30±0.15
mg/100 mL) in rats serum. It
decreased (p<0.01) creatinine clearance (1.78±0.27 mL min-1)
but elicited a significant increase (p<0.01) in the albumin:creatinine ratio
(3.27±0.32) of the rats. Improved kidney histology as indicated by lots
of renal corpuscles, was observed in the ARG-fed group while correlation analysis
showed that urea correlated positively (r = 0.01) with creatinine, albumin and
creatinine clearance, but negatively (r = 0.01) with Albumin: Creatinine ratio.
The study suggests that L-arginine ingestion could improve these renal function
markers and perhaps, metabolic syndrome related to kidney dysfunction, in female
Wistar rats. The effect could be concerted and significant as indicated by the
histomorpholgy and correlation results. Thus, with the abundance of ARG in nuts,
including walnut, cashew nut, ground nut and even coconut, the implication of
this study in the prevention and management of MES in, especially female, animals
is noteworthy hence, deserve follow up, probably in humans.
Received: November 11, 2011;
Accepted: February 16, 2012;
Published: October 04, 2012
Metabolic syndrome (MES) is a cluster of cardiovascular risk factors that is
characterized by obesity, atherogenic dyslipidemia, insulin resistance and hypertension
(Gallagher et al., 2010; Mahajan
et al., 2010). It is not a disease entity, but a cluster of medical
disorders in an individual that could predispose animals to further health challenges.
These include type 2 diabetes mellitus (Azhar, 2010),
cancer (Siddiqui, 2011; Rosato et
al., 2011; Capasso et al., 2011), obstructive
sleep apnea (Mugnai, 2010) and Kidney damage (Mathur,
2010). Globally, the prevalence of MES has increased dramatically (Bakoma
et al., 2011) with possible huge economic implications.
In particular, the kidney is vital in the maintenance of homeostasis through
excretion of catabolites, including urea and creatinine (Uboh
et al., 2011; Atangwho et al., 2007)
and elevated concentration of these catabolites in the plasma or serum indicates
compromised renal function (Appel et al., 2003;
Zanna et al., 2008) and possibly incidence of
MES. Furthermore, the association of a significant reduction in NO with the
pathophysiology of MES (Garlichs et al., 2000)
suggested that L-arginine (ARG), a major precursor in the synthesis of NO (Ezeanyika
and Egbuonu, 2011), may improve MES in animals.
Nitric oxide, NO, is a vasodilator molecule that plays an important role in
the regulation of cardiovascular function (McGrowder and
Brown, 2007). Lokhande et al. (2006) reported
that abnormal concentration of NO could lead to pathological conditions, including
hypertension and diabetes. A decrease in ARG availability resulted in the reduction
of the biological activity of NO (Harisa, 2011) and
in the conversion of NO into peroxynitrites that could mediate cell damage (Subratty
et al., 2007). However, ARG supplementation resulted in the decrease
of the atherogenic index in hypercholesterolaemic rats (Harisa,
2011) and weight loss in experimental animal (Sepehri
et al., 2006), suggesting possible benefit of ARG supplementation
on MES since increase in weight and atherogenic index are major features of
MES (Gallagher et al., 2010).
Thus, the present study aimed to ascertain the effect of ARG on markers of
MES related to kidney damage through the specific objectives of studying the
effect of ARG on the concentration of urea, creatinine and albumin as well as
creatinine clearance, Albumin:creatinine ratio and histomorphology of the kidney,
using female rats as model. The choice of female rats in this study derived
from report that the female gender is an independent risk factor for incidence
of MES (Ravikiran et al., 2010) and that the
prevalence of MES is higher in the females (Mangat et al.,
2010; Kilic et al., 2010; Titty
et al., 2008) where it could result to polycystic ovary syndrome
(Mathur, 2010) that worsens infertility. ARG is abundant
in nuts, including walnut, cashew nut, groundnut and even coconut, thus possible
benefit of ARG on MES may be easily harnessed in dietary food choice and nutraceutical
formulation for the prevention and management of MES in animals.
