|Year : 2021 | Volume
| Issue : 1 | Page : 297-304
Nephroprotective effect of coadministration of curcumin and sildenafil in adenine-induced chronic renal failure in rats
Maha M El-Batsh1, Rehab M Samaka2, Emad Eldin M. Elhenawy1, Abd Elrahman A. Yassin1, Samar R Elnaggar1
1 Department of Clinical Pharmacology, Faculty of Medicine, Menoufia University, Shebin El Kom, Egypt
2 Department of Pathology, Faculty of Medicine, Menoufia University, Shebin El Kom, Egypt
|Date of Submission||27-Apr-2019|
|Date of Decision||18-May-2019|
|Date of Acceptance||20-May-2019|
|Date of Web Publication||27-Mar-2021|
Samar R Elnaggar
Shebin El Kom, Menoufia
Source of Support: None, Conflict of Interest: None
Chronic renal failure (CRF) is a major public health problem worldwide. The pathophysiological basis of the disease and its complication include inflammation and oxidative stress, which are similar in humans and animals. In this study, we seek to develop new therapeutic modalities for CRF.
This study aimed to investigate the nephroprotective effects of curcumin (CUR) and/or sildenafil in adenine (AD) model of CRF.
Materials and methods
Rats were divided into five groups as follows: control naive group, AD group received AD 200 mg/kg/day orally to induce CRF, CUR group received CUR 200 mg/kg/day in addition to AD, sildenafil group received sildenafil 0.5 mg/kg/day in addition to AD, and combination group received combination of CUR 200 mg/kg/day and sildenafil 0.5 mg/kg/day in addition to AD. After consecutive 28 days of treatment, body weight, kidney index, and Doppler on renal artery assessments were done for all groups. In addition, kidney function tests and markers of oxidative stress were evaluated. Histopathological assessment of renal tissues and immunohistochemical staining for tumor necrosis factor-α were performed.
CUR, sildenafil, and their combination significantly decreased body weight loss and urine volume and improved renal hemodynamic changes caused by AD. In addition, they significantly improved kidney function tests and biomarkers of oxidative stress. A significant down-regulation of tumor necrosis factor-α immunohistochemical expression was noted. They also brought histopathological changes induced by AD toward normal.
CUR and sildenafil may play a role in renal protection in AD-induced nephrotoxicity. The combined treatment showed better nephroprotective effect than either treatment alone did.
Keywords: adenine, anti-inflammatory, chronic renal failure, curcumin, oxidative stress, sildenafil
|How to cite this article:|
El-Batsh MM, Samaka RM, Elhenawy EE, Yassin AE, Elnaggar SR. Nephroprotective effect of coadministration of curcumin and sildenafil in adenine-induced chronic renal failure in rats. Menoufia Med J 2021;34:297-304
|How to cite this URL:|
El-Batsh MM, Samaka RM, Elhenawy EE, Yassin AE, Elnaggar SR. Nephroprotective effect of coadministration of curcumin and sildenafil in adenine-induced chronic renal failure in rats. Menoufia Med J [serial online] 2021 [cited 2021 May 8];34:297-304. Available from: http://www.mmj.eg.net/text.asp?2021/34/1/297/312002
| Introduction|| |
Chronic renal failure (CRF) is considered as a public health priority worldwide . According to Global Burden of Disease study that ranked the causes of death worldwide in 1990 and 2017, it is expected that in 2040 CRF will climb the list from 16th to 5th position as a cause of early death worldwide . Moreover, in 2015, 1.2 million people died owing to kidney failure, an increase of 32% since 2005 . The heave of the CRF epidemic over these decades produced an 82% increase in years of life lost owing to CRF . Early mortality is not the only problem, because most of the CRF survivors develop end-stage renal disease (ESRD), a condition causing disability, poor quality of life, and large social and financial costs. In Africa, Egypt has the second highest rate of CRF prevalence, estimated by 669 patients per million populations . The pathophysiological basis of CRF and its complications includes inflammation, oxidative stress, and apoptosis . These pathophysiological changes are always seen in both humans and animals .
