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The kidney is an important organ in the maintenance of body homeostasis. Dietary compounds, reactive metabolites, obesity, and metabolic syndrome (MetS) can affect renal filtration and whole body homeostasis, increasing the risk of chronic kidney disease (CKD) development. Gamma oryzanol ( γ Oz) is a compound with antioxidant and anti-inflammatory activity that has shown a positive action in the treatment of obesity and metabolic diseases. Aim . To evaluate the effect of γ Oz to recover renal function in obese animals by high sugar-fat diet by modulation of adiponectin receptor 2/PPAR- α axis Methods . Male Wistar rats were initially randomly divided into 2 experimental groups: control and high sugar-fat diet (HSF) for 20 weeks. When proteinuria was detected, HSF animals were allocated to receive γ Oz or maintain HSF for more than 10 weeks. The following were analyzed: nutritional and biochemical parameters, systolic blood pressure, and renal function. In the kidney, the following were evaluated: inflammation, oxidative stress, and protein expression by Western blot. Results . After 10 weeks of γ Oz treatment, γ Oz was effective to improve inflammation, increase antioxidant enzyme activities, increase the protein expression of adiponectin receptor 2 and PPAR- α , and recover renal function. Conclusion . These results permit us to confirm that γ Oz is able to modulate PPAR- α expression, inflammation, and oxidative stress pathways improving obesity-induced renal disease.
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Research Article
Gamma Oryzanol Treats Obesity-Induced Kidney Injuries by
Modulating the Adiponectin Receptor 2/PPAR-αAxis
Fabiane Valentini Francisqueti ,
1
Artur Junio Togneri Ferron,
1
Fabiana Kurokawa Hasimoto,
2
Pedro Henrique Rizzi Alves,
2
Jéssica Leite Garcia,
1
Klinsmann Carolo dos Santos ,
1
Fernando Moreto,
1
Vanessa dos Santos Silva ,
1
Ana Lúcia A. Ferreira,
1
Igor Otávio Minatel,
2
and Camila Renata Corrêa
1
1
Medical School, São Paulo State University (UNESP), Botucatu, SP, Brazil
2
Institute of Biosciences, São Paulo State University (UNESP), Botucatu, SP, Brazil
Correspondence should be addressed to Fabiane Valentini Francisqueti; fabiane_vf@yahoo.com.br
Received 17 May 2018; Accepted 22 July 2018; Published 9 September 2018
Academic Editor: Germán Gil
Copyright © 2018 Fabiane Valentini Francisqueti et al. This is an open access article distributed under the Creative Commons
Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work
is properly cited.
The kidney is an important organ in the maintenance of body homeostasis. Dietary compounds, reactive metabolites, obesity, and
metabolic syndrome (MetS) can aect renal ltration and whole body homeostasis, increasing the risk of chronic kidney disease
(CKD) development. Gamma oryzanol (γOz) is a compound with antioxidant and anti-inammatory activity that has shown a
positive action in the treatment of obesity and metabolic diseases. Aim. To evaluate the eect of γOz to recover renal function in
obese animals by high sugar-fat diet by modulation of adiponectin receptor 2/PPAR-αaxis Methods. Male Wistar rats were
initially randomly divided into 2 experimental groups: control and high sugar-fat diet (HSF) for 20 weeks. When proteinuria
was detected, HSF animals were allocated to receive γOz or maintain HSF for more than 10 weeks. The following were analyzed:
nutritional and biochemical parameters, systolic blood pressure, and renal function. In the kidney, the following were evaluated:
inammation, oxidative stress, and protein expression by Western blot. Results. After 10 weeks of γOz treatment, γOz was
eective to improve inammation, increase antioxidant enzyme activities, increase the protein expression of adiponectin
receptor 2 and PPAR-α, and recover renal function. Conclusion. These results permit us to conrm that γOz is able to modulate
PPAR-αexpression, inammation, and oxidative stress pathways improving obesity-induced renal disease.
1. Introduction
Kidneys exert a central role in the maintenance of body
homeostasis by regulating electrolyte concentrations, blood
pressure, degradation of hormones, lipid metabolism, and
excretion of waste metabolites [1]. Despite many factors
leading to kidney disease, such as age, gender, smoking
status, alcohol use, physical inactivity, diabetes mellitus,
and hypertension, studies reveal that obesity is an inde-
pendent risk factor for development of CKD [13].
The pathways activated by obesity to induce kidney
disease are not fully understood. Studies have identied
several new injurious pathways in the kidney led by insulin
resistance (IR), chronic inammation (a major contributor
to microvascular remodeling), dyslipidemia and excessive
nutrient availability (both may induce mitochondrial dys-
function and oxidative stress), and adipokine production
unbalance [46].
Adiponectin is an adipocyte-derived protein hormone
which plays a role in the suppression of inammation-
associated metabolic disorders. Adiponectin receptor 1
(Adipo-R1) and adiponectin receptor 2 (Adipo-R2) are the
two major receptors for adiponectin and appear to be integral
membrane proteins [7], expressed in dierent tissues, among
them the kidney [8]. Kadowaki et al. [7] reported previously
that the receptor expression levels are reduced in obesity,
apparently in correlation with reduced adiponectin sensitiv-
ity. Moreover, the authors relate that Adipo-R1 may be more
Hindawi
Oxidative Medicine and Cellular Longevity
Volume 2018, Article ID 1278392, 9 pages
https://doi.org/10.1155/2018/1278392
tightly linked to activation of AMPK pathways, whereas
Adipo-R2 seems to be associated with the activation of
PPAR-αpathways and the inhibition of inammation. So,
the modulation of these pathways could be important to treat
renal injuries.
