Protective Effect of Vaccinium Arctostaphylos L. Fruit Extract on Gentamicin-Induced Nephrotoxicity in Rats

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Comparative Clinical Pathology https://doi.org/10.1007/s00580-018-2743-0

ORIGINAL ARTICLE

Protective effect of Vaccinium arctostaphylos L. fruit extract on gentamicin-induced nephrotoxicity in rats

Mohsen Akbari Bazm1 & Mozafar Khazaei2 & Elham Ghanbari2 & Leila Naseri1

Received: 22 March 2018 /Accepted: 16 May 2018 # Springer-Verlag London Ltd., part of Springer Nature 2018

Abstract Aminoglycosides are extensively used owing to advantages such as low cost and availability. Nephrotoxicity induced by antibiotics has been analyzed in different animal models. This study was aimed to investigate the effect of Vaccinium arctostaphylos L. fruit extract on gentamicin-induced nephrotoxicity in rats. In this experimental study, 25 rats were divided into five groups, including negative control (0.5 ml normal saline), positive control (80 mg/kg gentamicin and 0.5 ml normal saline), and three Vaccinium arctostaphylos L. fruit extract groups at 100, 200, and 400 mg/kg concentrations plus 80 mg/kg gentamicin. All administrations were done intraperitoneally for 7 days. Thirty days after the first injection, blood samples were taken from the heart. Serum creatinine (Cr), blood urea nitrogen (BUN), and sodium and potassium levels were measured. To prepare histological sections, the kidneys were kept in 10% formalin. Having prepared the histological sections, the volume of renal tubules (proximal and distal convoluted tubules and loop of Henle), renal vessels, interstitial tissue, and number and volume of renal glomeruli were measured. Vaccinium arctostaphylos L. fruit extract significantly increased serum urea (p =0.023), creatinine (p = 0.009), volume of proximal convoluted tubules (p = 0.02), volume of distal convoluted tubules (p = 0.032), loop of Henle (p = 0.038), and glomeruli (p = 0.015). However, it significantly reduced the volume of vessels (p = 0.009) and interstitial tissue (p = 0.001). The 400 mg/kg concentration exerted the highest effect. Vaccinium arctostaphylos L. fruit extract has protective effects against gentamicin-induced renal impairments.

Keywords Kidney . Vaccinium arctostaphylos L. . Gentamicin . Stereology

Introduction erythropoietin, which is effective in stimulating the production of erythrocytes, and gluconeogenesis are performed with co- Kidneys play a key role in establishing physiological balance, operation of the kidneys. Acute injury to the kidney leads to regulating the balance of water and electrolytes, excreting changes in the ratio of body ions, which in turn results in metabolic and bioactive waste like many drugs, and regulating blood acid-base imbalance (Coca et al. 2008). arterial blood pressure by secreting renin. Secretion of Various factors such as aminoglycoside antibiotics cause acute renal impairments. Gentamicin is an antibiotic from this family that leads to acute renal impairments despite effects on * Leila Naseri infections induced by gram-positive and -negative bacteria [email protected] (Rodieux et al. 2015). The destructive effect of gentamicin Mohsen Akbari Bazm can be observed through measurement of serum urea and cre- [email protected] atinine levels of patients. Gentamicin has been used in many Mozafar Khazaei studies as one of the toxic compounds inducing acute renal [email protected] dysfunctions (Morin et al. 1980). Production of free radicals Elham Ghanbari and nitrogen compounds by these antibiotics causes renal tox- [email protected] icity. Reactive oxygen species (ROS) causes lipid peroxidation of cell membrane, denaturation of proteins, DNA damage 1 Department of Anatomical Sciences, Medical School, Kermanshah and apoptotic induction, and cell death. Gentamicin is able to University of Medical Sciences, Kermanshah, Iran induce histological damage by reducing the activity of antiox- 2 Fertility and Infertility Research Center, Kermanshah University of idant enzymes such as catalase (CAT), superoxide dismutase Medical Sciences, Kermanshah, Iran Downloaded from http://iranpaper.ir http://www.itrans24.com/landing1.html