CRF animal models are helpful tools in understanding the fundamental biochemical, pathophysiological, and histopathological processes involving CRF and in developing and trying potential therapeutic agents.
Adenine (AD) model of CRF is considered one of the most successfully adopted models of CRF. It was first described by Yokozawa et al. . The mechanism by which AD induces CKD is not well elucidated. AD-administered to rats along with its metabolite, 2,8-dihydroxyadenine has a low solubility and precipitate in the renal tubules, leading to their occlusion, resulting in inflammation accompanied by oxidative stress and fibrosis, leading to development of CRF and growth retardation which are similar to human CRF .
Curcumin (CUR) is the active component in the traditional herbal remedy and dietary spice turmeric (Curcuma longa) and is undergoing clinical trials for a variety of diseases, including cancer, Alzheimer's disease, and ulcerative colitis . It is also shown to have a wide variety of therapeutic effects that encompass anti-inflammatory, antioxidant, antibacterial, antimutagenic, anticoagulant, and the anticancer effects .
Sildenafil is one of the phosphodiesterase-5 inhibitors developed to treat angina pectoris and was afterward used for the treatment of erectile dysfunction and pulmonary hypertension . Experimental studies have verified that sildenafil improves endothelial dysfunction and reduces the infarct size in a rat model of myocardial infarction . The antioxidant, anti-inflammatory, and antiapoptotic properties of sildenafil may play an important role in its renoprotective effect in different models of acute and chronic renal injury .
The current work aimed to evaluate the potential nephroprotective effect of sildenafil, CUR, and their combination biochemically and histopathologically using a rat model of CKD.
| Materials and methods|| |
AD powder was purchased from Acros (Waltham, Massachusetts, USA). CUR powder was purchased from Sigma (Egypt). Sildenafil powder was purchased from Hi Pharm (El Obour City, CAIRO Egypt). Biochemicals and substrates were purchased from Sigma-Aldrich Chemicals (St Louis, Missouri, USA).
A total of 30 young adult male Sprague-Dawley rats weighing 110–200 g were purchased from a local vendor. Animals were acclimatized to the laboratory conditions for 1 week before the experiments. Animals were housed in cages under controlled conditions of temperature of 25 ± 2°C, relative humidity of ∼50%, and 12 h light/dark cycles throughout the experiment. Standard food and water were allowed. All experiments were carried out in accordance with protocols approved by the local experimental ethics committee for animal research in Faculty of Medicine, Menoufia University, and complied with the Guide for the Care and Use of Laboratory Animals (ILAR 1996).
Rats were randomly divided into five groups (six rats for each) and were subjected to treatment as follows: (a) control naive group is the vehicle-treated group, (b) AD group received a single daily dose of AD 200 mg/kg dissolved in normal saline orally at 9 a.m. for 28 successive days to induce CRF , (c) CUR group was treated with a single daily dose of CUR 200 mg/kg dissolved in olive oil orally at 12 p.m. concomitant with AD 200 mg/kg/day dissolved in normal saline at 9 a.m. orally for 28 successive days , (d) sildenafil group was treated with a single daily dose of sildenafil 0.5 mg/kg dissolved in normal saline orally at 3 p.m. concomitant with AD 200 mg/kg/day dissolved in normal saline orally at 9 a.m. for 28 successive days , and (e) the combination group was treated with a combination of CUR (200 mg/kg/day) orally at 12 p.m. and sildenafil (0.5 mg/kg/day) orally at 3 p.m. concomitant with AD 200 mg/kg/day orally at 9 a.m. for 28 successive days. Initial and final body weight was measured for each rat.