Considering this situation, natural compounds have
received attention as a promising pool of substances to treat
diseases [9]. Rice bran is rich in gamma oryzanol (γOz), a
natural compound with antioxidant and anti-inammatory
activities that showed a positive action in the treatment of
hyperlipidemia, hyperglycemia, insulin resistance, and
increased levels of adiponectin [1014]. So, considering that
obesity, inammation, and oxidative stress are able to induce
renal disease and there are no studies that evaluate the eect
of γOz in renal disease, the aim of this study was to evaluate
the eect of γOz in the recovery of renal function in obese
animals by high sugar-fat diet by modulation of the adipo-
nectin receptor 2/PPAR-αaxis.
2. Methods
2.1. Experimental Protocol. All of the experiments and proce-
dures were approved by the Animal Ethics Committee of
Botucatu Medical School (1150/2015) and were performed
in accordance with the National Institute of Healths Guide
for the Care and Use of Laboratory Animals. Male Wistar
rats (±187 g) were kept in an environmental controlled
room (22
°
C±3
°
C, 12 h light-dark cycle, and relative humid-
ity of 60 ±5%) and initially randomly divided into 2 experi-
mental groups (control, n=15, and high sugar-fat diet
(HSF), n=30) for 20 weeks. HSF groups also received
water + sucrose (25%). The diets and water were provided
ad libitum. The HSF diet contained soybean meal, sorghum,
soybean peel, dextrin, sucrose, fructose, lard, vitamins, and
minerals, plus 25% sucrose in drinking water; the control diet
contained soybean meal, sorghum, soybean peel, dextrin, soy
oil, vitamins, and minerals. The nutrients and nutritional
composition of each diet was described in our previous study
[15]. At week 20 of this study, when proteinuria was detected
in the HSF groups, animals were divided to begin the treat-
ment with γOz or continue receiving HSF for 10 more weeks
as described below.
2.2. Group Characterization. After 20 weeks of experimental
protocol, a 95% condence interval (CI) was built for the
protein/creatinine ratio from the HSF and control groups
and was adopted as the separation point (SP) between the
groups, the midpoint between the upper limit of the control
group and the lower limit of the HSF group. The protein/cre-
atinine ratio was adopted since it reects proteinuria and is
considered a marker of kidney function [16]. From this point,
the control animals with a protein/creatinine ratio above of
SP and the HSF animals with a protein/creatinine ratio below
the SP were excluded from the control and HSF groups,
respectively, ensuring the homogeneity of the treated and
control groups. About the remaining animals in the HSF
group, they were randomly divided to receive γOz or only
diet. This criterion was adopted because animals submitted
to dierent diet models do not always present the expected
response. This fact can lead to erroneous animal classica-
tion and, consequently, false conclusions. The values for pro-
tein/creatinine ratio on the 20th week were 2.5 for the control
group and 3.3 for the HSF group (p=0 0006).
2.3. Treatment with Gamma Oryzanol. After the characteri-
zation on the 20th week, the groups were the following: con-
trol diet (control, n=8), high sugar-fat diet (HSF, n=8), and
HSF/HSF + gamma oryzanol (HSF/HSF + γOz, n=8). The
treatment duration was 10 weeks, totaling 30 weeks of exper-
iment. The γOz dose used in this study was added in the
chow (0.5 w/w) according to our previous study [15].
2.4. Body Composition and Caloric Ingestion. The nutritional
prole was evaluated according to the following parameters:
caloric intake, body weight, and adiposity index. Caloric
intake was determined by multiplying the energy value of
each diet (g ×kcal) by the daily food consumption. For the
HSF group, caloric intake also included calories from water
(0.25 ×4×mL consumed). Body weight was measured
weekly. After euthanasia, fat deposits (visceral (VAT), epi-
didymal (EAT), and retroperitoneal (RAT)) were used to cal-
culate the adiposity index (AI) by the following formula:
VAT + EAT + RAT /FBW × 100.
2.5. Metabolic and Hormonal Analysis. After 12 h fasting,
blood was collected and the plasma was used to measure
insulin and biochemical parameters. Glucose concentration
was determined by using a glucometer (Accu-Chek Per-
forma, Roche Diagnostics Brazil Limited); triglycerides
were measured with an automatic enzymatic analyzer system
(Chemistry Analyzer BS-200, Mindray Medical International
Limited, Shenzhen, China). The insulin and adiponectin
levels were measured using enzyme-linked immunosorbent
assay (ELISA) methods using commercial kits (EMD Milli-
pore Corporation, Billerica, MA, USA). The homeostatic
model of insulin resistance (HOMA-IR) was used as an
insulin resistance index, calculated according to the follow-
ing formula: HOMA-IR = (fasting glucose (mmol/L) ×fast-
ing insulin (μU/mL))/22.5.
2.6. Systolic Blood Pressure. Systolic blood pressure (SBP)
evaluation was assessed in conscious rats by the noninvasive
tail-cumethod with a Narco Bio-Systems® electrosphygmo-
manometer (International Biomedical, Austin, TX, USA).
The animals were kept in a wooden box (50 ×40 cm) between
38 and 40
°
C for 4-5 minutes to stimulate arterial vasodilation
[17]. After this procedure, a cuwith a pneumatic pulse sen-
sor was attached to the tail of each animal. The cuwas
inated to 200 mmHg pressure and subsequently deated.
The blood pressure values were recorded on a Gould RS
3200 polygraph (Gould Instrumental Valley View, Ohio,
USA). The average of three pressure readings was recorded
for each animal.
