The kidney is a vital organ for a healthy life and kidney disease can lead to life-threatening consequences. Many environmental contaminants and chemical variables, including drugs, alter the functions of the kidney. Intoxication of both acute and chronic nature has been reported to cause nephropathies with various levels of severity ranging from tubular dysfunctions to acute renal failure [1,2]. Nephrotoxicity is of critical concern when selecting new drug candidates during the early stage of drug development because of its unique metabolism .
Mesangial cells (MCs) form a supporting framework that maintains the structural integrity of the glomerular capillaries. Both the glomerular basement membrane (GBM) and the MCs establish a biomechanical unit capable of developing wall tension against a higher intraglomerular pressure and of changing the geometry of glomerular capillaries following mesangial contraction or relaxation. Moreover, MCs express several kinds of receptors for vasoactive agents such as angiotensin-II, vasopressin and endothelin .
Gentamicin is an aminoglycoside antibiotic that is very effective in treating life-threatening Gram-negative infections . Unfortunately, 30% of patients treated with gentamicin for more than 7 days show some signs of nephrotoxicity . The specificity of gentamicin for renal toxicity is apparently related to its preferential accumulation in the renal proximal convoluted tubules (50–100 times greater than serum) . The exact mechanism of gentamicin-induced nephrotoxicity is unknown. However, gentamicin has been shown to enhance the generation of reactive oxygen species (ROS) that cause deficiency in intrinsic antioxidant enzymes [7–9].
Recently, much attention has been focused on the protective effects of antioxidants and naturally occurring substances against oxidative stress damage. Oxidative stress was reported to be induced by reactive intermediates produced by various chemicals and drugs [10,11].
Medicinal plants have been known to play an important role in pharmacology and medicine since many years. Today, it is estimated that about 80% of the world's population relies on botanical preparations as medication to meet their health needs . Zingiber officinale Roscoe, known as ginger, is one of the most commonly used spices in the world. Ginger contains active phenolic compounds that have anti-inflammatory  and antioxidant properties . Among the pharmacological effects demonstrated are antiplatelet, antioxidant, antitumour, antihepatotoxicity and antiarthritic effects [15–17]. Ginger has been found to have a hypocholesterolaemic effect and reduces body weight, blood glucose, serum total cholesterol and alkaline phosphatase in adult male rats .
Many studies revealed episodes of acute tubular necrosis and/or acute interstitial nephritis attributed to gentamicin medication and determined the incidence to be 18.3% . However, little is known about its effect on glomeruli. Hence, the aim of the present study was to detect the effect of gentamicin on renal Malpighian corpuscles and to assess the protective role of ginger as an antioxidant on renal function, histology and immunohistochemistry.
Materials and methods
The study was conducted on 24 healthy adult male albino rats (5–7 months) weighing 200–250 g. These rats were obtained from the animal house of the Faculty of Medicine, Zagazig University, and kept under controlled laboratory conditions under a 12/12 h light/dark cycle at 25°C and provided with standard rodent pellet diet and water ad libitum. The experiment was conducted according to the norms of the Ethical Committee of the Zagazig University (Egypt).
The rats were divided into four groups (six rats each):
- Group I (the control group): The rats in this group were divided into two subgroups (three rats each):
Group II (the ginger group): The rats in this group were given only an aqueous extract of ginger at a daily dose of 1 ml through a gastric tube for 7 days . One kilogram of fresh ginger rhizome was cleaned, washed under running tap water, cut into small pieces, air dried and powdered. The concentration of the extract was 24 mg/ml .
Group III (the gentamicin-treated group): The rats in this group were given gentamicin sulphate intraperitoneally at a dose of 80 mg/kg/day for 7 days [21,22].
Group IV (the gentamicin and ginger group): The rats in this group were given an aqueous extract of ginger and gentamicin at the same doses, through the same route and for the same time periods as the previous groups.
- (a) Group Ia: The rats in this subgroup were given no medications to measure the basic parameters.
- (b) Group Ib: The rats in this subgroup were injected intraperitoneally with normal saline.
At the end of the experiment and after ether inhalation, venous blood samples were drawn from the retro-orbital sinus. The blood samples were allowed to clot at room temperature before being centrifuged at approximately 3000 rpm for 15 min. The serum was stored at −20°C until it was assayed for biochemical parameters . The following markers were measured in the serum and plasma:
- Blood urea nitrogen (BUN) and creatinine assessment in serum using a commercially available spectrophotometric enzymatic kit (Thermo Trace BECGMAN, Germany).