On the 29th day, rats were placed individually in metabolic cages for 24 h to collect urine. Immediately after urine collection, each rat was anesthetized by diethyl ether, then was laid on its back, and midline laparotomy was done to expose the renal artery. Doppler on renal artery was done for all animals. Blood and urine samples were collected and used for estimation of urine volume, serum blood urea nitrogen (BUN), serum creatinine, serum malondialdehyde (MDA), and creatinine clearance (CrCl). After the animals were killed, right and left kidneys for each rat were removed, blotted on a filter paper, and weighed. One kidney was homogenized in 5–10 ml cold buffer per gram tissue and then centrifuged at 4000 rpm for 15 min. The supernatant was removed for estimation of reduced glutathione (GSH).
The other kidney was preserved in 10% formalin for histological assessment by hematoxylin and eosin stain, Masson Trichome (MT) stain to identify the extent of fibrosis, and immunohistochemical (IHC) staining for tumor necrosis factor-α (TNF-α). IHC staining was performed on formalin-fixed paraffin-embedded sections at 5-μm thickness and placed on positive charged slides. Mouse monoclonal antibody (Ab) was used against purified full-length native TNF-α of human origin. The Ab was provided by Santa Cruz biotechnology [TNF-α (52B83): SC-52746; Santa Cruz, California, USA] in a single vial containing 100 μg IgG1 in 1.0 ml. All slides were dewaxed and rehydrated in graded alcohol solutions. Antigen retrieval using microwave heating (20 min; 10 mmol/citrate buffer, pH 6.0) after inhibition of endogenous peroxidase activity (0.3) hydrogen peroxidase for 15 min) were used. The primary antibodies were applied to the slides. The slides were incubated overnight with the primary antibody at room temperature, and washed by using PBS then incubated with secondary antibody (Dako Laboratories, Santa Clara, California , USA) for 15 min followed by PBS wash. Finally, the detection of bound antibody was accomplished using a modified labeled avidin–biotin reagent for 20 min followed by PBS wash. A 0.1% solution of diaminobenzidine was used for 5 min as a chromogen. Slides were counterstained with Mayer's hematoxylin for 5–10 min. Positive control for the reaction was performed using ovarian tissue and negative control was made by substituting the primary antibodies with non-immune serum.
Positive TNF-α expression was considered when cytoplasmic immune-localization was detected at any number of cells. TNF-α was further evaluated by the reproducible histo-score (H-score) system. Mild staining is assigned as 1+, moderate staining as 2+ and strong staining as 3+. In H-score system, both the intensity and percentage are considered. The score was calculated as follows: H- score = (1% + cells × 1) + (2% + cells × 2)+ (3% + cells × 3) .
Unintentional bias was prevented by coding tissue samples, so that IHC study was done without knowing the used component characteristics.
Results were collected, tabulated, and statistically analyzed by statistical package for the social sciences, version 20 (SPSS Inc., Chicago, Illinois, USA). Results were expressed as mean ± SEM and percentage.
The statistical significance between the means of different groups was analyzed using one-way analysis of variance or Kruskal–Wallis test (nonparametric method) followed by Tukey's post-hoc test. Level of statistical significance was set at P value less than 0.05.
| Results|| |
Regarding the effects of therapy on physiological indices, AD treatment significantly reduced body weight and renal blood flow velocity and significantly increased urine volume, kidney index, and renal vascular resistance compared with the control group (P = 0.0001 for all). Treatment of AD group with CUR, sildenafil, or their combination significantly decreased body weight loss (P = 0.0001), kidney index (P = 0.000), and renal vascular resistance (P = 0.049, 0.0001, and 0.0001, respectively) and significantly increased renal blood flow velocity (P = 0.017, 0.003, and 0.0001, respectively) compared with AD group [Table 1].
|Table 1: Comparison between the studied groups regarding body weight change, kidney index, urine volume, renal blood flow velocity, and renal vascular resistance|
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Regarding urine volume, administration of CUR or combination of CUR and sildenafil significantly reduced urine volume (P = 0.000) compared with AD group. However, the reduction in urine volume in sildenafil-treated group failed to reach the level of significance [Table 1].