Comp Clin Pathol

(SOD), and glutathione peroxidase (GPX) in the kidneys (El- approved by a botanist from Razi University, Kermanshah. Razek and Kamel 2011). Antioxidant compounds decrease The fruit was dried and powdered by a mill, and 1500 g of the release of free radicals and inhibit histological damage. powder was kept in 70% ethyl alcohol solution for 72 h. The Various plant extracts and compounds with antioxidant prop- solution was then filtered by filter paper (Whatman U.K. 2). A erties have been used to improve toxicity due to toxic com- vacuum distillation apparatus (Heidolph Collegiate, pounds such as gentamicin, cisplatin, and acetaminophen LABOROTA 4000, Germany) was sued to condensate the (Raoofietal.2015; Khoursandi and Ourazizadeh 2016; solution at 50 °C. The obtained extract was kept at 4 °C Khazaei et al. 2012). (Khazaei et al. 2006). A total of 25 male Wistar rats with the Vaccinium arctostaphylos L., a member of Ericaceae fam- mean weight of 130 ± 10 g were used in this study. The ani- ily, is a shrub with no thorns and with heart-shaped leaves and mals were kept at 12/12 dark/light cycle at 22–35 °C and toothed edges found in the northern and northwestern parts of humidity of 40–65, with free access to standard pellet. The Iran. Vaccinium arctostaphylos L. is native to Iran, and other rats were kept for 3 days to adapt to the environment. species of this plant (Vaccinium myrtillus)arefoundin The study groups consisted of five groups, each with five Georgia and Russia. This plant is inflorescence and contains rats, including negative control receiving 0.5 ml normal sa- 20–40 flowers. The plant fruit constitutes the pharmaceutical line, positive control receiving 80 mg/kg gentamicin, and part of it, which is in red to dark purple and matures in late three case groups receiving 80 mg/kg gentamicin plus summer or early fall (Akhondzadeh 2000). Vaccinium arctostaphylos L. extract at 100, 200, and Studies have documented the presence of anthocyanin, 400 mg/kg concentrations (Feshani et al. 2011; Baradaran et phenolic, flavonoid, and coumarin compounds in the fruit al. 2014;Ismailetal.1994). All administrations were done and leaves of this plant. Also, glucose compounds and organic intraperitoneally. At the end of the study (30 days after the first acids constitute the components of the fruit of this plant administration), the animals were anesthetized, and blood (Nickavar et al. 2002). These pigments and generally phenolic samples were taken from the heart. Serum urea (BUN) and compounds present in the cells of this plant protect it from creatinine levels were measured by Pars Azmoon assays and ultraviolet ray and insects’ attacks. spectrophotometry method (SINCO), and serum sodium and In traditional medicine, this plant has been used to reduce potassium ions were measured by photometric method blood sugar and lipid and to treat hypertension (Hakimi et al. (Jenway Flame photometer PFP) (Hald 1947). Then, the kid- 2014;Su2012). The most important antioxidant compound of neys were extracted from the body and weighed by a digital this plant is anthocyanin. This compound inhibits the free scale (AND FA 2014, China). radicals and apoptosis and prevents the oxidation of cell mem- The samples were preserved in 10% formalin for 72 h. The brane lipids (Akhondzadeh 2000). volume of the kidneys was determined by Cavallier’s method Researchers have reported antioxidant and anticancer prop- after estimating the tissue shrinkage rate. To this end, first, the erties for anthocyanins in reducing coronary diseases initial volume of the kidneys was measured by immersion (Nickavar and Amin 2004). Flavonoids are antimicrobial, an- technique, and isotropic uniform random (IUR) sections were tiviral, anti-atherosclerotic, antidiabetic, antioxidant, and anti- prepared by orientator method. In this method, the samples inflammatory compounds that exert their effects through inhi- were placed on circles divided into ten equal parts, and each bition of enzymes responsible for production of superoxide sample in the first section was cut into two halves by selecting anions such as xanthine oxidase and protein kinase C a random number from 0 to 10. Then, the surface of each (Nickavar and Amin 2004; Middleton and Kandaswami section was placed parallel to another circle with previous 2000; Robak and Gryglewski 1988). Vaccinium specifications; and the same as the former stage, another sec- arctostaphylos L. fruit is proposed as a medicinal plant owing tion was prepared, and 2-mm sections were prepared from the to important antioxidant compounds. This study was conduct- sections of previous stage. Next, 6–8sectionswererandomly ed to investigate the protective effect of Vaccinium selected from each kidney (Gundersen and Jensen 1987; arctostaphylos L. fruit extract on serum and morphologic fac- Akbari et al. 2017). A circle was prepared from one of the tors of the kidney following gentamicin-induced renal sections by punching, and its diameter was measured by cal- impairment. iper. After that, each section was subjected to conventional successive stages of tissue passage and was molded in molten paraffin. Then, 5-μ sections were prepared from it by a rotary Materials and methods microtome (Leica RM2235, USA). To measure tissue shrinkage, the final diameter of circular section was measured after Plant tissue passage stages and was inserted in the following relation (Gundersen et al. 1988): In this study, Vaccinium arctostaphylos L. fruit was collected from the mountainous regions of Fooman city and was Downloaded from http://iranpaper.ir http://www.itrans24.com/landing1.html