2.7. Renal Function. Renal function was evaluated by mea-
surements of plasma and urine. At twenty-four hours,
urine was collected from the metabolic cages to measure
the excretion of creatinine and the total protein. The urea
and creatinine content of the plasma were measured. All
2 Oxidative Medicine and Cellular Longevity
analyses were performed with an automatic enzymatic
analyzer system (biochemical analyzer BS-200, Mindray,
China). The glomerular ltration rate (GFR = (urine crea-
tinine ×ux)/plasma creatinine) and proteinuria were also
calculated.
2.8. Renal Tissue Analysis
2.8.1. Inammatory Parameters. Renal tissue (±150 mg) was
homogenized (ULTRA-TURRAX® T 25 basic IKA® Werke,
Staufen, Germany) in 1.0 mL of phosphate-buered saline
70
80
90
100
110
120
Calories/day
(kcal/d)
HSFControl HSF/HSF + Oz
(a)
0
5
10
15
Adiposity index (%)
Control HSF/HSF + Oz
HSF
(b)
0
50
100
150
Glucose (mg/dl)
HSF/HSF + Oz
HSFControl
(c)
0
20
40
60
80
HOMA-IR
HSF HSF/HSF + Oz
Control
(d)
0
50
100
150
Triglycerides (mg/dL)
Control HSF/HSF + Oz
HSF
(e)
100
120
140
160
180
Systolic blood pressure
(mmHg)
HSF HSF/HSF + Oz
Control
(f)
Figure 1: Nutritional, metabolic, and cardiovascular parameters: (a) caloric intake (kcal/day); (b) adiposity index (%); (c) glucose (mg/dL);
(d) HOMA-IR; (e) triglycerides (mg/dL); (f ) systolic blood pressure (mmHg). Data expressed in mean ±standard deviation or median.
Comparison by one-way ANOVA with Tukey post hoc. HSF: high sugar-fat diet; γOz: gamma oryzanol. indicates p<005;n=8
animals/group.
3Oxidative Medicine and Cellular Longevity
(PBS) pH 7.4 cold solution and centrifuged at 800gat 4
°
C for
10 min. The supernatant (100 μL) was used in analysis.
Tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6),
and monocyte chemoattractant protein-1 (MCP-1) levels
were measured using the enzyme-linked immunosorbent
assay (ELISA) method using commercial kits from R&D
System, Minneapolis, USA. The supernatant (100 μL)
was used for analysis, and the results were corrected by the
protein amount.
2.8.2. Hydrophilic Antioxidant Capacity. The hydrophilic
antioxidant capacity in the kidney was in the prepared
supernatant as described in the previous item. It was
determined uorometrically, using a VICTOR X2 reader
(PerkinElmer, Boston, MA). The antioxidant activity was
quantitated by comparing the area under the curve relating
to the oxidation kinetics of the suspension phosphatidylcho-
line (PC), which was used as the reference biological matrix.
The peroxyl radical 2,2-azobis-(2-amidinopropane) dihy-
drochloride (AAPH) was used as an initiator of the reaction.
The results represent the percent inhibition (4,4-diuoro-5-
(4-phenyl 1-3 butadiene)-4-bora-3,4-diaza-s-indacene)
(BODIPY) 581/591 plasma with respect to the control
sample of BODIPY 581/591 PC liposome. All analyses were
performed in triplicate. The results are reported as a percent-
age of protection [18].
2.8.3. Antioxidant Enzyme Activity. For these analyses, a
100 mg kidney was homogenized (1 : 10 v/v)inKH
2
PO
4
(10 mmol/L)/KCl (120 mmol/L), pH 7.4, and centrifuged at
2.000 ×g for 20 min. Superoxide dismutase (SOD) activity
was measured based on the inhibition of a superoxide radical
reaction with pyrogallol, and the absorbance values were
measured at 420 nm [19]. Catalase activity was evaluated by
following the decrease in the levels of hydrogen peroxide in
240 nm [20]. The activity is expressed as pmol of H
2
O
2
reduced/min/mg protein. Glutathione peroxidase (GP)
activity was measured by following β-nicotinamide ade-
nine dinucleotide phosphate (NADPH) oxidation at 340 nm
as described by Flohé and Günzler [21]. The results were
expressed as μmol hydroperoxide-reduced/min/mg protein.
Protein was quantied based on Lowry et al.s method [22]
using bovine serum albumin as the standard. The absor-
bance values for all analyses were measured in a UV/VIS spec-
trophotometer (Pharmacia Biotech, Houston, Texas, USA),
and the values are expressed as units per milligram of protein.
0
20
40
60
80
100
Plasma urea (mg/dL)
HSFControl HSF/HSF + Oz
(a)
HSFControl HSF/HSF + Oz
0.0
0.2
0.4
0.6
0.8
Plasma creatinin
(mg/dL)
(b)
⁎⁎
0
1
2
3
4
Glomerular ltration rate (GFR)
(mL/min)
HSF/HSF + Oz
HSFControl
(c)
⁎⁎
HSFControl HSF/HSF + Oz
0
1
2
3
4
5
Protein/creatinine ratio
(d)
Figure 2: Renal function parameters: (a) plasma urea (mg/dL); (b) plasma creatinine (mg/dL); (c) glomerular ltration rate (GFR) (mL/min);
(d) protein/creatinine ratio. Data expressed in mean ±standard deviation or median. Comparison by one-way ANOVA with Tukey post hoc.
indicates p<005;n=8 animals/group.
4 Oxidative Medicine and Cellular Longevity
2.8.4. Western Blot. Renal samples were homogenized in
RIPA buer with a protease and phosphatase cocktail inhib-
itor. After determination of protein concentration by the
Bradford method [23], samples were diluted in Laemmli
buer and loaded (50 μg of protein) into a 10% SDSpoly-
acrylamide gel. Transfer to a nitrocellulose membrane was
carried out using Trans-Blot Turbo-Transfer System
(BioRad). Incubation with the primary antibodies was per-
formed overnight at 4
°
C in Tris-buered saline solution con-
taining Tween 20 (TBS-T) and 3% bovine serum albumin.