Effects of therapy on biochemical parameters
AD significantly increased serum levels of BUN, serum creatinine, and CrCl as compared with the control group (P = 0.0001 for all). However, CrCl was significantly decreased in AD-administered group compared with the control group (P = 0.0001). On the contrary, treatment of AD-ingested rats with either CUR or sildenafil or their combination significantly decreased BUN (P = 0.0001, 0.001, and 0.0001, respectively), serum creatinine levels (P = 0.001, 0.05, and 0.0001, respectively), and significantly increased CrCl (P = 0.001, 0.05, and 0.0001, respectively) compared with AD-administered group [Table 2].
|Table 2: Comparison between the studied groups regarding serum creatinine, blood urea nitrogen, glutathione reduced, malondialdehyde levels, and creatinine clearance|
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AD administration resulted in a significant increase in serum MDA level and a significant decrease in the renal content of GSH (P = 0.0001) compared with control rats. Treatment with CUR, sildenafil, or their combination significantly restored the normal values for the serum MDA level (P = 0.001, 0.001, and 0.0001, respectively) and the renal content of GSH (P = 0.002, 0.014, and 0.0001, respectively) as compared with AD group [Table 2].
Effects of therapy on histopathological analysis
Histopathological assessment of renal tissues of rats in the different groups using the hematoxylin and eosin and MT stains showed that control rats exhibited normal architecture and histology of renal tissues with the two stains employed [Figure 1]a and [Figure 1]b. In AD group, there were intensive tubular atrophy, tubular dilatation, crystals, tubular cast formations, and cellular shedding. In addition, there were periglomerular inflammation and fibrosis, severe interstitial inflammation, foreign body granulomatous reaction, and fibrosis detected by MT [Figure 2]a and [Figure 2]b.
|Figure 1: Histopathological analysis in the control group: (a) H and E-stained section showed renal tissue with unremarkable pathological changes. (b) MT-stained section showed no fibrosis. (c) IHC expression of TNF-α showed mild cytoplasmic staining (×200 for a, c; ×100 for b). H and E, hematoxylin and eosin; IHC, immunohistochemical; MT, Masson Trichome; TNF, tumor necrosis factor.|
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|Figure 2: Histopathological analysis in AD group: (a) H and E-stained section showed severe tubular atrophy, dilatation, crystals, tubular cast formations, and cellular shedding; inset foreign body granuloma was demonstrated. (b) MT-stained section showed severe periglomerular and interstitial fibrosis; inset periglomerular fibrosis was appreciated. (c) IHC expression of TNF-a showed marked increase in the intensity of TNF-α staining; inset strong tubular IHC expression for TNF-α was appreciated (×100 for a–c). AD, adenine; H and E, hematoxylin and eosin; IHC, immunohistochemical; MT, Masson Trichome; TNF, tumor necrosis factor.|
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In CUR-treated and sildenafil-treated groups, there were moderate degrees of tubular atrophy, tubular dilatation, crystals, tubular cast formations, periglomerular inflammation and fibrosis, and moderate interstitial inflammation and fibrosis [Figure 3]a and [Figure 3]b for CUR; ([Figure 4]a and [Figure 4]b for sildenafil).
|Figure 3: Histopathological analysis in AD + CUR group: (a) H and E-stained section showed moderate tubular atrophy, dilatation, crystals, cast formations demonstrated at inset. (b) MT-stained section showed moderate periglomerular fibrosis, interstitial inflammation, and fibrosis; inset periglomerular fibrosis was appreciated. (c) IHC expression of TNF-α showed marked reduction in the intensity of TNF-α staining; inset moderate tubular IHC expression for TNF-α was appreciated (×200 for a, c; ×100 for b). AD, adenine; CUR, curcumin; H and E, hematoxylin and eosin; IHC, immunohistochemical; MT, Masson Trichome; TNF, tumor necrosis factor.|
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|Figure 4: Histopathological analysis in AD + sildenafil group: (a) H and E-stained section showed moderate tubular atrophy, dilatation, crystals, and cast formations demonstrated at inset. (b) MT-stained section showed moderate periglomerular fibrosis, interstitial inflammation, and fibrosis; inset the periglomerular fibrosis was appreciated. (c) IHC expression of TNF-α showed marked reduction in the intensity of TNF-α staining; inset moderate tubular IHC expression for TNF-α was appreciated (×100 for a, b; ×200 for c). AD, adenine; H and E, hematoxylin and eosin; IHC, immunohistochemical; MT, Masson Trichome; TNF, tumor necrosis factor.|
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Coadministration of CUR and sildenafil caused a marked improvement in the histological structure when compared with the AD group, as there were mild dilatation of tubules, less interstitial inflammatory cells infiltration, and less tubular atrophy. MT revealed mild interstitial fibrosis [Figure 5]a and [Figure 5]b.
