FLAVONOIDS IN KIDNEY PROTECTION

www.wjpps.com Vol 4, Issue 03, 2015.

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Achyut et al. World Journal of Pharmacy and Pharmaceutical Sciences

FLAVONOIDS IN KIDNEY PROTECTION

Achyut Dahal* and Sirisha Mulukuri

Karnataka College of Pharmacy, Banglore-64, India.

ABSTRACT

Flavonoids are having different therapeutic activities like, anti-

hyperglycemic, anti hyperlipidemic, hepatoprotective and several

others like antiviral,anti inflammatory. Different Flavonoids like

silymarin, hesperedin, morin hydrates, propinol, naringenin,

querecetin, rutin have protective effect on kidney.This review is

concerned with flavonoids having wide range of nephro protective

activities in different conditions like glomerulonephritis in diabetic

nephropathy and other chemical induced kidney failure like

gentamycin, ccl4 and cyclosporine.

KEYWORDS: Nephro protective activities, Glomerulo-nephritis.

INTRODUCTION

Kidney failure is nowadays increasing at an alarming rate. It is therefore a matter of concern

to all how kidney can be protected especially in conditions like diabetes mellitus and persons

under long drug therapy. Nephropathy is one of the most important complications of diabetes

mellitus and drug induced toxicity. Nephrotoxicity is mostly related to oxidative stress and

nowadays much attention has been made towards the possible kidney protective properties of

medicinal plants and hence Flavonoids now have been come under light as they found to

have protective effect in kidney.

More than 80 per cent of all kidney cancers are associated with renal cell carcinoma

(RCC).[1]

According to the charity Cancer Research UK, kidney cancer is the tenth most

common form of the disease, with a male: female incidence ratio of 5:3. In the UK alone,

around 6,600 new cases of kidney cancer are diagnosed each year, and the disease results in

around 3,600 deaths. The researchers, led by Cristina Bosetti from Milan's Istituto di

Ricerche Farmacologiche, "Mario Negri", then published data to calculate the six major

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Article Received on

26 Dec 2014,

Revised on 21 Jan 2015,

Accepted on 14 Feb 2015

*Correspondence for

Author

Achyut Dahal

Karnataka College of

Pharmacy, Banglore-64,

India.


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classes of flavonoids - isoflavones, anthocyanidins, flavan-3-ols, flavanones, flavones, and

flavonols - from the participant's food and beverage intake.After adjusting the results to

eliminate possible confounding factors, such as age, BMI, sex, smoking habits and alcohol

consumption, the researchers calculated that the highest intake of total flavonoids was

associated with a 20 per cent reduction in the risk of RCC, compared to the lowest intake of

all flavonoids.

Flavonoids are compounds regarded as C6-C3-C6in which each C6 moiety is a benzene ring,

the variation in the state of oxidation of the connecting C3 moiety determines the properties

and class of compounds.flavonoids usually occur in all parts of the plants as glycosides.

flavonoids are having physiological activities like cardiac stimulants, diuretics,kidney

protection and as antioxidants.[2]

Flavonoids (or bioflavonoid), collectively known as Vitamin

P and citrin, are a class of plant secondary metabolites. They are commonly found in fruits,

vegetables, nuts, seeds, stems, flowers, tea, wine, propolis and honey.

Major dietary sources of Flavonoids are in the form of flavonols, flavones, isoflavones,

flavonones,bioflavones are, tea , red wine , apple, tomato, cherry, onion, thyme, parsley,

soyabeans, and other legumes, grapes, orange, lemon, ginkgo, and neem.[3]

Flavonoids like kaempferol, myricetin, and quercetin are strong inhibitors of xanthine

oxidase, and indicated in the treatment of gout, hyperuricemia, and reperfusion injury and

renal protection.

Classes of flavonoids

Flavones: fistein, quercetein

flavanones: naringin,hesperidin

isoflavonones: genistein ,diadzein

flavonols: kaempferol,myrcetin

aurones: bractetin,sulfuretin

leucoanthocyanidins: peltogynol


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working mechanisms of Flavonoids[4]

1. Anti oxidative effect: Flavonoids act as antioxidants and oxidises free radicals and

prevent lipid peroxidation.