Antibody dilutions were 1 : 1000 for Adipo-R1 (ABCAM
ab126611), 1 : 1000 for Adipo-R2 (ABCAM ab77612),
1 : 500 for PPAR-α(ABCAM ab8934), 1 : 1000 for total
AMPK (Cell Signaling #2532), 1 : 1000 for phospho-AMPH
(Thr172) (Cell Signaling #2531), and 1 : 1000 for beta-actin
(ABCAM ab8227). After incubation overnight at 4
°
Cin
TBS-T containing 1% nonfat dried milk with the Abcam
secondary antibodies (dilution 1 : 3000 for anti-goat and
1 : 1000 for anti-rabbit). Protein was revealed using the
chemiluminescence method according to the manufacturers
instructions (ECL SuperSignal® West Pico Chemilumines-
cent Substrate, Thermo Scientic). Band intensities were
evaluated using ImageQuant TL 1D Version 8.1 (GE Health-
care Life Sciences).
2.9. Statistical Analysis. Data are presented as means ±stan-
dard deviation (SD) or median (interquartile range). Dier-
ences among the groups were determined by one-way
analysis of variance. Statistically signicant variables were
subjected to the Tukey post hoc test to compare all the
groups. Statistical analyses were performed using Sigma
Stat for Windows Version 3.5 (Systat Software Inc., San
Jose, CA, USA). A pvalue of 0.05 was considered statisti-
cally signicant.
3. Results
Figure 1 shows caloric intake, adiposity index, and cardio-
metabolic risk factors for kidney disease (glucose, HOMA-
IR, triglycerides, and systolic blood pressure). It is possible
to verify that both HSF groups presented higher values for
all the parameters. There was no dierence for caloric intake.
Figure 2 shows renal function parameters. Gamma oryza-
nol was eective for recovery of renal function of the HSF/
HSF + γOz group, characterized by lower proteinuria and
high glomerular ltration rate compared to the HSF group.
Figure 3 shows inammatory parameters in kidney tis-
sue. γOz was eective to reduce the inammatory response
for levels similar to those observed in the control group.
HSFControl HSF/HSF + Oz
0
200
400
600
Renal TNF-
(pg/gprotein)
(a)
⁎⁎
HSFControl HSF/HSF + Oz
0
500
1000
1500
2000
2500
Renal IL-6
(pg/gprotein)
(b)
0
50
100
150
200
Renal MCP-1
(pg/gprotein)
HSFControl HSF/HSF + Oz
(c)
Figure 3: Inammatory parameters in kidney tissue: (a) tumor necrosis factor-alpha (TNF-α; pg/g protein); (b) interleukin-6 (IL-6; pg/g
protein); (c) monocyte chemoattractant protein-1 (MCP-1; pg/g protein). Data expressed in mean ±standard deviation or median.
Comparison by one-way ANOVA with Tukey post hoc. indicates p<005;n=8 animals/group.
5Oxidative Medicine and Cellular Longevity
Figure 4 shows redox state parameters in the kidney. It
is possible to verify a positive action of γOz on the HSF/
HSF + γOz group to increase hydrophilic antioxidant protec-
tion, catalase, and superoxide dismutase levels compared
to HSF.
Figure 5 presents plasma adiponectin levels. The HSF
group presented higher levels while the treatment with
gamma oryzanol was able to reduce the levels.
Figure 6 shows protein expression of Adipo-R1, Adipo-
R2, phosphorylated and total AMPK, and PPAR-αin the kid-
ney. It is possible to note the eect of γOz which increased
the expression of Adipo-R2 and PPAR-αwhen compared
to HSF.
4. Discussion
The aim of this study was to evaluate the potential of γOz to
recover renal function in obese animals by high sugar-fat
diet consumption. In this study, the animals feeding on a
HSF diet developed obesity and signals of kidney injury,
characterized by proteinuria and decreased glomerular
ltration rate. Obesity, insulin resistance, hypertension,
chronic inammation, dyslipidemia, and oxidative stress are
considered the major risk factors for renal disease [1, 4, 6].
The HSF group developed all these risk factors, which were
expected considering the diet used in this study, rich in sugar
and fat [15], but the noneect of γOz on these parameters
was observed. In opposition to our results, Wang et al. and
⁎⁎
0
20
40
60
0
8
Hydrophilic antioxidant capacity
(% protection/g protein)
HSF HSF/HSF + Oz
Control
(a)
⁎⁎
0
2
4
6
Catalase
(pmol/mg protein/min)
HSF HSF/HSF + Oz
Control
(b)
5
6
7
8
9
10
Glutathione peroxidase
(mol/mg protein/min)
HSF HSF/HSF + Oz
Control
(c)
⁎⁎
0
2
4
6
8
Superoxide dismutase
(U/mg protein/min)
HSF HSF/HSF + Oz
Control
(d)
Figure 4: Redox state parameters in the kidney: (a) hydrophilic antioxidant capacity (% protection/g protein); (b) catalase (pmol/mg protein/
min); (c) glutathione peroxidase (μmol/mg protein/min); (d) superoxide dismutase (U/mg protein/min). Data expressed in mean ±standard
deviation. Comparison by one-way ANOVA with Tukey post hoc. indicates p<005;n=6animals/group.
⁎⁎
0
10,000
20,000
30,000
40,000
Plasma adiponectin (ng/ml)
HSFControl HSF/HSF + Oz
Figure 5: Plasma adiponectin levels (ng/mL). Data expressed in
mean ±standard deviation. Comparison by one-way ANOVA with
Tukey post hoc. indicates p<005;n=8animals/group.