MATERIALS AND METHODS
Chemicals: The chemicals used in this study were of analytical grade and
were products of reputable companies based in Europe and America.
Concentration determination/justification: The test concentration, ARG
(60 mg kg-1 b.wt.) was calculated and adjusted based on the WHO reported
daily ARG oral intake (Marshal, 1994) and the concentration
used in earlier studies (Alexander et al., 2004;
Egbuonu et al., 2010a-c).
Animals and treatment: Procurement of female weanling Wistar rats used in
this study was from the animal house of the Faculty of Biological Sciences University
of Nigeria, Nsukka. The rats weighed 60-80 g. The animal study was according
to International guidelines for the care and use of laboratory animals in Biomedical
Research (World Medical Association, American Physiological
Society, 2002). The animal study was carried out between August/September,
The rats acclimatized for a week and immediately thereafter were randomized
into two groups (based on their body weight) with sample size of eight rats
each. Group B rats were exposed to ARG (60 mg kg-1 b.wt.) whereas
Group A rats were given Distilled Water (DW) (3 mg kg-1 b.wt.), corresponding
to the volume of vehicle. Exposure route was by oral intubation, which was consecutive
for 28 days.
The rats, housed in a well-ventilated stainless steel cages at room temperature
(28±2°C) and tropical humid condition, were maintained under standard
natural illumination of twelve hours of light alternating with twelve hours
of darkness (i.e., a normal daylight/dark cycle). In compliance with the ethical
guidelines for treating laboratory animals, the rats were allowed unrestricted
access to tap water and standard rat chow (Grand Cereals and Oil Mills Limited,
Jos, Nigeria) for the experimental period.
Sample collection and preparation: The animals were fasted overnight
before sacrifice after 28 days. Collection of the respective blood samples of
animals was by ophthalmic venous plexus or retro orbital sinus venipuncture.
This involved inserting a sterile capillary tube into the medial canthus of
the eye of the rat to puncture the retro-bulbar plexus resulting in out flow
of blood into clean non-anticoagulated glass tube for serum tests.
Centrifugation of clotted blood at 3000 rpm for 10 minutes yielded the serum.
Thereafter, the serum (aspirated separately into stoppered polystyrene tubes)
was stored in a deep freezer for subsequent use in determining the selected
biochemical markers of metabolic syndrome. Kidney specimen promptly excised
from the sacrificed rats for histology were fixed in 10% formaldehyde buffered
saline (formal saline) until used.
Creatinine clearance: Creatinine clearance was calculated using Cockroft
formula (Demirovic et al., 2009; Hjelmesaeth
et al., 2010), but with adjustment for size and assumption of uniform
Serum urea concentration: The determination of serum urea concentration
was by the method of Alexander and Grifith (1992). In
this method, conversion of ammonia (obtained from the hydrolysis of urea to
ammonia and carbon dioxide in a reaction catalyzed by urease) in the presence
of sodium nitroferricyanide-phenol and hypochlorite reagents yields indophenol
blue that was measured colorimetrically at 625 nm.
Serum creatinine concentration: The determination of serum creatinine
concentration was by the method of Wilding and Kennedy (1977)
based on the Jaffe alkaline picrate reaction that forms reddish alkaline solution
of sodium picrate that was measured colorimetrically at 500 nm.
Serum albumin concentration: This was estimated by the Bromocresol green
(BCG) method as described by Ochei and Kolhatkar (2008).
This method is based on the principle that under acidic conditions, serum albumin
binds specifically with bromocresol green to form a green coloured complex that
was measured colorimetriclly at 640 nm.
Calculation of the diagnostic ratio: The diagnostic ratio (albumin:
Creatinine ratio) were calculated from the corresponding parameters obtained
in this study.
Organ histology: Organ specimen (kidney) promptly excised from the sacrificed
rats for histological examination were fixed in 10% formaldehyde buffered saline
(formal saline) until used as reported (Egbuonu et al.,
2010c). In brief, after dehydration (in graded levels (70-100%) of alcohol),
clearing (in xylene impregnated with paraffin wax) and sectioning (at 5 microns
thickness using rotary microtome) the sections were floated on a water bath
maintained at a temperature of 2-3°C below melting point of the paraffin
wax. Thereafter, drying of the sections was performed on a hot plate maintained
at a temperature of 2-3°C above the melting point of the paraffin followed
by staining and mounting of the sections using haematoxylin and eosin.