2. Direct radical scavenging

3. Xanthine oxidase

The xanthine oxidase pathway has been implicated as an important route in the oxidative

injury to renal tissues, especially after ischemia-reperfusion. Xanthine oxidase is a source of

oxygen free radicals. In the reperfusion phase (ie, reoxygenation), xanthine oxidase reacts

with molecular oxygen, thereby releasing superoxide free radicals. quercetin and silibin,

inhibit xanthine oxidase activity, thereby resulting in decreased oxidative injury .


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4. Leukocyte immobilization

The immobilization and firm adhesion of leukocytes to the endothelial wall is another major

mechanism responsible for the formation of oxygen-derived free radicals, but also for the

release of cytotoxic oxidants and inflammatory mediators and further activation of the

complement system. Oral administration of a purified micronized flavonoid fraction was

reported to decrease the number of immobilized leukocytes during reperfusion.

5. Antithrombogenic effects

Selected flavonoids, such as quercetin, kaempferol, and myricetin were shown to be effective

inhibitors of platelet aggregation in dogs and monkeys . Flavonols are particularly

antithrombotic because they directly scavenge free radicals, thereby maintaining proper

concentrations of endothelial prostacyclin and nitric oxide.

6. Antiviral effects

Some of the viruses reported to be affected by flavonoids are herpes simplex virus,

respiratory syncytial virus, parainfluenza virus, and adenovirus. Quercetin was reported to

exhibit both antiinfective and antireplicative abilities.

7. Antitumor effects

Some Flavonoids such as fisetin, apigenin, and luteolin are stated to be potent inhibitors of

cell proliferation. A large clinical study suggested the presence of an inverse association

between flavonoid intake and the subsequent incidence of lung cancer. This effect was

mainly ascribed to quercetin, which provided >95% of the total flavonoid intake in that

particular study.

8. Renal protective effects

Flavonoids prevents renal oxidative stress may include an increasing rate of GSH or by

induction of its synthesis or by a scavenger effect. Instead of the toxic reactive metabolites

binding to glutathione and consume, they will be captured by the flavonoids (naringenin,

pinostrombin and galangin).

This is intriguing considering the fact that many commonly prescribed drugs are known to be

associated with nephrotoxicities, like analgesic and non-steroidal antiinflammatory

drugs,sulfonamides, aminoglycosides and cephalosporins.


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Several different mechanisms have been proposed for anagelsic associated nephropathy[5]

.

(1) direct toxic effect by the high concentration in the medullary tissue (loop of Henle);

(2) anoxia caused by vasoconstriction or mesengial thickening,platelet aggregation, occlusion

of blood vessels by interstitial hyperplasia, changes in the oxygen binding of hemoglobin,

and changes in blood viscosity.

(3)metabolic effects, e.g., reduced intracellular adenosinetriphosphate (ATP) and

glucogenesis, and uncouplingof oxidative phosphorylation by salicylates and some phenolic

compounds.

(4) inhibition of prostaglandin synthesis

Antioxidant polyphenols may prevent nephropathy by interfering with the generation of

reactive oxygen species.

Hence Literature survey revealed that Flavonoids have renoprotective avctivities, our review

was mainly focussed on different Flavonoids and their activities with procedures.

Flavonoids have been found effective in diabetic nephropathy and also in gentamycin

induced, cyclosporine induced ,ccl4 induced and cadmium induced oxidative stress in kidney.

The administration of various natural or synthetic antioxidants has been shown to be of

benefit in prevention and attenuation of renal scaring in numerous animal models of kidney

diseases. LUT(Luteolin ) and other natural flavonoids have recently been reported to have an

antioxidative, anti-cancerogenic, antihypertensive, proinflammatory effect, neuroprotective

activities and renoprotective effect.[6]

Different research methodologies of flavanoids for their nephro protective activity.