6 Oxidative Medicine and Cellular Longevity
Justo et al. found in their studies improvement in some param-
eters after treatment with γOz [10, 24]. It is important to
emphasize that in these studies, animal models and the
dose of γOz were dierent from ours, which can explain
these opposite results.
Once metabolic disorders are risk factors for renal dis-
ease, it would be expected that both HSF groups presented
renal function impairment. However, analyzing the clinical
signals of renal disease (proteinuria, most conveniently per-
formed by estimation of the protein/creatinine ratio and glo-
merular ltration rate) [25], we can note an improvement in
the treatment group with γOz characterized by lower pro-
teinuria and higher GFR. Therefore, better understanding
of the mechanisms by which γOz acted in this group is very
important to enable novel therapeutic target development.
Oxidative stress is one condition associated with
impaired renal function [8, 26]. Kidney disease progression
is related with a signicant increase of ROS, which inuences
cell function and damages proteins, lipids, and nucleic acids,
and can also inhibit enzymatic activities of the cellular respi-
ratory chairs. On the other hand, endogenous enzymatic and
nonenzymatic antioxidant mechanisms protect against dam-
aging eects of oxidative products [27]. The rst line of enzy-
matic antioxidant defense is SOD, which accelerates the
dismutation rate of oxygen to H
2
O
2
, but the catalase reduces
H
2
O
2
to water. Glutathione peroxidase reduces H
2
O
2
and
other organic peroxides to water and oxygen and requires
glutathione as a hydrogen donor which is a scavenger for
H
2
O
2
, hydroxyl radicals, and chlorinated oxidants [27]. Usu-
ally, patients suering from renal insuciency have dimin-
ished antioxidant defense when compared to healthy
controls [28]. In the case of this study, the results showed
an increase of antioxidant capacity, SOD, and catalase activ-
ities after treatment with gamma oryzanol, conrming the
potential of the compound to improve the antioxidant
system. But some authors relate diculty in establishing a
pattern of antioxidant status in kidney disease due to assess-
ment by dierent measurement techniques [28]. In this case,
Adipo-R1
-Actin
Control HSF
HSF/HSF
+ Oz
0.5 1.0 1.50.0
Control
HSF
HSF/HSF + Oz
Adipo-R1/-actin
(relative expression)
(a)
Control HSF
Adipo-R2
-Actin
HSF/HSF
+ Oz
123450
Control
HSF
HSF/HSF + Oz
Adipo-R2/
-actin
(relative expression)
(b)
Phospho-
AMPK
Total AMPK
Control HSF HSF/HSF
+ Oz
0.5 1.0 1.50.0
Control
HSF
HSF/HSF + Oz
phospho-AMPK total AMPK
(relative expression)
(c)
PPAR-
-Actin
Control HSF
HSF/HSF
+ Oz
0.5 1.0 1.50.0
Control
HSF
HSF/HSF + Oz
PPAR-
/
-actin
(relative expression)
(d)
Figure 6: Relative protein expression in kidney tissue: (a) Adipo-R1; (b) Adipo-R2; (c) phospho-AMPK; (d) PPAR-α. Data expressed in
mean ±standard deviation. Comparison by one-way ANOVA with Tukey post hoc. indicates p<005;n=6animals/group.
7Oxidative Medicine and Cellular Longevity
information associating various parameters can give a better
representation of a patients current antioxidant status.
The literature reports that the renoprotection can also
be related to some mechanisms involving improvement
of the endothelial dysfunction, reduction of oxidative stress,
and upregulation of endothelial nitric oxide synthase expres-
sion, all eects dependent on adiponectin receptor activation
[29]. In contrast, the dysfunction regulation of adiponectin
and its receptors has been observed in the development of
various diseases, including obesity, insulin resistance, type 1
and type 2 diabetes, and chronic kidney disease [29].
Adiponectin is secreted primarily by adipose tissue and
plays a key role in kidney disease. In obesity, reduced adipo-
nectin levels are also associated with insulin resistance and
cardiovascular disease. However, in conditions of established
chronic kidney disease, adiponectin levels are elevated and
positively predict progression of disease [30, 31]. Corroborat-
ing these ndings, the HSF group presented higher levels of
adiponectin associated with reduced GFR which conrms
kidney disease. In opposition, the HSF group that received
the compound showed reduction in the levels, which can be
explained by the amelioration of glomerular ltration rate
by γOz in these animals, since adiponectin is excreted via
kidney glomerular ltration [32].
Adipo-R1 and Adipo-R2 are expressed in many tissues
[8], but in the specic case of the kidneys, no studies evaluated
the eect of γOz in this pathway and its role on renal function.
The compound showed capacity to upregulate the Adipo-R2/
PPAR-αaxis. PPAR-αis highly expressed in tissues that pos-
sess high mitochondrial and β-oxidation activity, as the kid-
ney. Decreased renal PPAR-αexpression might contribute
to the pathogenesis of kidney injuries [33], whereas its high
expression is associated with metabolic control in the organ
[34]. Moreover, PPAR-αactivation can attenuate or inhibit
several mediators of vascular injury involved in renal damage,
such as lipotoxicity, reactive species oxygen (ROS) genera-
tion, and inammation [34, 35]. Corroborating this informa-
tion, our animals of the HSF/HSF + γOz group did not
present inammation in the kidney, showing lower levels of
TNF-α, IL-6, and MCP-1 compared to the HSF group.
In summary, this study introduces very important nd-
ings since γOz was eective in ameliorating renal dysfunc-
tion by acting on the Adipo-R2/PPAR-αaxis and also by
improving the antioxidant response in the organ. γOz could
be a therapeutic alternative for restoring/ameliorating meta-
bolic dysfunctions, in special renal injuries that are developed
in an obese individual. These results permit us to conrm
that γOz is able to modulate PPAR-αexpression, inamma-
tion, and oxidative stress pathways improving obesity-
induced renal disease.
