الفهرس 
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Abstract
Cisplatin (CP)-induced nephrotoxicity and hepatotoxicity are the major limitations for use of CP in tumor chemotherapy. Although, the exact mechanism by which CP produces hepato-renal toxicity remains largely uncertain, it thought to be the oxidative stress, inflammation and apoptosis signaling pathways are the forerunners and corner stones in development and prognosis of CP-induced renal and hepatic toxicity.
The present study was conducted to investigate whether or not naringin (NAR) and/ or telmisartan (TEL) could abate CP-induced renal and hepatic toxicity using a murine paradigm. In this study, induction of nephrotoxicity and hepatotoxicity in male Swiss albino rats was achieved by challenging the animals with a single dose of CP (7 mg/kg bw, i.p).
At the end of the experiment, rats were anesthetized, blood samples were withdrawn for biochemical assay including kidney and liver function parameters. Then, the kidney and liver of each rat were excised for biochemical and molecular analysis as well as, histopathological investigations.
Relative kidney/body weight ratio and liver/ body weight ratio determined as an index of edema and inflammation. The biochemical and molecular analyses include the determination of renal and hepatic contents of reduced glutathione (GSH), malndialdehyde (MDA) and nitric oxide (NO) as biomarkers of oxidative stress, while myeloperoxidase (MPO) activity, cyclooxygenase-2 (COX-2) level and tumor necrosis factor alpha (TNF-α) expression as biomarkers of inflammation. Also, caspase-3 and B-cell lymphoma-2 (Bcl-2) expression have been undertaken and determined as markers of apoptosis.
Data in the present study showed that CP caused marked increase in kidney body weight ratio and liver body weight ratio by about 147% and 136% respectively, while significant decrease in the final body weight (41%) in comparison with control group.
Also, CP injection resulted in a significant increase in serum levels of creatinine (324%), urea (274%), ALT (153%), AST (213%) and ALP (110%) with respect to normal values.
Moreover, CP disturbs the oxidative stress biomarkers as manifested by significant increase in renal and hepatic contents of MDA (153% and 243%) and NO (177% and 227%), while significant reduction in GSH (66% and 64%) respectively. Inflammation biomarkers were elevated following CP as characterized by remarkable increase of renal and hepatic MPO activity (244% and 129%), COX-2 level (194% and 129%) and TNF-α (54 and 8 folds) expression respectively in comparison with control group.
Furthermore, CP induces caspase-3 and downregulates Bcl-2 mRNA expression regarding control animals. In addition, histopathological finding of the kidney tissue showed that CP-induced apparent alterations in the kidney tissues in the form of congestion of renal blood vessel and focal hemorrhage in between renal tubules associated with degeneration in the tubular lining epithelium at the cortex as well as focal inflammatory cell infiltration in the cortical portion in comparison with control group.
Also, histopathological examinations of the liver tissue revealed that, administration of CP was induced apparent alterations in the hepatic tissues in the form of fatty changes of hepatocytes and sinusoidal leukocytosis with focal hepatic necrosis associated with inflammatory cell infiltration and congestion of central vein.
Since ROS generation with subsequent induction of inflammatory and apoptotic signaling cascades represent the solid foundation, by which CP-induced renal and hepatic injury, the use of drugs with antioxidants, anti-inflammatory and antiapoptotic properties could minimize the harmful effects of CP on kidney and liver tissues. Hence, this work have addressed the possible therapeutic effects of two compounds known to have anti-radical, anti-inflammatory and antiapoptotic potentials, namely Naringin (NAR) and telmisartan (TEL) in the murine model of of CP-induced renal and hepatic toxicity.
NAR treatment to animals challenged CP significantly increased the final body weight by about 38% and markedly reduced the relative kidney- liver body weight ratios by about 32 % and 33% respectively, as compared to CP-treated animals. NAR markedly decrease the serum levels of creatinine and urea by about 49% and 36% respectively, as well as, ALT, AST, ALP amounting to 30%, 34% and 23% respectively, as compared to CP-treated rats. These results may be attributed to antioxidant, anti-inflammatory and antiapoptotic action of NAR. Also, NAR oral treatment to CP-challenged animals notably increased renal and hepatic contents of GSH (147% and109%) accompanied by significantly decreased in MDA (41% and 45%) and NO (37% and 35%) respectively in comparison with animal model. These effects could be ascribed to antioxidant effect of NAR via direct effects and activation of the classical upstream regulator of antioxidant members; namely Nrf2 transcription factor.