Hesperidin found in oranges and lemons[7]

Hesperidin is an abundant flavonoid found in citrus fruit. It is the predominant flavonoid in

lemons and oranges.

Hesperidin, a citrus bioflavonoid, decreases the oxidative stress produced by carbon

tetrachloride in rat liver and kidney.[8]

Animals were pretreated with Hesperidin (100 and 200 mg/kg orally) for one week and then

challenged with CCl4 (2 ml/kg/s.c.) in olive oil. Rats were sacrificed by carotid bleeding

under ether anesthesia. Liver enzymes, urea and creatinine were estimated in serum.

Oxidative stress in liver and kidney tissue was estimated using Thiobarbituric acid reactive

http://www.raysahelian.com/flavonoids.html


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substances (TBARS), glutathione (GSH) content, superoxide dismutase(SOD), and Catalase

(CAT) CCl4 caused a marked rise in serum levels of ALT and AST. TBARS levels were

significantly increased whereas GSH, SOD and CAT levels decreased in the liver and kidney

homogenates of CCl4 treated rats. Hesperidin (200 mg/kg) successfully attenuated these

effects of CCl4: In conclusion, our study demonstrated a protective effect of Hesperidin in

CCl4 induced oxidative stress in rat liver and kidney. This protective effect of Hesperidin can

be correlated to its direct antioxidant effect.

Protective activity of hesperidin and lipoic acid against sodium arsenite acute toxicity in

mice.[9]

The objective of the present work was to evaluate the toxic effects of sodium arsenite,

As(III), in mice and the protective effect of 2 antioxidants, hesperidin and lipoic acid, against

the observed As(III)-induced toxicity. In each study, mice were assigned to 1 of 4 groups:

control, antioxidant, antioxidant + arsenite, and arsenite. Animals were first injected with the

vehicle or 25 mg antioxidant/kg BW. After 30 minutes they received an injection of 10 mg

arsenite/kg BW or 0.9% NaCl. Two hours after the first injection, the liver, kidney, and testis

were collected for histological evaluation. Liver samples were also taken for quantification of

arsenic. In mice exposed only to As(III), various histopathological effects were observed in

the liver, kidneys, and testes. In mice pretreated with either hesperidin or lipoic acid, a

reduction of histopathologic effects on the liver and kidneys was observed. No protective

effects were observed in the testes for either of the 2 studied antioxidants. In conclusion,

hesperidin and lipoic acid provided protective effects against As(III)-induced acute toxicity in

the liver and kidneys of mice. These compounds may potentially play an important role in the

protection of populations chronically exposed to arsenic.

Renal protective effects of Porphyra dentate aqueous extract in diabetic mice[10]

Oxidative stress emanating from hyperglycemia impairs organs functions and facilitates

diabetic deterioration . data agreed with previous studies: oxidative stress present in kidneys

of diabetic mice.Intake of purple laver aqueous extract mitigated renal oxidative injury. It is

possible that this extract retained renal GSH content, which in turn lowered ROS formation,

indicating this extract could spare renal GSH. Likewise, it is reported that intake of purple

layer effectively maintains renal activity.


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Pei-ChunResults: PLE was rich in anthocyanins. PLE intake at 0.5 and 1% lowered plasma

glucose level (P<0.05); only at 1% raised plasma insulin level, and decreased plasma

triglyceride and total cholesterol levels (P<0.05). PLE treatments at 1% lowered hepatic

triglyceride and total cholesterol.

(P<0.05); it reduced renal reactive oxygen species level (P<0.05); retained renal

glutathione level, maintaining renal glutathione peroxidase and catalase activities

(P<0.05).

This result suggests that flavonoids present in the porphyra dentate aqueous extract do lessen

the renal reactive oxygen species and prevents it from injuring the nephrons in kidney.

