Sinapic acid ameliorate cadmium-induced nephrotoxicity: In vivo possible involvement of oxidative stress,apoptosis, and inflammation via NF-κB downregulation

Cadmium (CD), an environmental and industrial pollutant, generates reactive oxygen species (ROS) and NOS responsible for oxidative and nitrosative stress that can lead to nephrotoxic injury, including proximal tubule and glomerulus dysfunction. Sinapic acid (SA) has been found to possess potent antioxidant and anti-inflammatory effects in vitro and in vivo. We aimed to examine the nephroprotective, anti-oxidant, anti-inflammatory, and anti-apoptotic effects of SA against CD-induced nephrotoxicity and its underlying mechanism. Kidney functional markers (serum urea, uric acid, creatinine, LDH, and calcium) and histopathological examinations of the kidney were used to evaluate CD-induced nephrotoxicity. Oxidative stress markers (lipid peroxidation and total protein), renal nitrosative stress (nitric oxide), antioxidant enzymes (catalase and NP-SH), inflammation markers (NF-κB [p65], TNF-α, IL-6, and myeloperoxidase [MPO]), and apoptotic markers (caspase 3, Bax, and Bcl-2) were also assessed. SA (10 and 20 mg/kg) pretreatment restored kidney function, upregulated antioxidant levels, and prevented the elevation of lipid peroxidation and nitric oxide levels, significantly reducing oxidative and nitrosative stress. CD upregulated renal cytokine levels (TNF-α, IL-6), nuclear NF-κB (p65) expression, NF-κB-DNA-binding activity, and MPO activity, which were significantly downregulated upon SA pretreatment. Furthermore, SA treatment prevented the upregulation of caspase 3 and Bax protein expression and upregulated Bcl-2 protein expression. SA pretreatment also alleviated the magnitude of histological injuries and reduced neutrophil infiltration in renal tubules. We conclude that the nephroprotective potential of SA in CD-induced nephrotoxicity might be due to its antioxidant, anti-inflammatory, and anti-apoptotic potential via downregulation of oxidative/nitrosative stress, inflammation, and apoptosis in the kidney.     

柚皮苷对人皮肤角质细胞分泌趋化因子RANTES及其核转录因子-κB信号通路影响的实验研究

目的:研究炎症性细胞因子肿瘤坏死因子α(TNF-α)和γ干扰素(IFN-γ)对人皮肤角质细胞(HaCaT)分泌趋化因子RANTES的诱导作用;以阿维A为阳性对照药,研究柚皮苷对此诱导作用的抑制作用及其机制。方法:将HaCaT分为阴性对照组、模型刺激组(TNF-α+IFN-γ)、阿维A预处理组(TNF-α+IFN-γ+阿维A)和柚皮苷预处理组(TNF-α+IFN-γ+柚皮苷)等;采用酶联免疫吸附(ELISA)法测定HaCaT细胞经单用和合用TNF-α、IFN-γ刺激以及加入阿维A和柚皮苷后RANTES的分泌量。采用免疫细胞化学方法和Western blot法检测HaCaT中核转录因子-κBP6(5NF-κBP65)蛋白的表达。结果:单用或合用TNF-α、IFN-γ可显著诱导细胞分泌RANTES,并以合用组作用最显著(P<0.01)。柚皮苷、阿维A均能明显抑制TNF-α、IFN-γ诱导的RANTES的分泌(P<0.01)及NF-κBP65蛋白的表达。结论:柚皮苷可以抑制TNF-α、INF-γ诱导RANTES的分泌及相关蛋白的产生,其机制可能是通过抑制NF-κB信号传导途径的活化而实现。     