Data Availability
The data used to support the ndings of this study are
available from the corresponding author upon request.
Conflicts of Interest
The authors declare no conict of interest.
Acknowledgments
This work was supported by Fundação de Amparo à Pesquisa
do Estado de São Paulo (FAPESP) (2015/10626-0 and 2018/
15288-3).
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9Oxidative Medicine and Cellular Longevity
... Gamma-oryzanol (γOz) is a nutraceutical obtained from rice bran oil and composed of a mixture of ferulic acid esters of phytosterols and triterpenoids, cycloartenyl ferulate, 24-methylenecycloartanyl ferulate, and campesteryl ferulate [7]. The positive effects of γOz include antioxidant and anti-inflammatory action, effects on the immune system, and treatment or attenuation of dyslipidemia, diabetes, obesity, and neurological disorders, as demonstrated in preclinical experiments, models, and observations [8][9][10][11]. However, there is a lack of studies about the effects of γOz as a possible modulator of the physiopathological process involved in NAFLD. ...
... Body weight was measured weekly. To estimate animal body fat, the adiposity index (AI) was used and obtained by the formula: [(VAT + EAT + RAT)/FBW] × 100 [10]. ...
... Glycemia was determined in a blood drop using a glucometer (Accu-Chek Performa; Roche Diagnostics Brazil Limited, São Paulo, Brazil). The insulin level was measured using the enzyme-linked immunosorbent assay (ELISA) method (EMD Millipore Corporation, Billerica, MA, USA) and the HOMA-IR was calculated by the following formula: HOMA-IR = (fasting glucose (mmol/L) × fasting insulin (µU/mL))/22.5 [10]. ...
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Nonalcoholic fatty liver disease (NAFLD) is the main cause of liver disease. The physiopathological processes involved in the disease are metabolic syndrome (MetS) components (central obesity, dyslipidemia, insulin resistance/type 2 diabetes, hypertension), genetic, and dietary factors, including unsaturated fats and sweetened beverages, which are able to lead to inflammation and oxidative stress, conditions associated with progression and severity of NAFLD. Gamma-oryzanol (γOz) is a nutraceutical obtained from rice brain oil with many benefits to health, from immunological to metabolic. The aim of this study is to test the preventive effect of γOz on the physiopathological process related to nonalcoholic fatty liver disease in animals submitted to high sugar/fat diet. Male Wistar rats (±187 g) were randomly divided into four experimental groups to receive: control diet (C, n = 6), control diet plus γOz (C + γOz, n = 6), high sugar/fat diet (HSF, n = 6), or high sugar/fat diet plus γOz (HSF + γOz, n = 6) during 30 weeks. HSF groups also received water plus sucrose (25%). γOz was added to diets to reach 0.5% of final concentration. The HSF group presented MetS, liver inflammation and oxidative stress, and micro and macrovesicular steatosis. HSF plus γOz was protected against these changes. It is possible to conclude that gamma-oryzanol was effective in modulating the physiopathological process related to nonalcoholic fatty liver disease in animals submitted to a high sugar/fat diet.
... Since obesity and its related disorders are becoming increasingly prevalent, several researchers have been using high-fat diet models to induce obesity, typically characterized by weight gain and increased body fat. 7,15,22,23 In the present study, we chose ~40% of kcal from fat, as we believe this is closer to what is consumed by humans. However, some individuals remain resistant to becoming obese, a condition also observed in some animals' fed with high-fat diets, which are defined as obesity-resistant animals. ...
... 8 Several experiments have demonstrated that obese rats due to a high-fat diet intake develop obesity-related disorders that are similar to human disorders, such as glucose intolerance, insulin resistance, hypertension, and dyslipidemia. 16,22,26 However, in ROb models, there are controversies regarding the presence of comorbidities. 9,10,23,27 In the current study, the ROb group presented relevant metabolic, hormonal, and cardiovascular changes commonly found in obesity and associated with increased adiposity. ...
... Increased leptin and insulin are common in obesity. 16,22 However, the present study also observed this condition in the ROb animals. Increased insulin can be due to insulin resistance or elevated gastric inhibitory polypeptide levels induced by high-saturated fatty acid intake. ...
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Background: As some individuals present resistance to obesity development, experiments have been trying to understand their susceptibility to cardiometabolic diseases. Objective: To evaluate if the cardiac remodeling was related to collagen protein expression change. Methods: Male Wistar rats were randomized into two experimental groups: control diet (CD, n=15) or high-fat diet (HFD, n=15) for 30 weeks. Rats fed with HFD were ranked based on their adiposity indexes and classified as obese (Ob, n = 8) or obesity-resistant (ROb, n = 6). Rats that failed to present the normal characteristic of the control group while fed with CD were excluded (Control, n = 8). Nutritional profile, comorbidities (dyslipidemia, hypertension, glucose metabolism, hyperleptinemia), cardiac remodeling, and collagen protein expression were evaluated. The groups were compared by One-Way ANOVA, together the Tukey post hoc test, with p<0.05 considered significant.Results: The Ob rats presented an increased adiposity index when compared to C and ROb. Both groups Ob and ROb presented increased low-density lipoprotein (LDL), insulin, homeostatic model assessment of insulin resistance (HOMA- IR) and systolic blood pressure (SBP), and low high-density lipoprotein (HDL) levels when compared to the control group. The levels of triglycerides, non-esterified fatty acid (NEFA), and leptin were lower in ROb as compared to Ob, but higher than the control group. The Ob and ROb groups presented cardiac remodeling, evidenced by echocardiographic and post-mortem analysis. The collagen protein expression did not differ among the groups. Conclusion: The ROb animals present cardiac remodeling that is not related to collagen type I and III protein expression change. (1) (PDF) Cardiac Remodeling in Obesity-Resistance Model is not Related to Collagen I and III Protein Expression. Available from: https://www.researchgate.net/publication/353256712_Cardiac_Remodeling_in_Obesity-Resistance_Model_is_not_Related_to_Collagen_I_and_III_Protein_Expression [accessed Jul 15 2021].