- Oxidative marker plasma superoxide dismutase (SOD): SOD was assessed colorimetically (absorbance 450 nm) using a commercially available kit (Biovision, cat. No. K335-100, San Francisco, USA) following the manufacturer's instructions.
- Lipid peroxidation marker malondialdehyde (MDA): MDA was assessed colorimetically (absorbance 532 nm) using a commercially available kit (Biovision, cat. No. K739-100) following the manufacturer's instructions.
At the end of the experiment, all studied animals were sacrificed after ether inhalation. The two kidneys of each rat were excised and prepared for the following studies:
Light microscopic study
The specimens were fixed in 10% neutral-buffered formalin, dehydrated, embedded in paraffin, cut at 5 μm and stained with H&E for routine histological examination and PAS stains .
Paraffin sections of 5 μm thickness were stained with modified avidin–biotin peroxidase for α-smooth muscle actin (α-SMA) to demonstrate MC expansion. Primary antibodies were purchased from Thermo Scientific Company. Sections were deparaffinized and subjected to hydration. They were treated with 0.01 mol/l citrate buffer (pH 6.0) for 10 min to unmask antigen. Thereafter, the sections were incubated in 0.3% H2O2 for 30 min to abolish endogenous peroxidase activity before being blocked with 5% horse serum for 1–2 h. The slides were incubated with the primary antibody (1 : 100 monoclonal mouse anti-α-SMA) at 4°C for 18–20 h, and then washed and incubated with biotinylated secondary antibodies and then with the avidin–biotin complex. Finally, sections were developed with 0.05% diaminobenzidine. The slides were counterstained with haematoxylin, dehydrated, cleared and mounted .
Electron microscopic study
Specimens from the kidney cortex were taken. They were immediately fixed in 2.5% glutaraldehyde buffered with 0.1 mol/l phosphate buffer at pH 7.4 for 2 h and then postfixed in 1% osmium tetroxide in the same buffer for 1 h at 4°C. The specimens were processed and embedded in Embded-812 resin in BEEM capsules at 60°C for 24 h. Semithin sections (1 mm thick) were stained with 1% toluidine blue for light microscopic examination . Ultrathin sections were obtained using Lecia ultracut UCT, (Germany) and stained with uranyl acetate and lead citrate  and were examined with a JEOL JEM 1010 electron microscope (Tokyo, Japan) at the Electron Microscope Research Laboratory (EMRL) of the Histology and Cell Biology Department, Faculty of Medicine, Zagazig University, and with a JEOL 1010 electron microscope at Mycology and Regional Biotechnology Center, Al Azhar University (Cairo, Egypt).
The image analyzer computer system Leica Qwin 500 (Cambridge, UK, Leica Microsystems Imaging Solutions Ltd) in the image analysing unit of the Pathology Department, Faculty of Dentist, Cairo University (Egypt), was used to evaluate α-SMA surface areas (mesangial expansions). The area percentage and standard measuring frame of a standard area equal to 118 476.6 mm2 were chosen from the parameters measuring 10 readings from five sections from each rat of the randomly chosen five rats. In each randomly chosen field, the section of the kidney was enclosed inside the standard measuring frame; then, α-SMA immunoexpression was masked by blue binary colour to be measured.
Statistical analysis was performed on all parameters. The obtained data were expressed as mean values ± SD and analysed using analysis of variance.
All the examined parameters in the ginger group were similar to those of the control group. There was no significant change in BUN, creatinine, SOD and MDA (Tables 1–4 & Histograms 1–4).
Gentamicin-treated rats showed a highly significant increase in BUN and serum creatinine levels. Treating animals with gentamicin and ginger induced a significant decrease in both BUN and serum creatinine levels when compared with the gentamicin-only group (Tables 1 and 2 & Histograms 1 and 2).
With regard to evaluation of oxidative and antioxidant enzymes, there was a highly significant increase in the levels of MDA, whereas the SOD was significantly decreased in animals treated with gentamicin compared with controls. Animals treated with both gentamicin and ginger showed a significant decrease in MDA and increase in SOD levels compared with the gentamicin-only group (Tables 3 and 4 & Histograms 3 and 4).
For evaluation of mesangial expansion, there was a highly significant increase in the α-SMA immunoexpression surface area in the gentamicin-treated group and a significant increase in the group treated with gentamicin and ginger compared with controls (Table 5 & Histogram 5).