柚皮苷对人皮肤角质细胞分泌趋化因子RANTES及其核转录因子-kB信号通路影响的实验研究

目的：研究炎症性细胞因子肿瘤坏死因子α（TNF-α）和γ干扰素（IFN-γ）对人皮肤角质细胞（HaCaT）分泌趋化因子RANTES的诱导作用;以阿维A为阳性对照药,研究柚皮苷对此诱导作用的抑制作用及其机制。方法：将HacaT分为阴性对照组、模型刺激组（TNF-α＋IFN—γ）、阿维A预处理组（TNF-α＋IFN—γ＋阿维A）和柚皮苷预处理组（TNF-α＋IFN—γ＋柚皮苷）等;采用酶联免疫吸附（ELISA）法测定HaCaT细胞经单用和合用TNF-α、IFN-γ刺激以及加入阿维A和柚皮苷后RANTES的分泌量。采用免疫细胞化学方法和Western blot法检测HaCaT中核转录因子-KB P65（NF—kB P65）蛋白的表达。结果：单用或合用TNF—α、IFN-γ可显著诱导细胞分泌RANTES,并以合用组作用最显著（P〈0．01）。柚皮苷、阿维A均能明显抑制TNF-α、IFN-γ诱导的RANTES的分泌（P〈O．01）及NF—kB P65蛋白的表达。结论：柚皮苷可以抑制TNF-α、INF-γ诱导RANTES的分泌及相关蛋白的产生,其机制可能是通过抑制NF—kB信号传导途径的活化而实现。     

Protective effect of empagliflozin on gentamicin-induced acute renal injury via regulation of SIRT1/NF-κB signaling pathway

Gentamicin is a highly effective antibiotic. However, its major complication is nephrotoxicity. This study investigated the beneficial effects of empagliflozin against gentamicin-induced nephropathy. Kidney damage was induced in male Wistar rats by administration of gentamicin (100 mg/kg/day, i.p.) for 8 days. Two doses of empagliflozin (10 and 20 mg/kg, p.o.) were concomitantly given with gentamicin for 8 days. Gentamicin administration increased serum creatinine, urea, and cystatin C concentrations. Empagliflozin in both doses ameliorated these changes via mitigation of gentamicin-induced increase in renal oxidative stress, inflammation, and apoptosis. Empagliflozin added to GM treatment led to lower measured levels of TGF-B, NF-κB and caspase 3, and only the higher dose increased PAX2 levels indicating an improvement in tubular regeneration. Additionally, empagliflozin (20 mg/kg/day) markedly prevented gentamicin-induced histopathological changes. The protective effects of empagliflozin may be mediated by decreasing gentamicin concentration in renal tissue and possibly other effects like antioxidant and antiapoptotic effects.     

Naringin attenuates acute lung injury in LPS-treated mice by inhibiting NF-κB pathway

Naringin has been reported as an effective anti-inflammatory compound. We previously showed that naringin had antitussive effect on experimentally induced cough in guinea pigs. However, the effects and mechanism of naringin on lipopolysaccharide (LPS)-induced acute lung injury (ALI) in mice are not fully understood. In this study, our aim was to evaluate the anti-inflammatory activities of naringin on LPS-induced ALI in mice and clarify its underlying mechanisms of action. We found that in vivo pretreatment with naringin markedly decreased the lung wet weight to dry weight ratio, and led to significant attenuation of LPS-induced evident lung histopathological changes. Meanwhile, naringin significantly reduced bronchoalveolar lavage fluid (BALF) total cell and neutrophil (PMN) counts after LPS challenge. Furthermore, naringin inhibited myeloperoxidase (MPO: a marker enzyme of neutrophil granule) and inducible nitric oxide synthase (iNOS) activities in lung tissue and alleviated LPS-induced tumor neurosis factor-α (TNF-α) secretion in BALF in a dose-dependent manner. Additionally, Western blotting showed that naringin efficiently blunt NF-κB activation by inhibiting the degradation of I?B-α and the translocation of p65. Taken together, these results suggest that naringin shows anti-inflammatory effects through inhibiting lung edema, MPO and iNOS activities, TNF-α secretion and pulmonary neutrophil infiltration by blockade of NF-κB in LPS-induced ALI.     