|Figure 5: Histopathological analysis in AD + combination group: (a) H and E-stained section showed mild dilatation of tubules, less interstitial inflammatory cells infiltration, and less tubular atrophy; inset interstitial and periglomerular fibrosis were seen. (b) MT-stained section revealed mild interstitial fibrosis that demonstrated inset. (c) IHC expression of TNF-α showed mild intensity of TNF-α IHC staining; inset mild to faint tubular epithelium IHC expression for TNF-α was appreciated (×100 for a, b; ×200 for c). AD, adenine; H and E, hematoxylin and eosin; IHC, immunohistochemical; MT, Masson Trichome; TNF, tumor necrosis factor.|
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Regarding IHC expression of TNF-α in the studied groups [Figure 1]c, [Figure 5]c, TNF-α immunoreactivity was assessed by using intensity and H-score. Control naive group showed positive cytoplasmic TNF-α IHC staining with absolute mild degree of intensity and low H-score. AD-treated group showed marked increase in the intensity of TNF-α IHC staining and significantly increase in TNF-α H-score (P < 0.001) compared with control naive group.
CUR-treated, sildenafil-treated or combination-treated groups in comparison with AD group exhibited marked reduction in the intensity of TNF-α IHC staining and significant decrease in TNF-α H-score (P < 0.001 for all) compared with AD group. In addition, the combination treatment significantly decreased intensity of TNF-α IHC staining and H-score (P < 0.001) compared with each single drug alone [Table 3].
|Table 3: Comparison between the studied groups regarding immunohistochemical expression of tumor necrosis factor-α|
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| Discussion|| |
The incidence of CRF is increasing worldwide; nevertheless, renal replacement therapy, either transplantation or dialysis, is limited in several regions of the world owing to need of financial and clinical resources . Therefore, it is necessary to develop new therapeutic modalities to delay the development of ESRD and onset of dialysis or to improve uremia.
AD-induced CRF is one of the most suitable animal models for testing new therapies. The reason for that is it is easy to conduct and produces biochemical and histopathological changes similar to what happen in humans .
Recent studies showed that CUR and sildenafil can be used as nephroprotective agents that offer a safe, effective, and commercial alternatives to protect kidneys against damaging factors ,. Furthermore, they might prevent the progression of renal impairment to the ESRD where the renal replacement therapy is the only way of therapy, which may be expensive or even unavailable in many developing countries .
In this study, AD administration decreased the final body weight and increased the relative kidney weight and urine volume. These results were in agreement with Diwan et al. .
In this study, the development of CRF in AD group was confirmed by elevated serum creatinine and BUN levels and decreased CrCl, which was in accordance with El-Safti and Mohammed .
Moreover, results of this study revealed that AD administration significantly decreased renal blood flow velocity and significantly increased renal vascular resistance compared with control rats. These results were in agreement with Al Zaabi et al. . The changes in renal hemodynamics could be explained by the findings of Hussein et al.  who reported that AD impaired the vasodilator responses of the vascular endothelium by downregulating endothelial nitric oxide synthase, which enhanced the production of vasodilator NO in kidney tissues in AD-treated group.