Control group Ia, b and II
Light microscopic findings:
The renal cortices of rats in the control subgroups and those of ginger-treated rats were similar.
H&E-stained sections showed the renal corpuscles formed of glomerular capillaries surrounded by Bowman's capsule. Also, peritubular blood capillaries could be seen (Fig. 1a). Positive reaction for PAS showed thin basement membrane of Bowman's capsule, thin GBM and diffuse inter-capillaries mesangial matrix (Fig. 1B). Faint or no reaction for α-SMA appeared in a few MCs (Fig. 1c).
Toluidine blue-stained semithin sections showed the renal glomeruli formed of an anastomosing network of blood capillaries. Endothelial cells with flat nuclei were bulging into the capillary lumens. MCs and their matrix were seen between the capillaries. Bowman's capsules had regular parietal layers of attenuated flat cells and irregular visceral layers of podocytes (Fig. 2).
Electron microscopic findings:
Ultrastructurally, podocytes were seen to have euchromatic indented nuclei. Their cytoplasm contained mitochondria and a few rough endoplasmic reticulum. Primary (major processes) and secondary foot processes (pedicles) were observed. The spaces between the pedicles (filtration slits) were clearly seen and laid on a thin regular GBM. Fenestrations in the endothelial lining of the glomerular capillaries could be observed (Fig. 3).
Gentamicin-treated group III
Light microscopic findings:
H&E-stained sections showed variable focal changes in the structures of renal corpuscles. Some corpuscles appeared with congested glomerular capillaries and also with peritubular capillaries (Fig. 4a). Rupture of some glomerular capillaries with extravasated blood, an obvious thick irregular parietal layer of Bowman's capsule and periglomerular cellular infiltration were detected in other areas (Fig. 4b). Glomerular hypocellularity (a few MCs), clear swollen vacuolated parietal cells and obvious haemorrhage were observed (Fig. 4c). Other corpuscles showed glomerular hypercellularity (numerous MCs) (Fig. 4d). Glomerular hypercellularity with intertubular cellular infiltration was detected (Fig. 4e). Empty corpuscles with atrophic glomeruli and thick acidophilic basement membrane of Bowman's capsule were observed (Fig. 4f). Positive reaction of PAS appeared in the mesangial matrix of abundant intercapillaries (Fig. 5a). Atrophic glomeruli with a very thick basement membrane of Bowman's capsule and also GBMs were observed (Fig. 5b).
Immunohistochemical staining for α-SMA showed strong positive reaction in numerous MCs (Fig. 6).
Toluidine blue-stained semithin sections showed renal corpuscles with congested glomerular blood capillaries. Prominent endothelial cell nuclei were seen in some capillaries. MCs and their matrix were seen between the glomerular capillaries. Bowman's capsule had a regular parietal layer of flat cells and a visceral layer of large podocytes (Fig. 7a). Other distorted renal corpuscles with ill-defined glomerular capillary walls were detected. A few MCs and their matrix were observed between the capillaries. Bowman's capsule had a swollen parietal layer and a visceral layer of darkly stained podocytes (Fig. 7b).
Electron microscopic findings:
Podocytes with heterochromatic nuclei and distorted fused foot processes were detected. Irregular thickening of the GBM with lack of fenestration of glomerular capillaries was seen (Fig. 8). Lysosomes, phagolysosomes, dense bodies and vacuoles were observed in the cytoplasm of some podocytes (Figs 9 and 10). Numerous MCs with irregular heterochromatic nuclei were also observed (Fig. 10).
Gentamicin-treated and ginger-treated group IV
Light microscopic findings:
H&E-stained sections revealed most of the corpuscles as normal, whereas some of them were distorted. Numerous MCs (glomerular hypercellularity) were present (Fig. 11a). Positive reaction for PAS showed relatively thin basement membrane of Bowman's capsules and distributed inter-capillaries mesangial matrix (Fig. 11B). Also, positive reaction for α-SMA appeared in some MCs (Fig. 11c).
Toluidine blue-stained semithin sections showed renal glomeruli with anastomosing networks of blood capillaries. The capillary walls were lined by endothelial cells with flat nuclei. MCs and their matrix were seen between the capillaries. Bowman's capsule had a regular parietal layer of flat cells and a visceral layer of large podocytes (Fig. 12).