Comp Clin Pathol

Relation 1. Tissue shrinkage. AA: the area of the punched V v ¼ ∑Pstructure=∑Prefrence sample before tissue passage and AB: the area of the punched sample after tissue passage Finally, the relative volume of each structure was multiplied by the reference volume (final volume derived from subtracting the shrinkage rate) to calculate the final volume of each structure. AA Volume shrinkage¼1− 1=5 Physical dissector method was sued to estimate the number AB of glomeruli in each kidney. To this end, two sections with a distance of 30 μ (1–7 sections) were used in each kidney. The Tissue shrinkage level was multiplied by the initial volume first section was considered as the reference section, and the of the kidney to obtain the final volume of the kidney. seventh section was considered as control section. Two frame probes with equal area of 900 μm2 were placed on two mon- Relation 2. Final volume itors with similar software and camera (Fig. 2). The glomeruli that were inside the frame or were conventionally crossing one of the left or right and up or down sides and were not observed in the reference section (section 7) were counted. After V final ¼ Vprimary Â ðÞ1−volume shrinkage counting 100 glomeruli and calculating the dissector height The samples were stained by Periodic acid–Schiff (PAS) (30 μm), the obtained figures were inserted in the following staining method. relation and numerical density of glomeruli was computed. The point probe method was used to calculate the relative ∑Q− volume of structures (volume of the cortex, medulla, distant Nv¼ ∑P aðÞÂframe hÂ convoluted tubules, proximal convoluted tubules, loop of Henle, renal collecting tubule, volume of interstitial tissue, volume of vessels, and glomeruli). This probe is a transport plate with 10 × 10 dimensions and 25 printing points placed Relation 4. Calculation of the number of glomeruli on a monitor. Then, the points on each structure were counted in each field of view and inserted in the following relation to where ∑Q is sum of the counted glomeruli (100 glomeruli in compute the relative volume of each structure (Neyngaard each kidney), a is the area of dissector frame, h is the dissector 1999)(Fig.1). height (30 μm), and ∑P is the number of frames counted in each kidney. Relation 3. Calculation of relative volume of structure. After calculating the numerical density, the obtained figure Pstructure is the number of points crossing each structure was multiplied by the final volume of the kidney, and the and Preference is total number of points in the reference number of glomeruli was calculated (Akbari et al. 2017; volume Tavafi et al. 2011). Urea and creatinine levels were measured by PARS Azmoon Kits (ParsAzmun, Karaj, Iran) based on the protocols

Fig. 1 Estimation of relative volume using point probe (PAS staining, × Fig. 2 Frame probe (physical dissector) (PAS staining, × 100 100 magnification) magnification) Downloaded from http://iranpaper.ir http://www.itrans24.com/landing1.html

Comp Clin Pathol

Table 1 Serum levels of primary functional factors (urea and creatinine, mg/dl) and serum electrolytes (sodium and potassium, meq/L)