Naringenin protects against cadmium-induced oxidative renal dysfunction in rats.[11]

Cadmium (Cd) is an environmental and industrial pollutant that affects various organs in

human and experimental animals. Naringenin is a naturally occurring plant bioflavonoid

found in citrus fruits, which has been reported to have a wide range of pharmacological

properties. A body of evidence has accumulated implicating the free radical generation with

subsequent oxidative stress in the biochemical and molecular mechanisms of cadmium

toxicity. Since kidney is the critical target organ of chronic Cd toxicity, this study was carried

out to investigate the effects of naringenin on Cd-induced toxicity in the kidney of rats. In

experimental rats, oral administration of cadmium chloride (5mg/(kgday)) for 4 weeks

significantly induced the renal damage which was evident from the increased levels of serum

urea, uric acid, creatinine with a significant (p<0.05) decrease in creatinine clearance.

Cadmium also significantly decreased the levels of urea, uric acid and creatinine in urine. A

markedly increased levels of lipid peroxidation markers (thiobarbituric acid reactive

substances and lipid hydroperoxides) and protein carbonyl contents with significant (p<0.05)

decrease in non-enzymatic antioxidants (total sulfhydryl groups, reduced glutathione, vitamin

C and vitamin E) and enzymatic antioxidants (superoxide dismutase (SOD), catalase (CAT),

glutathione peroxidase (GPx) and glutathione S-transferase (GST)) as well as glutathione

metabolizing enzymes (glutathione reductase (GR) and glutathione-6-phosphate

dehydrogenase (G6PD)) were also observed in cadmium-treated rats. Co-administration of

naringenin (25 and 50mg/(kgday)) along with Cd resulted in a reversal of Cd-induced

biochemical changes in kidney accompanied by a significant decrease in lipid peroxidation

and an increase in the level of renal antioxidant defense system. The histopathological studies

in the kidney of rats also showed that naringenin (50mg/(kgday) markedly reduced the


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toxicity of Cd and preserved the normal histological architecture of the renal tissue. The

present study suggest that the nephroprotective potential of naringenin in Cd toxicity might

be due to its antioxidant and metal chelating properties, which could be useful for achieving

optimum effects in Cd-induced renal damage.

Supplementing the diet with naringenin, a compound from grapefruit, may reduce

markers of inflammation and boost kidney health in diabetics, suggests data from a

study with mice.[12]

Naringenin, responsible for the bitter taste in grapefruits, lemon and tomatoes, has already

been reported to offer potential benefits for people with diabetes, arteriosclerosis and hyper-

metabolism.

The new study, published in the Journal of Agricultural and Food Chemistry, adds to this

body of science, and suggests that the compound may boost kidney health in people with

diabetes. Diabetic renal injury (diabetic nephropathy) is just one potential complication of

diabetes, and it has been suggested that inflammation may contribute to its development.

Protection by alpha G-rutin, a water-soluble antioxidant flavonoid, against renal

damage in mice treated with ferric nitrilotriacetate.[13]

The protective effect of alpha G-Rutin against ferric nitrilotriacetate (Fe-NTA)-induced renal

damage was studied in male ICR mice. Fe-NTA induces renal lipid peroxidation, leading to a

high incidence of renal cell carcinoma in rodents. Administration of alpha G-Rutin (50

mumol as rutin/kg) by gastric intubation 30 min after i.p. injection of Fe-NTA (7 mg Fe/kg)

most effectively suppressed renal lipid peroxidation. Repeated i.p. injection of Fe-NTA (2 mg

Fe/kg/day for the first 3 days and 3 mg Fe /kg/day for 12 days, 5 days a week) causes

subacute nephrotoxicity as revealed by induction of karyomegalic cells in renal proximal

tubules. A protective effect was observed in mice given alpha G-Rutin 30 min after each Fe-

NTA treatment. To elucidate the mechanism of protection by alpha G-Rutin, the

pharmacokinetics and hydroxyl radical-scavenging effect of alpha G-Rutin were investigated

by HPLC analysis and by electron spin resonance (ESR) spin trapping with 5,5-dimethyl-1-

pyrroline-N-oxide (DMPO), respectively. When mice were given alpha G-Rutin (50 mumol

as rutin/kg) by gastric intubation, rapid absorption into the circulation was observed. The

plasma concentration of alpha G-Rutin reached the highest level 30 min after oral

administration and then decreased to the control level within 60 min, alpha G-Rutin inhibited

the formation of DMPO-OH in a concentration-dependent manner. Further, chelating activity


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of alpha G-Rutin to ferric ions was shown by spectrophotometric analysis. These results

suggest that absorbed alpha G-Rutin works as an antioxidant in vivo either by scavenging

reactive oxygen species or by chelating ferric ions and this serves to prevent oxidative renal

damage in mice treated with Fe-NTA.