Electron microscopic findings:
Ultrastructurally, some podocytes appeared with euchromatic indented nuclei and well-defined primary and secondary foot processes. The filtration slits in between the foot processes were preserved. Small mitochondria and few rough endoplasmic reticulum were seen in the cytoplasm of podocytes. Regular relatively thin GBMs were detected. Thickened areas lacking endothelial fenestrations were observed in some GBMs (Fig. 13).
Aminoglycosides have been known as highly effective antimicrobial agents for more than 50 years. They are considered to be very effective against many life-threatening infections, especially those caused by Gram-negative bacteria, as they display many highly desirable properties including low rate of true resistance, low cost of therapy and rapid concentration-dependent bactericidal effects [27,28]. Gentamicin is one of the most important and effective aminoglycoside antibiotics used widely for treatment of serious infections. Adverse effects such as nephrotoxicity constitute one of the major limitations to their use [29,30]. Several studies have shown that gentamicin causes other infections such as hepatotoxicity  and testicular toxicity .
The nephrotoxicity induced by gentamicin is because about 5% of the administered dose is retained in the epithelial cells of the proximal convoluted tubules after their filtration. They are located in endosomal and lysosomal vesicles and also within the Golgi complex. Moreover, renal toxicity can be the result of a direct toxic effect, haemodynamic changes, inflammatory tissue injury and/or obstruction of renal excretion . This nephrotoxicity manifests clinically as nonoliguric renal failure with a slow rise in serum creatinine and a hypo-osmolar urinary output developing after several days of treatment .
Renal toxicity of gentamicin is believed to be related to the generation of ROS in the kidney. ROS are considered as important modulators of renal blood flow and glomerular infiltration rate. Also, production of excessive amounts of ROS causes oxidative stress, which results in alterations in mitochondrial oxidative phosphorylation, depletion of ATP, an increase in intracellular Ca and activation of protein kinases, proteases and nucleases, leading to loss of cellular function/integrity . Therefore, several antioxidants such as ginger have shown a protective role in models of experimentally mediated nephropathies caused by alcohol  and by metalaxyl fungicide .
In the current work, all the examined parameters in the ginger group were similar to those of the control one. These results were in line with those of other investigators , who concluded that ginger is probably a safe medicinal plant as there were no significant harmful changes in BUN, creatinine, SOD and MDA levels. BUN and serum creatinine were estimated to assess the extent of nephrotoxicity. This agreed with other results . In the current work, gentamicin-treated rats showed a highly significant increase in BUN and serum creatinine. This goes in hand with the results of many other researchers [35,36], who considered this increase to be a result of nephrotoxicity. It was previously reported that the increase in BUN and serum creatinine is because of the decreased glomerular filtration rate (GFR) even if there is no glomerular damage . The GFR reduction is because of the autocrine and paracrine action of contracting factors such as angiotensin II, endothelin I and platelet-activating factor produced by endothelial and MCs . This decrease in GFR will aggravate tubular damage. This impairment in kidney functions may be because of tubular degeneration as a result of oxidative stress induced by gentamicin and evidenced by decreased SOD level with increased MDA . In contrast, in group IV, ginger can suppress the gentamicin-induced increases in serum BUN and creatinine levels. This is in agreement with the results of other investigators , who found that the ability of ginger to enhance the mitochondrial antioxidant system is likely related to the nephroprotection against gentamicin toxicity.
All the biochemical changes in the current work were concomitant with histological changes in the renal glomeruli. These lesions were represented by congestion and rupture of the glomerular capillaries. The glomerular lesions may be related to the interaction of the biological membranes with gentamicin during its passage through the filtration barrier [19,29]. In the present study, thickening of the GBM and excessive extracellular matrix were observed. It was previously found that the basement membrane changes in diethylstilbestrol-treated rat kidneys included modulation and thickening in many areas and deterioration in others. The researchers correlated this to the change in ultrafiltration and Na/H2O balance disorder in these rats . Moreover, the thickening in the basement membrane is a sign of damage because of ROS . ROS are involved in the production of extracellular matrix proteins, especially fibronectin . However, many authors  stated that endothelin-1 release from MCs as a result of glomerular injury stimulates hypertrophy, proliferation and extracellular matrix accumulation in the kidney, primarily through endothelin type-A receptor stimulation.