Potassium (meq/L) Sodium (meq/L) (mg/dl) Urea Creatinine (mg/dl) Groups

12/0 ± 9/4 20/21 ± 42/133 6/1 ± 14/66 04/0 ± 73/0 Negative control (healthy) 14/0 ± 1/2 17/40 ± 14/104 2/21 ± 14/152 5/0 ± 6/2 Positive control (patient) 16/0 ± 4/2 26.12 ± 16/108 97/16 ± 12/139 4/0 ± 4/2 Gentamicin + 100 mg/kg Vaccinium arctostaphylos L. 06/0 ± 6/2 94/14 ± 14/112 14/16 ± 14/122 3/0 ± 9/1 Gentamicin + 200 mg/kg Vaccinium arctostaphylos L. *12/0 ± 2/4 16/14 ± 14/118 *96/6 ± 41/88 *4/0 ± 4/1 Gentamicin + 400 mg/kg Vaccinium arctostaphylos L. 032.0 097.0 009.0 p

All values are presented as mean ± SEM *(p < 0.05) statistically significant compared positive control group (patient) with 400 mg/kg Vaccinium arctostaphylos L. treatment group. Between positive control group and other treatment groups was not statistically significant (p >0.05)

for each serum sample of rats. After running the protocol, Results optic absorption of urea and creatinine was measured by spectrophotometry. Lymphocytic infiltration was reported at × 400 Serum creatinine (mg/dl), urea (mg/dl), and sodium and po- magnification based on the spread of lymphocytes in the field tassium (meq/l) were assessed in each group. Between-group of view as follows: (1) 0–25%: field of view with lymphocytic comparison showed a dose-dependent reduction in creatinine infiltration, (2) 25–50%: field of view with lymphocytic infil- (p = 0.009), serum urea (p = 0.023), and serum potassium ion tration, (3) 50–75%: field of view with lymphocytic infiltra- (p = 0.032) in the groups treated with Vaccinium tion, and (4) 75–100%: field of view with lymphocytic arctostaphylos L. extract. The 400 mg/kg dose showed the infiltration highest reduction compared to positive and negative control groups (receiving gentamicin), but sodium reduction was not Statistical analysis statistically significant in between-group comparison of treatment groups (p > 0.05) (Table 1). The results are expressed as the mean ± SEM. One-way anal- After measurement of renal structures (kidney, proximal ysis of variance (ANOVA) was used in analyzing the differ- and distal convoluted tubules, loop of Henle, vessels, renal ences between groups and Duncan’s post hoc test with the aid collecting tubules, and interstitial tissue), the comparison of of Statistical Package for Social Sciences (SPSS) software, Vaccinium arctostaphylos L. extract groups with positive and SPSS Inc. p values < 0.05 were considered statistically negative control groups and comparison of treatment group significant. with Vaccinium arctostaphylos L. extract at 400 mg/kg

Table 2 Volume of the kidney, proximal and distant convoluted tubules, loop of Henle, vessels, and renal collecting tubules (Mean ± SD)

Vo lu me o f Volume of renal Vo lu me o f Volume of distal Volume of proximal Kidney volume interstitial tissue collecting tubules vessels convoluted (mm3) convoluted tubules (mm3) (mm3) (mm3) (mm3) (mm3)

1/12 ± 14/42 12/37 ± 14/135 9/6 ± 14/30 21/27 ± 14/161 91/84 ± 14/402 29/178 ± 14/840 Negative control (healthy) 6/14 ± 14/90 9/55 ± 14/105 18/12 ± 14/61 9/37 ± 21/111 14/104 ± 14/226 6/145 ± 14/961 Positive control (patient) 9/16 ± 12/83 4/32 ± 12/110 9/13 ± 14/56 96/25 ± 14/130 26/80 ± 12/241 91/146 ± 21/925 Gentamicin + 100 mg/kg Vaccinium arctostaphylos L. 12/12 ± 4/46 4/40 ± 16/116 4/10 ± 6/38 46/28 ± 9/136 2/52 ± 1/260 14/122 ± 4/914 Gentamicin + 200 mg/kg Vaccinium arctostaphylos L. *12/9 ± 11/31 14/38 ± 14/116 *12/9 ± 4/36 *21/35 ± 45/167 *16/77 ± 14/374 *96/104 ± 41/825 Gentamicin + 400 mg/kg Vaccinium arctostaphylos L. 001/0 06/0 009/0 032/0 02/0 082/0 p