... HSF animals 0.5 w/w (10 weeks) Increased protein expression of adiponectin receptor 2 and PPAR-α. [66] HFFD rat 0.16% (13 weeks) ...
... Numerous studies have shown that γ-oryzanol reduces obesity. It has been reported that (0.5 w/w) γ-oryzanol can increase the protein expression of adiponectin receptor 2 and peroxisomal proliferator-activated receptor-α (PPAR-α) and then suppress ROS production and inflammation response, also ameliorated the obesity-induced renal injuries in animals fed with high sugar-fat diet (HSF) after 10 weeks [66]. Wang et al. (2015) surveyed the effects of γ-oryzanol (0.16% of regular rodent diet) in a high-fat fructose diet (HFFD)-induced obesity, hyperlipidemia, hyperglycemia, and insulin resistance (IR) for 13 weeks in rats. ...
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Alpha-bisabolol (α-bisabolol), an unsaturated monocyclic sesquiterpene alcohol, is known as one of the "most-used herbal constituents" in the world. Various therapeutic and biological properties of α-bisabolol in preventing oxidative stress, inflammatory disorders, infections, neurodegenerative diseases, cancers, and metabolic disorders have been reported. In this review, we evaluated new findings regarding the molecular mechanisms of α-bisabolol published from 2010 until 2021 in PubMed, Science Direct, and Scopus. The antioxidant mechanism of α-bisabolol is mainly associated with the reduction of ROS/RNS, MDA, and GSH depletion, MPO activity, and augmentation of SOD and CAT. Additionally, upregulating the expression of bcl-2 and suppression of bax, P53, APAF-1, caspase-3, and caspase-9 activity indicates the anti-apoptotic effects of α- bisabolol. It possesses anti-inflammatory effects via reduction of TNF-α, IL-1β, IL-6, iNOS, and COX-2 and suppresses the activation of ERK1/2, JNK, NF-κB, and p38. The antimicrobial effect is mediated by inhibiting the viability of infected cells and improves cognitive function via downregulation of bax, cleaved caspases-3 and 9 levels, β-secretase, cholinesterase activities, and upregulation of bcl-2 levels. Finally, due to multiple biological activities, α-bisabolol is worthy to be subjected to clinical trials to achieve new insights into its beneficial effects on human health.
... This calculation considered the adiposity index of previous studies published by our group. [22][23][24] The animals were randomly divided into two experimental groups: the control group (C, n= 8 animals) that received standard diet/water and the obese group (OB, n= 8 animals) that received high sugar-fat (HSF) diet and water plus 25% of sucrose for 30 weeks. The diet model is a well-established model to induce obesity previously published by our research group. ...
... At the end of the experimental period, the results show that these animals presented higher adiposity index and several disorders, such as hyperglycemia, increased uric acid, insulin resistance, hypertriglyceridemia, elevated SBP, increased TNF-α and IL-6 levels in both heart and adipose tissue, confirming the efficacy of the diet model used. [22][23][24][25] The coexistence of obesity-related disorders -such as insulin resistance, diabetes, and dyslipidemia -associated with adipose tissue dysfunction, characterized by adipokine imbalance, promote maladaptive responses in the heart, such as myocyte hypertrophy, contractile dysfunction, and cardiac remodeling, which contribute to both the development and progression of chronic heart failure. [31][32][33] This condition was confirmed in this study, since the echocardiogram evaluation showed cardiac remodeling and diastolic dysfunction in the OB group. ...
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... This antioxidant and antinflammatory effect can also explain the protection against heart and kidney dysfunction even in the presence of hypertension, an independent factor for CRMS. Some studies of our research group showed a local antioxidant and antinflammatory effect of lycopene in the heart of obese animals and the same positive effect of gamma-oryzanol in the kidney of obese animals, preserving renal function (Ferron et al., 2020;Francisqueti et al., 2018). This same effect may be exerted BLE in the heart and kidney of animals from this study. ...
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... Due to the increased global obesity prevalence, it is important to find alternatives that can minimize the obesity-related disorders. Several researches have shown that the introduction of bioactive compounds with antioxidant and anti-inflammatory effects in eating habits have controlled the emergence of several diseases (Costa et al., 2019;Ferron et al., 2019;Francisqueti et al., 2018;Sengupta et al., 2011). Gamma-oryzanol (γOz) is a compound present in the whole grain of rice and consists of a mixture of sterile ferulates or triterpene alcohol with the carboxylic group of ferulic acid (Minatel et al., 2014). ...
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This chapter summarizes the entire literature available on the nutritional value and diverse therapeutic potentials Gamma-oryzanol, a nutraceutical obtained from rice brain oil, composed of a mixture of γ - oryzanol, a mixture of ferulic acid esters of phytosterols and triterpenoids, cycloartenyl ferulate, 24-methylenecycloartanyl ferulate, and campesteryl ferulate. In brief, the review covers the aspects such as the antioxidant mechanisms, effects on immune system, lipid disorders, diabetes, obesity and inflammation with the details of preclinical experiments, models and observations. Among the other highlights are the hepatoprotective, neuroprotective role in various neurological disorders such as Alzheimer’s, anxiety, Parkinson’s disease and wound healing effects. An overview of the sources, chemistry, physicochemical properties, pharmacokinetics and toxicity studies are also included.