Ameliorative effects of curcumin against renal injuries mediated by inducible nitric oxide synthase and nuclear factor kappa B during gentamicin-induced toxicity in Wistar rats

The ameliorative role of curcumin in attenuating gentamicin-induced nephrotoxicity has been reported earlier however, the mechanism of action remains unclear. Gentamicin was injected intraperitoneally (100 mg/kg body weight) once daily for 6 days. Curcumin was administered orally (200 mg/kg body weight) once daily for 7, 15 and 30 days. Gentamicin-induced rats showed significant increase in the levels of kidney markers and the activities of urinary marker enzymes, which was reversed upon curcumin treatment. A significant increase in kidney lipid peroxidation (LPO) and decrease in activities of superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), glutathione-S-transferase (GST) and reduced glutathione (GSH) were observed in gentamicin-induced rats. Immunohistochemical, Western blot and RT-PCR studies in gentamicin-induced rats also demonstrated an increase in the levels of inducible nitric oxide synthase (iNOS) and nuclear factor-κB (NF-κB). All these effects induced by gentamicin were reduced upon treatment with curcumin in a time dependent manner. To conclude, curcumin enhances antioxidants, and decreases iNOS and NF-κB, thereby protecting the cells against oxidative stress induced by gentamicin.     

Wound healing potential of naringin ointment formulation via regulating the expression of inflammatory,apoptotic and growth mediators in experimental rats

Context: Wound healing is a consequence of a complex process involving inflammatory, proliferative, and remodeling phases. Naringin, a flavanone glycoside, is associated with modulation of various oxido-inflammatory and growth factors.

Aim: The aim of this study is to evaluate the wound-healing activity of naringin ointment formulation (NOF) on experimental wound models.

Materials and methods: A soft paraffin-based cream containing 1, 2, and 4% (w/w) naringin was formulated and evaluated for physicochemical characters. Excision wounds and incisions wounds were used to study the topical effect of NOF for 20 d (once a day) on various biochemical, molecular, and histological parameters.

Results: NOF (2 and 4%, w/w) treatment showed a significant decrease (p?<?0.05) in wound area and epithelization period whereas the rate of wound contraction increased significantly (p?<?0.05). The altered levels of oxido-nitrosative stress (SOD, GSH, MDA, MPO, and NO) were significantly (p?<?0.05) restored by NOF. Treatment produced a significant increase (p?<?0.05) in tensile strength, hydroxyproline content, and protein content. TNF-α, IL-1β, IL-6, IL-8, NF-κB, smad-7, and Bax mRNA expression were significantly down-regulated (p?<?0.05) by NOF, whereas polymerase gamma (pol-γ), smad-3, VEGF and TGF-β, and collagen-1 mRNA expressions were significantly up-regulated (p?<?0.05) by NOF. Histological alterations in wound skin were also restored by NOF.

Conclusion: NOF exerts wound healing potential via down-regulated expression of inflammatory (NF-κB, TNF-α, and ILs), apoptotic (pol-γ and Bax), and up-regulated growth factor (VEGF and TGF-β) expression, thus modulating collagen-1 expression to induce angiogenesis leading to wound healing.     

Sulphated polysaccharide from Sargassum myriocystum confers protection against gentamicin-induced nephrotoxicity in adult zebrafish

The beneficial effect of purified fraction of sulphated polysaccharide extracted from Sargassum myriocystum (SMP) was examined on the gentamicin-induced nephrotoxicity in adult zebrafish. The major purified fractions (SMP1, SMP2 and SMP3) were obtained by anion-exchange and size-exclusion chromatography and characterized by FTIR, GCMS and NMR. The in vitro antioxidant activities of all purified SMP fractions were analysed. The SMP2 showed maximum carbohydrate, sulphate and fucose content with strong antioxidant activity than other fractions. Further, we evaluated the efficacy of SMP2 against gentamicin-induced nephrotoxicity in zebrafish model. The SMP2 administered group showed a significant attenuation in oxidative stress and histopathological alterations observed in renal tissues of gentamicin treated group. Moreover, the SMP2 supressed renal mRNA expression levels of KIM-1, NF-κB, TNF-α and IL-6 in dose-dependent manner. Thus, the present study suggests that the SMP2 is a potent antioxidant with anti-inflammatory and renoprotective properties that ameliorated the GEN induced nephrotoxicity in adult zebrafish.     