Comp Clin Pathol

Table 3 Vo lu me (m m 3) and number of glomeruli (mean ± SD)

Number of glomeruli Volume of glomeruli (mm3) Kidney weight (g) Groups

8/1121 ± 4/27412 96/9 ± 9/30 14/220 ± 14/950 Negative control (healthy) 2/880 ± 1/19450 2/11 ± 4/53 19/200 ± 12/1051 Positive control (patient) 2/740 ± 6/21324 6/14 ± 24/49 21/168 ± 14/985 Gentamicin +100 mg/kg Vaccinium arctostaphylos L. 9/630 ± 4/23514 4/12 ± 14/44 21/212 ± 14/980 Gentamicin + 200 mg/kg Vaccinium arctostaphylos L. *5/910 ± 4/25426 *1/9 ± 6/35 45/165 ± 1/900 Gentamicin + 400 mg/kg Vaccinium arctostaphylos L. 035/0 015/0 095/0 p

showed a significant reduction in the volume of vessels that 400 mg/kg Vaccinium arctostaphylos L. extract group (p = 0.009) and interstitial tissue (p = 0.001) in comparison caused a significant decrease in lymphocytic infiltration with positive control group. The comparison of Vaccinium (0.0018) and cast formation (p = 0.0023) in comparison with arctostaphylos L. extract groups with positive and nega- positive control group (Table 4). tive control groups showed a significant difference in the volume of proximal convoluted tubules (p = 0.02), distant convoluted tubules (p = 0.032), and loop of Henle (p = Pathologic findings of kidney tissue 0.038) only at 400 mg/kg dose, while renal collecting tubules and loop of Henle indicated no significant differ- The histopathological analyses of kidney tissue showed severe ence between the treatment groups and positive and neg- degeneration of epithelial tubules, lymphocytic infiltration in- ative control groups despite an increase in the volume to interstitial space, increased interstitial tissue, necrosis and (p >0.05)(Table 2). swelling of glomeruli in positive control group (Fig. 3).The After calculation of the volume and number of glomeruli, healthy kidney in the negative control group is shown in the comparison of Vaccinium arctostaphylos L. extract groups Fig. 4, which has a normal structure of glomeruli and renal with positive and negative control groups showed a significant tubules. Renal damage was reduced in a dose-dependent man- difference in the volume of glomeruli (p = 0.015) at 400 mg/ ner in the Vaccinium arctostaphylos L. extract groups. With a kg dose. The comparison of the number of glomeruli indicated rise in the dose of extract, tubular degeneration, lymphocytic a significant increase between Vaccinium arctostaphylos L. infiltration and necrosis of glomeruli decreased. At lower extract groups and positive and negative control groups (p = doses (100 mg/kg), necrosis, mild tubular degeneration and 0.035) at 400 mg/kg dose in comparison with positive control mild lymphocytic infiltration were observed (Fig. 5). At 400 group (Table 3). mg/kg concentration, these damages highly reduced, tubules The comparison of results of lymphocytic infiltration and and glomeruli had a normal arrangement and structure and cast formation between control and treatment groups showed lymphocytic infiltration was very low (Fig. 6).

Table 4 Comparison of lymphocytic infiltration and cast formation by intensity

Cast formation (4–0 mean ± SD,) Lymphocytic infiltration mean ± SD, 0–4)) Groups

014/0 ± 23/0 014/0 ± 4/0 Negative control (healthy) 12/0 ± 2/2 16/0 ± 1/3 Positive control (patient) 14/0 ± 3/2 12/0 ± 2/3 Gentamicin + 100 mg/kg Vaccinium arctostaphylos L. 16/0 ± 8/1 16/0 ± 9/2 Gentamicin + 200 mg/kg Vaccinium arctostaphylos L. 12/0 ± 92/0 11/0 ± 6/1 Gentamicin + 400 mg/kg Vaccinium arctostaphylos L. *0023/0 *0018/0 p