Nephroprotective activities of the aqueous seed extract of Carica papaya Linn. in

carbon tetrachloride induced renal injured Wistar rats[14]

the dose related effect of the aqueous seed extract of Carica papaya Linn. Extract (CPE) was

evaluated by pre-treating three groups of rats (made up of six male rats per group) with 100–

400 mg/kg body weight per oral of the extract for 7 days before challenging with 1.5 ml/kg

body weight of 20% carbon tetrachloride in olive oil in addition to the untreated control and

model control rats. Also, the time-course effect of 400 mg/kg per oral of the extract were

determined at 3 hr pre-, 0 hr, 1 hr post-,3 hr post-, and 6 hr post-CCl4 induction, respectively,

in addition to the untreated control and model control groups. After 72 hours, serum levels of

uric acid, urea and creatinine of all study groups were measured using standard procedures.

Histological studies of rat kidneys of all study groups were also done. Results showed that

intraperitoneal injection of CCl4 caused a significant (p<0.001) elevation in the serum levels

of uric acid, urea and creatinine and induced histological features of severe

tubulointerstitialnecrosis. However, elevations in the measured biochemical parameters were

significantly (p<0.05, p<0.01 and p<0.001) attenuated in rats pre-treated with the graded oral

doses of the extract, in dose related fashion. Maximum nephroprotection was offered by the

extract at 400 mg/kg/day CPE which lasted up to 3 hours post-CCl4 exposure and these

biochemical evidences were corroborated by improvements in the renal histological lesions

induced by CCl4 intoxication. In conclusion, our study showed that CPE has

nephroprotective effect on CCl4 renal injured rats, an effect which could be mediated by any

of the phytocomponents present basically flavonoids in it via either antioxidant and/or free

radical scavenging mechanism(s).

Ameliorative effect of morin hydrate, a flavonoid against gentamicin induced oxidative

stress and nephrotoxicity in sprague-dawley rats[15]

Morin Hydrate was recently shown to provide a protection cultured rat glomerular cells in

vitro against oxyradical damage, and as a anticancer agent through inhibition of NF-ǨB

pathway. Mainly, free radical mechanism mediates, in part in Gentamicin induced

nephrotoxicity. The main purpose of the study is to determine the protective effect of Morin


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Hydrate, mediated through inhibition of free radical mechanism against Gentamicin induced

nephrotoxicity in-vivo.

Morin Hydrate is a natural yellow crystalline polyphenolic compound coming from branches

of Morus alba L (white mulberry) and red Wine , in the family of Moraceae [white mulberry

(morus alba)] and in in almond (Prunus dulcis, family Rosaceae), in sweet chestnut (Castanea

sativa, family Fagaceae) having antioxidant and Hypouricemic activity. It also protects the rat

mesangial glomerular cells against the oxyradical damage.

Effect of Morin Hydrate on kidney/body-weight ratio

At the end of the study, a significant increase in kidney/body-weight ratio (p<0.01) was

observed as a result of Gentamicin administration when compared to the normal control

group. Both Pre-treatment for 3 days of Gentamicin administration and treatment (100mg/kg

and 200mg/kg body weight) for 15 days significantly (p<0.01) reduced the Gentamicin-

induced changes kidney/body-weight ratio.

Effect of Morin Hydrate on renal dysfunction

Effect of Morin Hydrate on Blood Urea Nitrogen (BUN) level

There was significant difference in serum BUN levels between normal control and Morin

Hydrate control (p<0.01) group.