In the current work, features of apoptosis were seen in some podocytes, which appeared small with darkly stained nuclei. Their cytoplasm contained multiple lysosomes and vacuoles. They had distorted fused foot processes. This was in accordance with other previous findings [29,40]. The researchers mentioned that cellular damages could be referred to renal ischaemia caused by toxic effect of gentamicin on renal blood vessels; they added that gentamicin leads to generation of ROS, which are important modulators of renal blood flow. Moreover, the fusion of pedicles after administration of adriamycin in rats was suggested to be a result of loss of electrical load in podocyte pedicles . Also, gentamicin chelates mitochondrial iron, forming a very oxidant Fe-II gentamicin complex capable of causing cell death and triggering the apoptotic pathway . The increased number of lysosomes found in experimental animals administered gentamicin could be explained by their uptake and accumulation of gentamicin as previously reported . In addition, the external surface of podocytes is covered with a sialic acid rich in glycocalyx known as podocalyxin. Podocalyxin is the target of glomerular diseases that affect the shape of foot processes and reduce the components of slit diaphragm with subsequent development of albuminuria .
Cellular infiltration was observed in this study. This result is in accordance with those of previous investigators [42,43], who stated that gentamicin evokes an inflammatory response in experimental animals and in humans with cell infiltration, increased cytokine production and increased capillary permeability. They added that the inflammatory response initially appears as a defense mechanism, but after that it contributes to renal damage progression.
In the present work, alterations in the renal corpuscles of gentamicin-treated rats appeared in the form of a hydropic change or swelling with cytoplasmic vacuolization in the parietal cells. This is in agreement with the results of other researchers  who observed the same in tubular epithelial cells. This was attributed to the fact that toxic potential of individual aminoglycosides agents is directly related to its ability to bind and disrupt the plasma membrane.
MCs resemble smooth muscle cells; they can modulate glomerular haemodynamics by controlling the glomerular capillary surface area. Only activated proliferating cells express α-SMA in mesangial injury and that was thought to be a sign of activation . In the current work, immunoexpression for α-SMA was not detected in normal glomeruli. Also, mesangial hypercellularity was confirmed by extensive positive PAS staining of the mesangial matrix and strong positive α-SMA immunoexpression in MCs. Moreover, hypertrophy and proliferation of endothelial and MCs were recorded. This is in agreement with previous studies [2,28,44,45]. Those researchers reported that MCs secrete endothelin-1 in response to glomerular injury. Endothelin-1 acts by autocrine and paracrine mechanisms on MCs, causing their proliferation and excessive accumulation of its matrix. Hypertrophy and proliferation of MCs occurred because of the mitogenic effect of endothelin-1 and by mediating the proliferative effect of other growth factors such as angiotensin II. They added that endothelin I increased fibronectin, type IV collagen and type I collagen by MCs.
The immunohistochemical assessment of α-SMA was carried out to determine the role of MCs and glomerular myofibroblasts in the progression of gentamicin glomerular injury and to assess their value in determining long-term renal outcome. Increased expression of α-SMA in glomerulonephropathies was previously observed by many authors , who regarded this increase as a sign of mesangial activation and proliferation at sites of mesangial injury. They suggested that the possible myofibroblast migration from the interstitium to the damaged glomeruli could be associated with mesangial injury. Recently, smooth muscle protein was seen to be expressed in glomeruli during glomerulogenesis and to decrease with glomerular maturation. It is increased again in some glomerulopathies and this correlates with a worse disease prognosis as a higher rate of apoptosis and lower rate of proliferation occurred with it .
In this study, administration of ginger with gentamicin resulted in a significant alleviation of kidney injures as evidenced by biochemical indices and improvement in the histological profile. These improvements were attributed to the antioxidant protective and scavenger effects of ginger. This agreed with the results of other studies [19,23,33] and also confirmed the protective role of ginger in alcohol and metalaxyl fungicide-induced nephrotoxicities. Ginger-free phenolic and ginger-hydrolysed phenolic fractions exhibited free radical scavenging, inhibition of lipid peroxidation and DNA protection, indicating strong antioxidant properties . Moreover, the young rhizosome of Z. officinale had a higher content of flavonoids with high antioxidant activity .
In conclusion, results of this study revealed the injurious effects of gentamicin on renal corpuscles. Coadministration of ginger during gentamicin treatment can ameliorate both the functional and histological changes induced by gentamicin. These findings may be of major importance for the introduction of a safe, inexpensive and feasible method for attenuation of gentamicin-induced nephrotoxicity.
Conflicts of interest
There is no conflict of interest to declare.
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