Statistical analysis: Analysis of data to determine the significant
differences in means was by Students
t-test, using the Statistical Package for the Social Sciences (SPSS) for Windows
version 16.0 (SPSS Inc., Chicago, IL, USA). Results were expressed as mean and
standard deviation (Mean±SD) of eight rats per group at significance
levels of p<0.01. Furthermore, correlation of the results for possible association
among the studied parameters was by Pearsons
bivariate method (r = 0.01).
Serum urea concentration: The results of this study on serum urea concentration
as presented in Fig. 1 show that serum urea concentration
decreased in rats treated with ARG (6.34±0.23 mg/100 mL) when compared
with the control (10.52±0.60 mg/100 mL). The observation (representing
a decrease of 39.73% in ARG-treated group) was statistically significant (p<0.01).
Serum creatinine concentration: When compared with the control (9.07±0.44
mg/100 mL), the serum creatinine concentration was significantly (p<0.01)
reduced in ARG-treated group (4.41±0.50 mg/100 mL) (Fig.
2). The present observation shows a decrease of 51.38% in the ARG-treated
group relative to the control.
Creatinine clearance: The results of the present study as presented
in Fig. 3 reveal that the creatinine clearance decreased in
rats exposed to ARG (1.78±0.27 mL min-1) in contrast with
the control (3.73±0.23 mL min-1). The observed reduction in
creatinine clearance (representing a decrease of 52.28% relative to the control)
was statistically significant (p<0.01).
|| Effect of DW and ARG on serum urea concentration of rats
|| Effect of DW and ARG on serum creatinine concentration of
|| Influence of DW and ARG on calculated creatinine clearance
|| Effect of DW and ARG on serum albumin concentration of rats
Serum albumin concentration: The results of this study as presented
in Fig. 4 show that exposing rats to ARG elicited a significant
(p<0.01) reduction (14.30±0.15 mg 100 mL) in serum albumin concentration
in comparison with control (16.21±1.30 mg 10/mL).
|| Effect of DW and ARG on serum albumin:creatinine ratio of
||Kidney section of untreated (Group A) rats showing striated
ducts (arrow heads) devoid of renal corpuscles. H and E stains, x400
This represents a decrease of 11.78% in the ARG-treated rats relative to the
Serum albumin:creatinine ratio: The results of the present study as
shown in Fig. 5 reveal that the serum albumin:creatinine ratio
of the ARG-treated rats (3.27±0.32) increased (p<0.01) above that
of the control rats (1.78±0.14). This represents an increase of 83.71%
in the ARG-treated group relative to the control.
Histomorphology of the kidney: Kidney sections of the control (Group
A) rats showed striated ducts devoid of renal corpuscles (Fig.
6). Rats treated with ARG (Group B) showed improved kidney histology as
indicated by lots of renal corpuscles and devoid of striated ducts (Fig.
||Kidney section of rats treated with high ARG (Group A) showing
lots of renal corpuscles (arrow heads) devoid of striated ducts. H and E
|| Pearson two-tailed correlation analysis of urea, creatinine,
creatinine clearance, albumin and albumin:creatinine ratio
|**, *Correlation is significant at the 0.01 and at 0.05 level,
Correlation analysis: The results of Pearsons
correlations analysis (Table 1) revealed that urea correlated
positively (r = 0.01) with creatinine, albumin and creatinine clearance, but
negatively (r = 0.01) with Albumin:creatinine ratio.
Female gender is an independent risk factor for the development of Metabolic
Syndrome (MES) (Mangat et al., 2010; Kilic
et al., 2010) a cluster of features indicating metabolic disorders
that is associated with kidney damage, insulin resistance and a significant
reduction in Nitric Oxide (NO), a major metabolite of L-arginine (ARG) (Garlichs
et al., 2000). This study aimed to ascertain the effect of ARG on
selected markers of MES related to kidney damage in female Wistar albino rats.
