Histological And Histochemical Changes In The Rat Renal Cortex Induced By Cisplatin

Cisplatin was the first heavy metal compound shown to have antineoplastic activity. It is effective in Hodgkin's disease, thyroid, endometrial, bladder, ovarian and head & neck neoplasms (Perry, 2008).
Nephrotoxicity is considered the most toxic effect of cisplatin. Increased serum creatinine together with tubular damage was noticed after administration of cisplatin. As little as a single dose of cisplatin in rats or mice, injected intraperitoneally, caused a significant increase in the serum level of urea, creatinine and lipid peroxides measured as the malondialdehyde content of kidney; a significant decreases in serum albumin, glutathione, and the activity of antioxidant enzymes of kidney were also observed (McDuffie, 2013; Sahu, 2011; Yamasaki, 1996).
Evidence has been accumulated to demonstrate that these side effects are closely related to oxidative stress (Kuhad, 2007; Teranishi, 2001). Several studies suggest that supplementation with antioxidants like vitamin E can influence cisplatin-induced nephrotoxicity as measured by lipid peroxidation (MDA) and scavenging enzyme activity(Naziroglu, 2004). Vitamin E is found naturally in some foods, added to others, and available as a dietary supplement. "Vitamin E" is the collective name for a group of fat-soluble compounds with distinctive antioxidant activities. Naturally occurring vitamin E exists in eight chemical forms (alpha-, beta-, gamma-, and delta-tocopherol and alpha-, beta-, gamma-, and delta-tocotrienol) that have varying levels of biological activity. Alpha- (or ??-) tocopherol is the only form that is recognized to meet human requirements (Traber, 2006). Vitamin E is one of the antioxidant vitamins which were proved to enhance cisplatin-induced tumor growth inhibition and increase the uptake of cisplatin by tumor cells. It also reduced parenchymatous and hematologic toxicities in animals treated with cisplatin (Pace, 2003).
This study aims to investigate the histological and histochemical changes in the rat renal cortex induced by Cisplatin, and the possible protective effects of vitamin E.

Sixty adult male albino rats weighing 100-150 grams were used in this study. Rats were housed in single cages at 20??C on a 12 hours light/dark cycle and had free access to food and water. The animals were randomly divided into three equal groups; the first group is control and were injected intra-peritoneally with 0.9% saline. The second and third groups were injected intra-peritoneally with cisplatin once a week for five weeks in a dose of 5 mg/kg body weight. Additionally, animals of the third group received 100 mg vitamin E /rat using gastric tube 30 minutes prior to cisplatin injection (Dobyan, 1985; Li, 1997).
At the end of the experiment, animals from each group were anesthetized with ketamine HCl (46 mg/kg body weight) and the kidneys of each rat were dissected out and sliced. Some slices were fixed in 10% formalin for 24 hours and paraffin sections (5 microns) were prepared and stained with Hematoxylin & eosin for routine histological examination. Additional slide were stained with periodic acid methenamine silver (PAMS) for demonstrating the thickness of basement membranes (Drury and Wallington, 1980).
Other slices were fixed in absolute chilled acetone for 24 hours. Paraffin sections (8-10 micron) were treated histochemically to localize alkaline phosphatase enzyme activity (Bancroft, 1984; Kiernan, 2008).
Fresh frozen cryocut sections (10-12 microns) were prepared and treated for demonstration of acid phosphatase and succinic dehydrogenase enzyme activities (Bancroft, 1984; Kiernan, 2008).

A. Histology:
Examination of paraffin section in the renal cortex of the control rats revealed the presence of renal corpuscles with glomerular capillaries, Bowman's space & the parietal layer of Bowman's capsule. Oval rounded & oblong proximal tubules with acidophilic cytoplasm, rounded open face nuclei and acidophilic brush borders which may obliterate the lumens of the tubules were observed. Distal tubules with wider lumens, collecting tubules & peritubular capillaries were also seen (Figure 1a & 1b). The basement membranes of the parietal layer of Bowman's capsule, of the proximal tubules & of the distal tubules were thick. While those of the collecting tubules appeared relatively thinner (Figure 4).
Administration of cisplatin alone without vitamin E resulted in variable histological changes in the renal cortex of group II rats. Detachment of the apical parts of the cytoplasm, loss of brush borders with subsequent widening of the lumens of proximal tubules and formation of microcysts especially in the inner cortex were observed. In addition, pyknosis of the nuclei and necrotic debris were also observed (Figure 2a & 2b). The basement membranes of the wide proximal tubules & of the microcysts were greatly thickened in comparison with the control (Figure 5a & 5b). The renal cortical interstitium of group II rats was the site of heavy infiltration with inflammatory cells and excessive deposition of reticular fibers (figure 2b, 2c & 5a).
Minimal histological changes were reported in the renal cortex of group III rats after administration of vitamin E with cisplatin. Only partial loss of brush borders with no apparent infiltration with inflammatory cells & deposition of reticular fibers (Figure 3 & 6).

B. Histochemistry:
1. Alkaline phosphatase enzyme activity: strong positive alkaline phosphatase enzyme activity, a brush border membrane marker, was noticed only in the brush borders of the proximal tubules (Figure 7a & 7b). On contrary, the renal cortex of group II rats showed only few proximal tubules with moderately strong enzyme activity & the majority of proximal tubules had wide lumens with no enzyme activity (Figure 8). However, the enzyme activity in group III rats was not much affected (Figure 9).

2. Succinic dehydrogenase enzyme activity: examination of frozen sections in the control renal cortex revealed the presence of strong positive succinic dehydrogenase activity in the lining cells of the proximal & distal convoluted tubules especially in the basal parts of the cells (Figure 10). This activity was much reduced in the renal cortex of group II rats which showed large areas with no enzyme activity (Figure 11). Meanwhile, the renal cortex of group III rats was relatively less affected than in group II (Figure 12).

3. Acid phosphatase enzyme activity: Strong positive acid phosphatase enzyme activity was reported only in the lining cells of the proximal tubules of the control renal cortex (Figure 13a & 13b). However the renal cortex of group II rats showed only some proximal tubules with strong positive enzyme activity surrounding variable-sized cysts with no enzyme activity (Figure 14a & 14b). These cysts were not encountered in the renal cortex of group III rats which showed strong acid phosphatase activity in the majority of proximal tubules (Figure 15).

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