小檗碱通过破坏线粒体功能选择性诱导淋巴瘤细胞的凋亡

目的研究小檗碱(BBR)对T淋巴瘤细胞凋亡的影响及机制。方法正常T淋巴细胞、T淋巴瘤细胞、Jurkat细胞用BBR 0,10,20和40μmol·L^-1处理24 h,多柔比星(Dox)40μmol·L^-1为阳性对照;Jurkat p0细胞用BBR 0和40μmol·L^-1处理24 h。流式细胞术检测细胞凋亡率,Seahorse XF24细胞代谢分析仪和H2DCFDA活性氧探针检测细胞氧消耗率(OCR)和活性氧(ROS)水平。CellTiter-Glo发光法细胞活力检测试剂盒检测细胞ATP水平,试剂盒测线粒体呼吸链复合物Ⅰ,Ⅱ,Ⅳ和Ⅴ的活性。Western印迹法检测细胞内胱天蛋白酶3、Bcl-2、Bax、NF-κB抑制蛋白激酶α/β(IKKα/β)、磷酸化IKKα/β(p-IKKα/β)、NF-κB抑制因子α(IκBα)、p-IκBα和P65蛋白表达水平。结果BBR 40 mmol·L^-1明显增加T淋巴瘤细胞和Jurkat细胞凋亡率(P<0.01),胱天蛋白酶3和Bax蛋白表达水平显著上调(P<0.01),Bcl-2表达显著下调(P<0.01),但对正常T淋巴细胞的凋亡并无影响;BBR 40 mmol·L^-1明显降低Jurkat细胞的OCR及线粒体呼吸链复合物Ⅰ活性(P<0.01),增加ROS水平(P<0.01),降低ATP水平(P<0.01),但不影响线粒体缺陷型淋巴瘤Jurkat p0细胞呼吸链和凋亡;BBR 40μmol·L-1明显下调Jurkat细胞中NF-κB通路相关蛋白p-IKKα/β/IKKα/β、p-IκBα/IκBβ和核内P65表达(P<0.01)。结论BBR通过破坏线粒体功能选择性诱导淋巴瘤T细胞的凋亡,可能与抑制NF-κB通路有关。     

枸杞多糖对小鼠海马神经元细胞系缺糖缺氧损伤保护作用及机制研究

目的探讨枸杞多糖(LBP)对小鼠海马神经元细胞系HT22细胞缺糖缺氧损伤保护作用的机制。方法采用含1 mmol/L连二亚硫酸钠的无糖DMEM培养基建立HT22细胞缺糖缺氧损伤模型,设对照组、模型组和LBP高、中、低剂量(100、50、25 mg/L)组,以CCK8法检测细胞活性,流式细胞术检测检测细胞凋亡情况;Western blotting检测Bcl-2、Bax蛋白表达情况;利用实时荧光定量PCR(RT-qPCR)检测TNF-α、NF-κB、I-κBα、Caspase-9基因转录活性。结果与对照组比较,模型组HT22细胞存活率显著降低、凋亡率显著增加(P<0.05);TNF-α、NF-κB、Caspase-9基因转录活性显著上调,I-κBα基因转录活性显著下调(P<0.05);Bax蛋白表达水平显著升高,Bcl-2的蛋白表达水平显著降低(P<0.05)。与模型组比较,LBP各剂量组细胞存活率显著上升、凋亡率显著下降(P<0.05);TNF-α、NF-κB、Caspase-9基因转录活性显著下调,I-κBα基因转录活性显著上调(P<0.05);Bax蛋白表达水平显著降低,Bcl-2的蛋白表达水平显著增高(P<0.05)。结论 LBP可能是通过下调TNF-α、NF-κB、Caspase-9基因转录活性以及Bax蛋白表达,增强I-κBα基因转录活性及Bcl-2的蛋白表达,抑制缺糖缺氧损伤诱导神经细胞凋亡的发生。     