Comp Clin Pathol

Fig. 3 Kidney tissue of positive control group (gentamicin). Lymphocytic infiltration (arrow) (a), acute necrosis of kidney tubules and glomeruli (arrow) (b), increased glomerular volume (arrow) (c).Single asterisk indicates cast in tubules (PAS staining, × 400 magnification)

Discussion in the kidneys through inhibition of Na+/K + ATPase. Inhibition of this enzyme causes swelling and necrosis of tu- Vaccinium arctostaphylos L. fruit extract improved the serum bular cells and reduces the urine sodium. Studies have shown urea and creatinine, sodium ion, and factors such as volume of that treatment with antioxidants improves the expression of renal tubules, blood vessels, and volume and number of glo- AQP2 and inhibition of Na+/K + ATPase enzyme, thereby meruli. During damage to renal tubules, urea does not enter ameliorating the renal tubules and ion transfer (Bae et al. urine from blood plasma and increases in the serum. In addi- 2008). Studies on compounds containing flavonoid and phe- tion, during damage to glomeruli, serum creatinine increases. nolic antioxidants have reported increased excretion of sodium Use of Vaccinium arctostaphylos L. fruit extract reduced the and potassium ions (Zangeneh et al. 2018; Tsuruya et al. 2003). serum levels of both compounds, which can be attributed to Vaccinium arctostaphylos L. plant shows antioxidant ef- the improved performance of renal tubules and glomeruli. fects and has anti-cancer and anti-inflammatory effects due Vaccinium arctostaphylos L. fruit extract was used to im- to having anthocyanides (Babu et al. 1995). Gentamicin in- prove gentamicin-induced renal damages owing to having dif- duces cell toxicity by increasing ROS such as superoxidase 2− ferent antioxidants. Gentamicin reduced the expression of (O ) and hydrogen peroxide (H2O2), which leads to cell aquaporin-2 channels (AQP2), thereby decreasing urinary os- membrane oxidation and cell death. After destruction of tubu- molality, retention of plasma ion, and consequently causing lar cells by gentamicin, the excretion rates of urea, creatinine, inability in concentrating urine. Thus, sodium and potassium ions are increased (Sharififar et al. 2012; Lee et al. 2001). Moreover, gentamicin causes inability in concentrating urine

Fig. 4 Kidney tissue of negative control group (healthy kidney). Kidney tubules: proximal convoluted tubules (PCT), distal convoluted tubules Fig. 5 Kidney tissue of treatment group (100 mg/kg). Mild degeneration (DCT), loop of Henle (LH), and glomerulus (G), which is in normal of kidney tubules and healthy tubules along with lymphocytic infiltration condition (PAS staining, × 400 magnification) (PAS staining, × 400 magnification) Downloaded from http://iranpaper.ir http://www.itrans24.com/landing1.html

Comp Clin Pathol

cells, provide enough blood supply to the kidney tissue by decreasing the vascular damage factors, and prevent renal damage (Pedraza-Chaverrı́ et al. 2003). However, further molecular and ultrastructural studies are required to confirm this issue.