1

Effect of Morin Hydrate on Serum Creatinine (Scr) levels.

There was significant difference in Scr levels between normal control and control (p<0.001)

group. Gentamicin administration.

Effect of Morin Hydrate on total ROS level.

Gentamicin significantly (p<0.05) increased the total ROS levels in kidney tissues of

Gentamicin control group, indicating enhanced oxidative stress compared to normal control

group. Therapeutic treatment with Morin Hydrate at all doses (50mg/kg, 100mg/kg and

200mg/kg) for 15 days significantly (p<0.05) attenuated this rise in ROS in kidney tissues of

Gentamicin treated rats compared to the Gentamicin control group. Morin Hydrate alone had

no effects on the ROS generation and in the pre-treatment case there is no significant

reduction of this rise of ROS in the kidney samples.


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Effect of Morin Hydrate on tissue nitrite level

Renal tissue nitrite levels, which indicate the nitric oxide (NO) levels were significantly

(p<0.05) reduced in the kidneys of the Gentamicin group compared to the normal control

group.

Effect of Morin Hydrate on Lipid Peroxidation (MDA) Levels Kidney tissue

MDA levels were increased significantly (p<0.05) by Gentamicin administration as compared

to the normal control group. Both pre and therapeutic treatments with Morin Hydrate at all

doses significantly attenuated this effect compared to the gentamycin control.

Effect of Morin Hydrate on antioxidant profile

Effect of Morin Hydrate on Glutathione level

A significant reduction (p<0.05) of reduced glutathione was observed in Gentamicin control

group compared to the normal control. And in both pre and therapeutic treated groups with

Morin Hydrate there was a significant elevation of GSH compared to the Gentamicin control.

In therapeutic groups (50, 100, 200 mg/kg) observed there is dose.

Effect of Morin Hydrate on Catalase (CAT) activity

A significant (p<0.01) decrease in renal Catalase (CAT) activities was observed in

Gentamicin control group compared to the normal control. Both pre and therapeutic Morin

Hydrate treatment with Gentamicin administration had significantly higher catalase levels

compared to only Gentamicin group. Means a significant increase in the catalase levels were

observed in Morin Hydrate & Gentamicin treated groups at all doses and in therapeutic

treated animals there was a dose dependent increase from 50mg/kg to 200mg/kg.

Effect of Morin Hydrate on superoxide dismutase (SOD) activity

Kidney tissue Superoxide dismutase (SOD) levels decreased significantly (p<0.01) by

Gentamicin administration compared to the normal control group. Morin Hydrate pre-

treatment for 3 days of Gentamicin administration and treatment of Morin Hydrate (50,

100mg/kg and 200mg/kg body weight) for 15 days produced a significant increase in SOD

levels compared to Gentamicin control.


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Photomicrograph of rat kidney section

Several approaches involve the use of various natural antioxidantcompounds that ameliorate

the Gentamicin induced nephrotoxicity.Flavonoid compounds from natural sources are

known to be having the scavenging effect of reactive oxygen species. Morin Hydrate is a

memberof flavonoids having free-radical-trapping capacity.Also, it has been demonstrated

that treatment of Morin Hydrate in rats significantly protects against mercuric chloride

induced nephrotoxicity.


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Red Wine Polyphenols Prevent Cyclosporine-Induced Nephrotoxicity

At the Level of the Intrinsic Apoptotic Pathway [16]

A number of studies have found both pro/anti-apoptotic effects for many of these compounds.

For these reasons we investigated whether ProvinolsTM

, flavonoids obtained from red wine,

have antiapoptotic properties. The investigations have been carried out in rats treated with

Cyclosporine A (CsA). In particular, four groups of rats have been treated for 21 days with

either olive oil (control group), with CsA, with ProvinolsTM

, or with CsA and ProvinolsTM

simultaneously. Oxidative stress, systolic blood pressure, body weight, biochemical

parameters and different markers of pro/anti-apoptotic pathway were measured. CsA

produced an increase of systolic blood pressure, a decrease in body weight, serum creatinine

levels, urinary total protein concentration and creatinine clearance. Moreover, CsA induced

renal alterations and the translocation of Bax and cytochrome c from cytoplasm to

mitochondria and vice versa. These changes activated the caspase cascade pathway, that leads

to morphological and biochemical features of apoptosis. ProvinolsTM

restored morphological

and biochemical alterations and prevented nephrotoxicity.