Sappanone A protects mice against cisplatin-induced kidney injury

Cisplatin (CP) is an anti-cancer drug that often causes nephrotoxicity due to enhanced inflammatory response and oxidative stress. Sappanone A (SA), a homoisoflavanone isolated from the heartwood of Caesalpinia sappan, has been known to have antioxidant and anti-inflammatory effects. In this study, we aimed to investigate the protective effects and mechanism of SA on CP-induced kidney injury in mice. The results showed that treatment of SA improved CP-induced histopathalogical injury and renal dysfunction. SA also inhibited CP-induced MPO, MDA, TNF-α and IL-1β production and up-regulated the activities of SOD and GSH-PX decreased by CP. SA significantly inhibited the apoptosis rate of kidney tissues induced by CP. Furthermore, SA was found to inhibit CP-induced NF-κB activation. Treatment of SA up-regulated the expression of Nrf2 and HO-1 in a dose-dependent manner. In vitro, SA dose-dependently inhibited CP-induced TNF-α and IL-1β production and NF-κB activation in HK-2 cells. In conclusion, these results suggested that SA inhibited CP-induced kidney injury through activating Nrf2 and inhibiting NF-κB activation. SA was a potential therapeutic drug for treating CP-induced kidney injury.     

尼可地尔对哮喘气道重塑大鼠肺组织Toll样受体4以及核因子-κB p65表达的影响

目的观察尼可地尔对哮喘气道重塑大鼠肺组织中Toll样受体4(TLR-4)及核因子(NF)-κBp65的作用以及对Bax/Bcl-2的调节情况。方法 32只清洁级SD雄性大鼠,随机分为正常组、哮喘组、地塞米松组和尼可地尔组。采用5点注射和雾化吸入鸡卵清蛋白+氢氧化铝的方法复制大鼠哮喘模型,地塞米松组予地塞米松0.5 mg.kg-1.d-1雾化吸入,尼可地尔组予尼可地尔3 mg.kg-1.d-1雾化吸入,正常组与哮喘组雾化吸入生理盐水,共4 wk。观察大鼠肺组织病理学改变,NF-κB p65、Bax、Bcl-2的含量,以及TLR-4 mRNA的表达。结果与哮喘组相比,尼可地尔组大鼠的肺部组织炎症细胞浸润较少,肺泡的组织结构较为完整。哮喘组大鼠肺组织NF-κB p65、Bcl-2、TLR-4 mRNA表达高于正常组,Bax表达量较正常组低,差异均有显著意义(P<0.05)。尼可地尔组和地塞米松组大鼠NF-κB p65、Bcl-2、TLR-4mRNA表达低于哮喘组,Bax表达量较哮喘组高,均有显著差异(P<0.05)。结论尼可地尔能逆转哮喘大鼠肺组织病理变化,降低TLR-4介导的NF-κB p65表达,改善Bax/Bcl-2表达失调为其可能机制。     