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Patients with chronic kidney disease (CKD) have high incidence rates of cardiovascular disease and malignancy. Several factors contribute to these conditions. Structural characteristics in CKD, loss of renal energy, and uremia result in an imbalance between free radical production and antioxidant defenses. Also, CKD patients usually have multiple cardiovascular risk factors like diabetes mellitus, dyslipidemia, and hypertension. These conditions are associated with oxidative stress, which can trigger the inflammatory process and accelerate renal injury progression. There are some clinical biomarkers to detect oxidative stress and antioxidant status in CKD patients. Antioxidant therapies may be beneficial in reducing oxidative stress, lowering uremic cardiovascular toxicity, and improving survival. Therefore, their roles in CKD patients have been evaluated in several studies as a new target for therapeutic intervention. This review provides an overview of oxidative stress mechanisms, clinical squeals, biomarkers, and possible antioxidant therapies in CKD patients.
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A link between inflammation with obesity and metabolic syndrome has been found in patients with chronic kidney disease (CKD). Diacerein is an anthraquinone used to treat osteoarthritis that exerts anti-inflammatory action by inhibiting the synthesis and activity of proinflammatory cytokines. This study aimed to investigate the protective effect of diacerein on renal function and renal organic anion transporter 3 (Oat3) function in obese insulin-resistant condition. Obese insulin-resistant rats were induced by feeding a high-fat diet in male Wistar rats for 16 weeks. Diacerein or metformin (positive control) (30mg/kg/day) was administered orally for 4 weeks after insulin resistance had been confirmed. Obese insulin-resistant rats showed an impaired renal function as indicated by the increased serum creatinine and microalbuminuria along with the decreased renal Oat3 function and expression. Importantly, diacerein treatment not only improved insulin resistance but also restored renal function. The decreased renal malondialdehyde level, expressions of PKCα, angiotensin 1 receptor (AT1R), Nrf2, and HO-1, and increased expression of SOD2 were observed in diacerein treatment group, indicating the attenuation of renal oxidative stress condition. Moreover, renal inflammation and renal damage were also alleviated in diacerein-treated rats. Our results demonstrated for the first time that diacerein was effective to improve renal function and renal Oat3 function in obese insulin-resistance condition mediated by suppressing renal oxidative stress and inflammation. These findings suggest that anti-inflammatory agents can be used therapeutically to improve metabolic disorder and prevent organ dysfunctions in pre-diabetic condition.
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The metabolic syndrome (MetS) is a cluster of cardiovascular risk factors including insulin resistance (IR), dyslipidemia and hypertension, which may also foster development of chronic kidney disease. The mechanisms of MetS-induced kidney disease are not fully understood. The purpose of this review is to summarize recent discoveries regarding the impact of MetS on the kidney, particularly on the renal microvasculature and cellular mitochondria. Fundamental manifestations of MetS include insulin resistance (IR) and adipose tissue expansion, the latter promoting chronic inflammation and oxidative stress that exacerbate IR. Those in turn can elicit various kidney injurious events through endothelial dysfunction, activation of the renin-angiotensin-aldosterone system, and adipokine imbalance. IR and inflammation are also major contributors to microvascular remodeling and podocyte injury. Hence, these events may result in hypertension, albuminuria, and parenchymal damage. In addition, dyslipidemia and excessive nutrient availability may impair mitochondrial function and thereby promote progression of kidney cell damage. Elucidation of the link between MetS and kidney injury may help develop preventative measures and possibly novel therapeutic targets to alleviate and avert development of renal manifestations.
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The kidney ages quickly compared with other organs. Expression of senescence markers reflects changes in the energy metabolism in the kidney. Two important issues in aging are mitochondrial dysfunction and oxidative stress. Peroxisome proliferator-activated receptor α (PPARα) is a member of the ligand-activated nuclear receptor superfamily. PPARα plays a major role as a transcription factor that regulates the expression of genes involved in various processes. In this study, 18-month-old male C57BL/6 mice were divided into two groups, the control group (n=7) and the fenofibrate-treated group (n=7) was fed the normal chow plus fenofibrate for 6months. The PPARα agonist, fenofibrate, improved renal function, proteinuria, histological change (glomerulosclerosis and tubular interstitial fibrosis), inflammation, and apoptosis in aging mice. This protective effect against age-related renal injury occurred through the activation of AMPK and SIRT1 signaling. The activation of AMPK and SIRT1 allowed for the concurrent deacetylation and phosphorylation of their target molecules and decreased the kidney's susceptibility to age-related changes. Activation of the AMPK-FOXO3a and AMPK-PGC-1α signaling pathways ameliorated oxidative stress and mitochondrial dysfunction. Our results suggest that activation of PPARα and AMPK-SIRT1 signaling may have protective effects against age-related renal injury. Pharmacological targeting of PPARα and AMPK-SIRT1 signaling molecules may prevent or attenuate age-related pathological changes in the kidney.
Chapter
Renal disease may present in many ways, including: (1) the screening of asymptomatic individuals; (2) with symptoms and signs resulting from renal dysfunction; and (3) with symptoms and signs of an underlying disease, often systemic, which has resulted in renal dysfunction. History and clinical signs—in many cases these are nonspecific or not apparent, and detection of renal disease relies on a combination of clinical suspicion and simple investigations, including urinalysis (by dipstick for proteinuria and haematuria, with quantification of proteinuria most conveniently performed by estimation of the albumin:creatinine ratio, ACR, or protein:creatinine ratio, PCR) and estimation of renal function (by measurement of serum creatinine, expressed as estimated glomerular filtration rate, eGFR)....