Conclusion

Fig. 6 Kidney tissue of treatment group (400 mg/kg). Very mild Hydroalcoholic extract of Vaccinium arctostaphylos L. fruit degeneration and necrosis of tubules along with mild lymphocytic infiltration of interstitial tissue (PAS staining, × 400 magnification) protected the kidneys against gentamicin-induce toxicity. The antioxidant compounds in the fruit of this plant inhibited damage to renal tubular cells, thereby helping the kidneys to sodium, and potassium change; their serum levels increase maintain their normal function. and their urinary levels decrease (Walker and Shah 1988; Al-Majed et al. 2002). Nikavar et al. identified three anthocy- Compliance with ethical standards anin compounds, including petunidin, delphinidin, and malvidin (Nickavar and Amin 2010). Different studies have Conflict of interest The authors declare that they have no conflict of reported the antioxidant properties of anthocyanins, which interest. prevent cell death by inhibition of cell membrane oxidation. The effect of anthocyanin on cancer cells has shown that these Ethical approval All institutional and national standards for the care and use of laboratory animals were followed. This article does not contain any compounds lead to apoptosis of cancer cells (Hafeez et al. studies with human participants performed by any of the authors. 2008;Houetal.2005). Research on plants containing petunidin, delphinidin, and malvidin anthocyanins has indicated that they have protective effects on gentamicin- and References cisplatin- induced renal toxicity and improve BUM and Cr serum factors (Sharma et al. 2011;Adikayetal.2010). Adikay S, Belide P, Koganti B (2010) Protective effect of fruits of In the present study, urea and creatinine, as serum factors Syzygium cumini against cisplatin-induced acute renal failure in showing renal toxicity, increased significantly in the groups rats. J Pharm Res 3(11):2756–2758 receiving gentamicin, which is indicative of cell impairment in Akbari M, Goodarzi N, Tavafi M (2017) Stereological assessment of proximal convoluted tubules. Studies have shown that genta- normal Persian squirrels (Sciurus anomalus) kidney. Anat Sci Int 92:267–274 micin accumulates in the mitochondria of proximal tubules Akhondzadeh Sh.(2000) Encyclopedia of Iranian Medicinal Plants. and increases the production of free radicals such as hydrogen JRAN. Arjomand press. pp: 144 peroxidation, impairs the kidney tubules, reduces the number Al-Majed AA, Mostafa AM, Al-Rikabi A, C and Al-Shabanah O.A. of cells, and decreases the volume of tubules (Yang et al. (2002) Protective effects of oral arabic gum administration on – 1995). Pomegranate peel extract decreases oxidative stress gentamicin-induced nephrotoxicity in rats. Pharmacol Res 46:445 451 factors such as catalase (CAT) and superoxide dismutase Babu E, Gopalakrishnan V. K Gopalakrishnan V.K., Sriganth I.N.P., (SOD). In addition to other antioxidant compounds, Gopalakrishnan R., Sakthisekaran D. 1995. Cisplatin induced neph- delphinidin is found in the compounds of this fruit, which rotoxicity and the modulating effect of glutathione ester. Mol Cell reduces the destructive effects of free radicals. This anthocy- Biochem 144: 7–11 anin exists in Vaccinium arctostaphylos L. fruit extract, too Bae WK et al (2008) Decreased expression of Na+/K+-ATPase, NHE3, NBC1, AQP1 and OATin gentamicin-induced nephropathy. Korean (Boroushaki et al. 2013). J Physiol Pharmacol 12:331–336 Khalili et al. showed Vaccinium arctostaphylos L. extract Baradaran A, Nasri H, Nematbakhsh M, Rafieian-Kopaei M (2014) reduced renal blood pressure without changing the cardiac Antioxidant activity and preventive effect of aqueous leaf extract blood pressure (Khalili et al. 2011). Delphinidin in this plant of aloe vera on gentamicin-induced nephrotoxicity in male Wistar rats. Clin Ter 165:7–11 acts as a vasodilator, which can reduce the blood pressure. Boroushaki MT, Arshadi D, Jalili-Rasti H, Asadpour E, Hosseini A This anthocyanin leads to inhibition of angiotensin- (2013) Protective effect of pomegranate seed oil against acute tox- converting enzyme (ACE). Given the role of this enzyme in icity of diazinon in rat kidney. Iran J Pharm Res: IJPR 12:821 vasoconstriction process, it can lead to vasodilation Coca SG, Yalavarthy R, Concato J, Parikh CR (2008) Biomarkers for the (Nekooeian and Mashhoodi 2007; Ojeda et al. 2010). The fruit diagnosis and risk stratification of acute kidney injury: a systematic review. Kidney Int 73:1008–1016 extract of this plant lowers the blood pressure and reduces El-Razek FHA, Kamel EA (2011) Ameliorative effect of renal damages. In addition, anthocyanins affect many renal POMENGRATE peel water extract against folic acid-induced neph- vascular damages by inhibiting the free radicals in endothelial rotoxicity in rats. Int J Acad Res 3(4) Downloaded from http://iranpaper.ir http://www.itrans24.com/landing1.html

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