PCSK9抑制剂在ox-LDL诱导HUVECs损伤中的保护作用研究

目的　探讨人类枯草溶菌素转化酶9（PCSK9）抑制剂对氧化型低密度脂蛋白（ox-LDL）导致的人脐静脉内皮细胞（HUVECs）损伤的保护机制。方法　对数生长期HUVECs细胞分为Control组（正常培养）,ox-LDL组（50 mg/L ox-LDL诱导24 h）,低、中、高剂量PCSK9抑制剂组（分别用5、10、20 μmol/L PCSK9抑制剂预处理24 h,再加入50 mg/L ox-LDL诱导24 h）。采用CCK-8法检测各组细胞活性并计算细胞存活率,实时荧光定量PCR（qPCR）和酶联免疫吸附测定（ELISA）法检测细胞或细胞培养上清液中肿瘤坏死因子（TNF）-α,白细胞介素（IL）-6和单核细胞趋化蛋白（MCP）-1的转录和分泌水平;流式细胞术检测细胞凋亡情况。Western blot检测细胞凋亡相关蛋白（Bax、Bcl-2、Cleaved-Caspase-3）和核因子（NF）-κB通路相关蛋白的表达水平。结果　与Control组比较,ox-LDL组细胞存活率下降,TNF-α、IL-6和MCP-1转录及分泌水平升高,细胞凋亡率升高,促凋亡蛋白Bax、Cleaved-Caspase-3表达上调,抗凋亡蛋白Bcl-2下调,磷酸化NF-κB（p-NF-κB）水平上调;同时NF-κB在细胞核内表达上调,胞质中表达下调。中、高剂量PCSK9抑制剂处理后,与ox-LDL组比较,细胞存活率升高,TNF-α、IL-6和MCP-1转录和分泌水平下降,细胞凋亡率下降, Bax、Cleaved-Caspase-3表达下调,Bcl-2表达上调,p-NF-κB水平下降。进一步分析发现,PCSK9抑制剂下调ox-LDL导致的HUVECs细胞核中NF-κB表达,上调胞质中NF-κB的表达（P＜0.05）。结论　PCSK9抑制剂可以抑制ox-LDL导致的HUVECs炎症反应和细胞凋亡,发挥内皮功能保护作用。     

玉郎伞2种查尔酮单体对心肌细胞凋亡的抑制作用

目的研究从玉郎伞中首次分离的2种查尔酮单体2,6-二甲氧基查尔酮(YLSA)和17-甲氧基-7-羟基-苯骈呋喃查尔酮(YLSB)对心肌细胞凋亡的作用。方法原代培养大鼠心肌细胞,利用终浓度为100μmol·L-1的过氧化氢孵育16h建立凋亡模型;ELISA法测定心肌细胞培养上清液中TNF-α含量,Annex V-FITC/PI双染法检测心肌细胞凋亡,免疫组化法检测NF-κBp65、Bcl-2、Bax蛋白的表达。结果YLSA和YLSB均可抑制心肌细胞凋亡,降低TNF-α活性,下调NF-κBp65和Bax蛋白表达,上调Bcl-2蛋白表达,增加Bcl-2/Bax比值。结论YLSA和YLSB具有抑制心肌细胞凋亡的作用。     

Schisandrin B Enhances Renal Mitochondrial Antioxidant Status, Functional and Structural Integrity, and Protects against Gentamicin-Induced Nephrotoxicity in Rats

Schisandrin B (Sch B), a dibenzocyclooctadiene derivative isolated from the fruit of Schisandra chinensis, has been shown to protect against oxidative damage in liver, heart and brain tissues in rodents. In the present study, the effect of long-term Sch B treatment (1-10 mg/kg/d x 15) on gentamicin-induced nephrotoxicity was examined in rats. Sch B treatment protected against gentamicin-induced nephrotoxicity, as evidenced by significant decreases in plasma creatinine and blood urea nitrogen levels. The nephroprotection was associated with the enhancement in renal mitochondrial antioxidant status, as assessed by the level/activity of reduced glutathione, alpha-tocopherol and Mn-superoxide dismutase, as well as the improvement/preservation of mitochondrial functional and structural integrity, as assessed by the extents of ATP generation capacity, malondialdehyde production, Ca2+ loading and cytochrome c release, as well as the sensitivity to Ca2+-induced permeability transition, in control and gentamicin-intoxicated rats. In conclusion, long-term Sch B treatment could enhance renal mitochondrial antioxidant status as well as improve mitochondrial functional and structural integrity, thereby protecting against gentamicin nephrotoxicity.     