Effect of ProvinolsTM on CsA-induced oxidative stress

Glutathione (GSH), an antioxidant enzyme, was significantly reduced after CsA treatment

when compared to that of control rats. ProvinolsTM inhibited the CsAinduced depletion of

GSH. Thus GSH concentration was not significantly different between control and

ProvinolsTM

plus CsA group.

Histopathological studies hematoxylin-eosin

Renal CsA damage was mainly observed in the cortical region and consisted of tubular and

glomerular injury with dilation of the lumen and Bowman's capsule, respectively (Fig. 1A).

On the contrary, kidneys from control, ProvinolsTM

and CsA plus ProvinolsTM

-treated rats

showed normal cytoarchitecture (Figs 1B, 1C and1D).

DNA fragmentation (TUNEL staining)

The number of TUNEL-positive cells was high in CsA-treated rats (Fig. 2A) compared to

those from control and ProvinolsTM-treated animals (Figs 2B and 2C). Following 21 days of

CsA plus ProvinolsTM treatment, TUNEL-positive cells were significantly reduced (Fig.\2D)

compared to CsA group and it was similar to the control group (quantitative data - Fig. 2E).


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Immunohistochemical studies for SOD, caspase-3 and Bax

CsA treatment significantly decreased SODexpression (Fig. 3A) in cortical renal parenchyma

compared to control and ProvinolsTM-treated rats (Figs3B and 3C). CsA plus ProvinolsTM

increased SOD expression toward that of control rats (Fig. 3D). Figure 3G shows that CsA

administration induced a huge caspase-3 expression when compared to the weak expression

observed in control, ProvinolsTM and CsA plus ProvinolsTM-treated rats (Figs 3H, 3I and

3L). All data were confirmed also by quantitative analysis.

Cytochrome c histochemistry

We observed a diffuse positivity after CsA treatment (Fig. 4F) in renal tubules and a “dot

reaction product” in control, ProvinolsTM and CsA plus ProvinolsTM-treated animals (Figs

4G, 4H and 4I). Thiscytoplasmic positivity was evident in the epithelial cells of tubular

structures.


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Fig. Hematoxylin-eosin staining of renal cortex in rat

(A) CsA, (B) control, (C) Provinols™, (D) CsA + Provinols™ (Bar: 50 μm). T = tubules; G

= glomeruli; TD = tubular dilation; I = infiltrates.

The arrow shows renal fibrosis; the asterisk shows Bowman’s

capsule dilation


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Fig:Effect of ProvinolsTM on SOD (A-E) and caspase-3 (G-M) expression in CsA (A, G),

control (B, H), Provinols™ (C, I), CsA +Provinols™ (D, L)-treated rats and in negative

control (E, M) (Bar: 40 μm). (F, N) show quantitative analysis (IOD) of SOD and caspase-

3 expression. * Statistically significant (P<0.05) when compared with controls.


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Fig:Effect of ProvinolsTM on Bax (A-E) and cytochrome c (F-L) staining respectively in

CsA (A, F), control (B, G), Provinols™ (C, H), CsA + Provinols™ (D,I)-treated rats and in

negative control (E, L) (Bar: 4 μm). The arrows show the granular positivity; the asterisks

show the diffuse positivity.

Silmyrin: flavonoids as renal protective agent.[17]

Silymarin causes prevention of free radical damage, stabilization of plasma membranes and

stimulation of new liver cell production.

Previous in vitro studies reported a protective effectof silymarin on kidney cells against

oxidative damage induced by paracetamol cisplatin , aflatoxin B1, fumonisin B1 and

ischemia/ reperfusion injury(I/R). That protection occurs through decreasing the increased

risk of oxidative stress damage and a restoration of the thiol status (GSH) in the kidney.