The kidney is vital in the maintenance of homeostasis, including blood pH, water
and electrolyte balance, through excretion of catabolites, including urea and
creatinine (Uboh et al., 2011) after ultrafiltration
and reabsorption of desirable elements in the filtrate via urine (Ochei
and Kolhatkar, 2008). Thus, elevated concentration of these catabolites
in the plasma or serum indicates compromised renal function (Appel
et al., 2003; Zanna et al., 2008;
Ochei and Kolhatkar, 2008), enhanced oxidative stress
in animals (DApolito et al., 2010), hence,
could indicate presence of physiological dysfunction in animals, including incidence
Generally, the decrease in the concentration of urea and creatinine observed
with ARG ingestion by the rats suggest benefit on the renal function and possibly
MES (Ochei and Kolhatkar, 2008). Urea and creatinine are
products of protein catabolism eliminated via urine and their decrease
in serum as observed in this study indicated efficient elimination probably
by efficient renal organ and function. Thus, MES related to kidney damage may
be improved in rats exposed to ARG. Consistent with these results, exposing
the rats to ARG decreased albumin concentration in the rats serum, indicating
absence of renal and cardiovascular diseases as suggested by Cerasola
et al. (2009).
Exposing the rats to ARG decreased (p<0.01) the creatinine clearance of
the rats, suggesting a decrease in muscle mass (Ochei and
Kolhatkar, 2008) that could improve MES in the rats. On the other hand,
ARG ingestion by the rats caused an increase (p<0.01) in the serum albumin:
Creatinine ratio, indicating macroalbuminuria (large amount of albumin in urine),
slight kidney dysfunction (Khan, 2010) and insulin resistance
(Nitta, 2010). The apparent adverse influence of ARG on
this parameter (Albumin:creatinine ratio) of renal function is attributable
to multiple catabolic pathways of ARG (Schriek et al.,
2007). On the other hand, it may be due to the possibly unrealistic value
of creatinine clearance, which was not determined by gold standard method, but
calculated using Cockroft formula (Demirovic et al.,
2009; Hjelmesaeth et al., 2010) and with adjustment
for size and assumption of uniform age. This is a noted limitation of this study.
However, Albumin:creatinine ratio correlated negatively (r = 0.01) with the
other markers of renal function (Table 1), suggesting that
its contribution to renal dysfunction in the rats may be negligible.
Histomorphological alterations in organs were the most consistent treatment-related
changes and in concert with the serum chemistry results may give a clear picture
of physiological function in animals (Egbuonu et al.,
2010c). Agent-induced physiological and biochemical disturbances (Adeniran
et al., 2006), as well as alterations in liver and kidney histology
(Farrag and Shalby, 2007; Egbuonu
et al., 2010c) have been reported. In particular, the observed changes
in the histomorphology of the kidney sections of rats showed improvement in
the ARG-fed rats, seemingly supporting the serum chemistry results of this study.
Furthermore, Pearsons correlation analysis indicated that urea correlated
positively (r = 0.01) with creatinine, albumin and creatinine clearance but
negatively (r = 0.01) with Albumin: Creatinine ratio, suggesting concerted ARG-induced
benefit on the renal function and possibly on MES related to renal dysfunction
in the female rats.
In conclusion, the study suggests that L-arginine ingestion could improve these
renal function markers and perhaps, metabolic syndrome related to kidney dysfunction,
in female Wistar rats. This could be concerted and significant as indicated
by the histomorpholgy and correlation results. Thus, with the abundance of ARG
in nuts, including walnut, cashew nut, ground nut and even coconut, the implication
of this study in the prevention and management of MES in, especially female,
animals is noteworthy hence deserve follow up, probably in humans.
Strength and limitation: The validity of this study is strengthened
by the strict adherence to ethics in animal studies and to standard methods.
In terms of weakness, creatinine clearance was calculated rather than determined
by gold standard method, hence its value (and that of Albumin:creatinine ratio)
in this study may not be realistic.
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