Renoprotective effects of montelukast,a cysteinyl leukotriene receptor antagonist,against methotrexate-induced kidney damage in rats

Methotrexate (MTX) is a cytotoxic chemotherapeutic agent used for treatment of several cancers. Nephrotoxicity, an adverse side effect of high-dose MTX, is attributed to abnormal production of reactive oxygen species (ROS), inflammatory mediators, and neutrophil infiltration. Montelukast (MON) is a cysteinyl leukotriene receptor antagonist. Recently, it has gained a considerable interest as a ROS scavenger and inflammatory modulator. In this study, we investigated the effect of MON against MTX-induced nephrotoxicity. Rats were divided into four groups: control group, MON group (10 mg/kg, orally), MTX group (20 mg/kg, i.p., single injection), and MON + MTX group (MON was administered 5 days before and 5 days after MTX administration). At the end of the experiment, serum was collected for analysis of blood urea nitrogen (BUN) and creatinine. Glutathione (GSH), lipid peroxides (malondialdehyde), tumor necrosis factor alpha (TNF-α) levels, superoxide dismutase, myeloperoxidase activities, and nuclear factor kappa beta (NF-κB) protein expression were determined in renal tissues. In addition, kidney tissues were examined histopathologically and immunohistochemically for NF-κB. MTX administration produced acute renal damage as indicated from severe elevation in BUN and serum creatinine. The role of oxidative stress and inflammatory mechanisms in MTX-induced nephrotoxicity was evidenced from the unbalance in tissue oxidative parameters, increased TNF-α levels, and NF-κB expression in renal tissues. On the other hand, MON significantly reduced the toxic effects of MTX as indicted from normalization of kidney-specific parameters, oxidative stress, and inflammatory mediators. This data was further supported by histopathological studies. Thus, co-administration of MON may be promising in alleviating the systemic side effects of MTX.     

Amlodipine alleviates cisplatin-induced nephrotoxicity in rats through gamma-glutamyl transpeptidase (GGT) enzyme inhibition,associated with regulation of Nrf2/HO-1, MAPK/NF-κB,and Bax/Bcl-2 signaling

BackgroundThe therapeutic utility of the effective chemotherapeutic agent cisplatin is hampered by its nephrotoxic effect. We aimed from the current study to examine the possible protective effects of amlodipine through gamma-glutamyl transpeptidase (GGT) enzyme inhibition against cisplatin nephrotoxicity.MethodsAmlodipine (5 mg/kg, po) was administered to rats for 14 successive days. On the 10^th day, nephrotoxicity was induced by a single dose of cisplatin (6.5 mg/kg, ip). On the last day, blood samples were collected for estimation of kidney function, while kidney samples were used for determination of GGT activity, oxidative stress, inflammatory, and apoptotic markers, along with histopathological evaluation.ResultsAmlodipine alleviated renal injury that was manifested by significantly diminished serum creatinine and blood urea nitrogen levels, compared to cisplatin group. Amlodipine inhibited GGT enzyme, which participates in the metabolism of extracellular glutathione (GSH) and platinum-GSH-conjugates to a reactive toxic thiol. Besides, amlodipine diminished mRNA expression of NADPH oxidase in the kidney, while enhanced the anti-oxidant defense by activating Nrf2/HO-1 signaling. Additionally, it showed marked anti-inflammatory response by reducing expressions of p38 mitogen-activated protein kinase (p38 MAPK) and nuclear factor-kappa B (NF-κB), with subsequent down-regulation of tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), and vascular cell adhesion molecule-1 (VCAM-1). Moreover, amlodipine reduced Bax/Bcl-2 ratio and elevated hepatocyte growth factor (HGF), thus favoring renal cell survival.ConclusionsEffective GGT inhibition by amlodipine associated with enhancement of anti-oxidant defense and suppression of inflammatory signaling and apoptosis support our suggestion that amlodipine could replace toxic GGT inhibitors in protection against cisplatin nephrotoxicity.