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Ccl4 treatment causes glomerular hypercellularity, moderate to severe necrosis and tubule

interstitial alterations which causes alteration in the capacity for tubular absorption thus

bringing about functional overload of nephrons with subsequent renal dysfunction. The

impairment in kidney function markers was coincident with a significant increase in the lipid

peroxidation product, malondialdehyde (MDA) and a decrease in their enzymatic and non-

enzymatic antioxidant defense system where there was a significant decrease in the level of

reduced glutathione (GSH) and in the activity of catalase enzyme in liver and kidney tissues

indicating a state of oxidative stress and lipid peroxidation in these tissuesThe protective

properties of silymarin against CCL4induced oxidative stress in rats might be attributed to

their antioxidant flavonoids , which can prevent lipid peroxidation, changes in composition of

the membrane Phospholipids and glutathione depletion .

0

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UREA

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fig::Effect of CCL4 alone and in combination with either Silymarin or Vitamin E on

serum urea and creatinine activities of rats.

Group:1=Control. 2:CCL4. 3: CCL4+Silymarin. 4: CCL4+ Vitamin E Values are

expressed as mean±S.E. N= 5.


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0

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Fig. 3: Effect of CCL4 alone and in combination with either Silymarin or Vitamin E on

index weight of liver and kidney of rats.

Group:1=Control. 2:CCL4. 3:CCL4+Silymarin. 4:CCL4+ Vitamin E Values are

expressed as mean±S.E. N= 5.

Epicatechin limits renal injury by mitochondrial protection in cisplatin induced

nephropathy[18]

One potential mechanism may be by enhancing mitochondrial anti-oxidative function by

activating MnSOD and glutathione. Epicatechin can also block NADPH oxidase activity in

the model of cyclosporine nephropathy.

Effect of propolis extract on renal functioning

The mechanism by which the natural product propolis extract prevents renal oxidative stress

may include an increasing rate of GSH or by induction of its synthesis or by a scavenger

effect. Instead of the toxic reactive metabolites binding to glutathione and consume, they will

be captured by the flavonoids (naringenin, pinostrombin and galangin).

DISCUSSION

Extensive study of Flavanoids research revealed that their kidney protection, by their anti

oxidant property and hence increases glutathione levels in kidney tissues.flavanoids have

main role in the treatment of renal toxicities caused due to long usage of antibiotics like


381


gentamycin,immunosuppresants like cyclosporine,and toxicity related to arsenite ,

cadmium,ccl4.

The improvement in kidney function is marked by the levels of creatinine and urea which is

seriously affected in drug induced and diabetes nephropathy.

The combination of metformin, silymarin and renin-angiotensin system inhibitors or

angiotensin receptor blockers may have additive kidney protective property to prevent or

slowing the progression of diabetic nephropathy.[19]

Hence flavonoids can be regarded as the most efficient agents for kidney protection.

Renal failure has become a serious problem so it is of prime importance now that it should be

controlled by a more authentic and more efficient way i.e.to have proper flavanoids in our

diet.

This review hence supports flavonoids as therapeutically important agents with additional

kidney protective property but its use clinically is still a wide area of research and clinical

trials.

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chi Lien1, Linda Lin-min Lien1, Rubin Wang2, and Jeffrey Wang3

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Husniye Birman1, Kadriye Akgun Dar2, Ayşegul Kapucu2, Samet Acar2, Gulay Uzum1

Balkan Med J, 2012; 29: 188-96 • DOI: 10.5152/balkanmedj.2011.030 © Trakya

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6. Hesperidin found in oranges and lemons Ray Sahelian, M.D.

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17. Epicatechin limits renal injury Katsuyuki Tanabe1, Yoshifuru Tamura1, Miguel A.

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http://www.raysahelian.com/

http://www.ncbi.nlm.nih.gov/pubmed/19063931

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FLAVONOIDS IN KIDNEY PROTECTION