Oral treatment with NAR remarkably reduced renal and hepatic MPO activity (42%, and 39%) COX-2 level (35% and39%) and TNF-α (62% and 57%) expression respectively in comparison with CP treated rats. These effects could be ascribed to NAR anti-inflammatory effect which might be mediated by ROS scavenging activity and intervening with several molecular events involved in the inflammatory response as activation of inflammatory mediators such as TNF-α and COX-2. Oral administration of NAR to CP treated animals resulted in a notable downregulation in caspase-3 and upregulation in Bcl-2 mRNA expression in renal and hepatic tissues in comparison with animal model. Morphological analysis of renal and hepatic tissues exhibited that NAR administration in concomitant with CP was able, to some extent, to calm down the CP -induced pathological alterations in the kidney and liver tissues architectures.
Also, TEL oral treatment to CP challenged animals significantly increased the final body weight by about 27% and markedly reduced the relative kidney-liver/ body weight ratio by about 24 % and 21%, respectively as compared to CP-treated animals. These results may be attributed to antioxidant, anti-inflammatory and antiapoptotic actions of TEL. These effects were confirmed by the observation that TEL treatment markedly decreased the serum level of creatinine and urea by about 45% and 24% respectively, as well as, ALT, AST, ALP amounting to 23%, 28% and 18% respectively, as compared to CP-treated rats. as compared to animals treated with CP alone.
Also, TEL oral treatments to CP-challenged animals markedly increased renal and hepatic content of GSH (69% and74%) concomitantly with significant decreases in renal and hepatic contents of MDA (22% and 22%) and NO (33% and 35%) respectively in comparison with animal model. These effects could be ascribed to antioxidant effect of TEL via blocking of angiotensin II (ANG II) receptors. Angiotensin II activates several enzymes involved in ROS generation as nicotinamide adenine dinucleotide phosphate oxidase (NADPH oxidase).
Oral treatment with TEL significantly ameliorated the elevated inflammatory biomarkers in renal and hepatic tissues as manifested by significant decrease of MPO activity (26% and 29%) COX-2 level (30% and 33%) and TNF-α (40% and 51%) expression respectively in comparison with CP treated rats. These effects could be attributed to the anti-inflammatory effect of TEL which is evoked by blocking of ANG II receptors and activation of peroxisome proliferator-activated receptor gamma (PPARγ). Oral administration of TEL to CP treated animals resulted in notable decrease in caspase-3 and marked increase in Bcl-2 mRNA expression in comparison with animal model. Morphological analysis of renal and hepatic tissues revealed that TEL administration in concomitant with CP was able, to some extent, to attenuate the CP-induced pathological changes in the kidney and hepatic tissues architecture.
The present study showed that treatment with combination of NAR and TEL significantly increases the final body weight by about 53%, and markedly reduces the relative kidney-liver/ body weight ratio by about 43 % and 50% respectively, in comparison with CP-treated animals. Also, this combination markedly decreased the serum levels of creatinine and urea by about 63% and 52% respectively as well as ALT, AST and ALP by about 53%, 57% and 46% respectively compared to rats model. Additionally, NAR and TEL oral treatments to CP-challenged animals notably increased the renal and hepatic contents of GSH (183% and 179%) accompanied by a significant decreases in renal and hepatic contents of MDA(56% and64%) and NO(56% and 62%) respectively in comparison with animal model.
Combination therapy significantly reduced renal and hepatic MPO activity (63% and 62%) COX-2 level (54% and 55%) and TNF-α (81% and 81%) expression respectively in comparison with CP treated rats. Drug regimen of NAR and TEL to CP treated animals resulted in significan downregulation and upregulation of caspase-3 and increase Bcl-2 mRNA expression respectively in comparison with CP model. Histopathological analysis showed that NAR and TEL administration in concomitant with CP was able to correct all pathological alterations evoked CP administration in the kidney and liver tissues.