The data of this study showed that administration of CUR or sildenafil reduced significantly body weight loss, kidney index, and urine volume compared with AD group. These results were in agreement with Ali et al. ,. In addition, CUR and sildenafil produced marked improvement in renal hemodynamics, as they produced significant increase in renal blood flow velocity and significant decrease in renal vascular resistance.
The mechanism by which CUR affected renal hemodynamics was unclear. However, Akazawa et al.  reported that CUR ingestion improved blood flow, endothelial dysfunction, and vascular remodeling by increasing in the circulating NO and the suppression of inflammation and/or oxidative stress via down-regulation of TNF-α.
The effect of sildenafil on renal hemodynamics was expected, as sildenafil is one of phosphodiesterase-5 inhibitors that inhibit degradation of cyclic guanosine monophosphate into guanosine monophosphate, which inhibits calcium entry into the smooth muscle cells by directly inhibiting calcium channels and phosphorylation of myosin light chain kinase enzyme, producing vasodilatation, increasing the release of NO, which is decreased by AD , and improving endothelial dysfunction . The current study showed reduction in serum creatinine and BUN and significant increase in CrCl in CUR-treated and sildenafil-treated groups compared with AD group, indicating improvement in renal function. These results were in agreement with the findings of Ali et al. ,. The renoprotective effect of these drugs may be owing to their antioxidant properties as they significantly decreased serum level of MDA and significantly increased renal tissue level of GSH in treated groups compared with AD group. These results were in agreement with the findings of Venkatesan et al. , Khames et al. , and Ali et al. ,.
Inflammation is one of the most important mechanisms of AD-induced CRF, where in the present study it caused severe inflammatory cell infiltration and significant increase in the infiltration of inflammation-related cytokine TNF-α in the tubulointerstitium of AD group compared with control naive group judged by immunohistochemistry. These results were in agreement with Chen et al. .
In this study, administration of CUR or sildenafil with AD to rats exhibited marked reduction in inflammatory cell infiltration and significant decrease in the infiltration of inflammation-related cytokine TNF-α in the tubulointerstitium of treated groups compared with AD group, judged by immunohistochemistry denoting their anti-inflammatory potential. These results were in agreement with the findings of Ghosh et al. , Khames et al. , and Ali et al. ,.
In this study, comparison between the combination-treated group and single drug-treated groups regarding physiological and biochemical parameters, histopathological examination, and IHC staining of TNF-α showed that these parameters improved in the combination-treated group more than the groups treated with CUR or sildenafil alone. So, this study revealed that administration of CUR and sildenafil together produced better nephroprotective effects compared with a single drug alone, reflected by decreased serum creatinine, BUN levels, and urine volume and increased CrCl, improved AD-induced changes in body weight, relative kidney weight, renal blood flow, and oxidative stress biomarkers, in which, both drugs increased renal tissue content of GSH, and also decreased IHC expression of TNF-α. Histopathologic examination of renal tissues showed improvement of all assessed tubular and interstitial parameters in combination group compared with CUR or sildenafil alone. The noted histopathological improvement was consistent with the observed biochemical changes. It is therefore conceivable that the combination of CUR and sildenafil may produce additive or synergistic effects.
In this study, the superiority of coadministration of CUR and sildenafil for attenuation of AD-induced CRF could be explained by antioxidant and anti-inflammatory potentials of both CUR and sildenafil, which were more apparent upon their combination together. These results were in agreement with Kaur et al.  who reported that coadministration of CUR and sildenafil together significantly improved alcohol-induced neuropathic pain compared with their individual administration.
| Conclusion|| |
CUR and sildenafil when administered alone or in combination could be promising drugs for protection against AD-induced nephrotoxicity. The nephroprotective effect of these drugs is best explained by their antioxidant and anti-inflammatory potentials. Observed data showed that the combination of the two drugs produced more marked antioxidant and anti-inflammatory effects than either of the treatment alone did, and therefore, this drug combination may represent a therapeutic advantage for protection against AD-induced nephrotoxicity.
The study was partially funded by Faculty of Medicine, Menoufia University.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5]
[Table 1], [Table 2], [Table 3]