Prohibitin的组蛋白乙酰化修饰介导庆大霉素诱导肾损伤的机制研究
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摘要
研究背景：肾脏是药物毒性的重要靶器官之一。药物源性肾脏损伤包括肾小球滤过功能障碍和肾小管功能障碍。庆大霉素是临床上广泛使用的抗生素,因其疗效确实,价格便宜,故深为临床医生乐用,但也有滥用倾向,其主要副作用肾毒性反应屡有报道。研究表明:庆大霉素进入人体后，其化学结构稳定，几乎不被代谢,绝大部分经肾小球以原形滤过,一部分被近端肾小管重新吸收,另一部分庆大霉素可经肾小管周围血管直接被肾小管上皮细胞摄取,导致药物聚集在肾皮质。晚期会出现肾小管坏死,肾小管阻塞，肾小球滤过率下降等肾功能损伤的改变，进而危及生命。因此研究庆大霉素诱导肾损伤的机制不仅具有较高的临床应用价值，而且具有较高的基础理论价值。PHB蛋白（Prohibitin protein）是广泛存在高度保守的一种蛋白，通过其独特的分子伴侣参与不同的生理病理过程。大量研究已经表明它可以通过调节基因转录和维持线粒体蛋白的稳定性抑制肿瘤细胞的增殖和凋亡；此外，它可抑制氧化应激引起的线粒体损伤参与心肌缺血再灌注损伤的保护作用。最近研究表明PHB蛋白参与肾小管间质纤维化，与肾小管间质损伤程度呈现负相关，暗示它可能是肾损伤潜在的治疗靶点。因此我们探讨PHB蛋白在庆大霉素诱导肾损伤过程中的作用。研究表明作为有效的组蛋白去乙酰化酶抑制剂，丁酸钠是具有抗抑郁，改善记忆功能，防止心肌缺血和再灌注损伤和减轻急性肺损伤和减少炎性细胞因子等作用。最近研究表明丁酸钠可以降低肾损伤大鼠NF-κB的激活；然而，丁酸钠对庆大霉素诱导肾损伤的影响尚未见报道。
目的：本研究应用庆大霉素慢性给药诱导大鼠肾损伤，观察组蛋白去乙酰化酶抑制剂对肾损伤的影响，并进一步研究prohibitin蛋白在肾损伤中的作用。
方法：本研究首先建立庆大霉素诱导肾损伤模型。对照组大鼠腹腔注射生理盐水。庆大霉素组大鼠腹腔注射不同剂量的庆大霉素（高剂量组150mg/kg、中剂量组100mg/kg和两个低剂量组50mg/kg与25mg/kg），连续给药8天，建立庆大霉素诱导肾损伤模型。大鼠用戊巴比妥钠麻醉后，腹主动脉取血，检测血清尿素氮和肌酐水平。代谢笼中收集尿液，检测Kim-1和NGAL含量。大鼠麻醉后取肾脏，放入预先配好的10％福尔马林固定液中，进行HE染色，观察庆大霉素诱导肾损伤的组织学改变。组蛋白的去乙酰化能到抑制转录因子与相关基因特异性结合，从而影响基因的转录。为研究组蛋白去乙酰化酶在庆大霉素诱导肾损伤中的作用，我们采用组蛋白去乙酰化酶抑制剂丁酸钠为研究对象。研究表明丁酸钠可有效增加转录活跃区组蛋白的乙酰化，促进转录因子与相关基因特异性结合，诱导非特异性基因表达的增加。在本研究中我们探讨了丁酸钠急慢性处理对100mg/kg庆大霉素诱导肾损伤的影响。100mg/kg庆大霉素连续给药8天，建立庆大霉素诱导肾损伤模型，在每日给庆大霉素前30分钟腹腔注射不同剂量的丁酸钠（高剂量组200mg/kg、中剂量组100mg/kg和低剂量组50mg/kg），研究丁酸钠慢性处理对庆大霉素诱导肾损伤的作用。在连续给庆大霉素后的第八天给一次丁酸钠，研究丁酸钠急性处理对庆大霉素诱导肾损伤的影响。并应用HE染色方法观察庆大霉素诱导肾损伤过程中，组蛋白乙酰基转移酶对庆大霉素诱导肾损伤的影响。本研究使用免疫组化、Western blot等法检测庆大霉素诱导肾损伤时prohibitin蛋白的表达情况及组蛋白去乙酰化酶抑制剂丁酸钠对肾损伤时prohibitin蛋白的影响。
结果：不同剂量的庆大霉素在连续给药8天后，血清中的BUN和CRE明显增高，表明庆大霉素能够诱导肾损伤。具体表现为：庆大霉素高剂量组150mg/kg和中剂量组100mg/kg明显增加了肾脏损伤时血清BUN水平（P<0.01，P<0.01）；两个低剂量组25mg/kg和50mg/kg也看到了类似的BUN升高（P<0.05，P<0.05）。同样不同剂量的庆大霉素明显增加了血清中的CRE水平，与生理盐水组比较具有显著地统计学意义。低剂量组25mg/kg无统计学意义（P>0.05）。
不同剂量的庆大霉素在连续给药8天后，尿液中尿蛋白标记物Kim-1和NGAL明显增高。与生理盐水比较，具有显著的统计学意义。此外，肾损伤大鼠的每日平均进食量进水量，体重明显降低，与正常组大鼠比较具有显著的统计学意义。通过观察不同剂量庆大霉素对肾损伤过程中血清中的BUN和CRE变化，及尿液中尿蛋白标记物Kim-1和NGAL水平的变化，我们选取中剂量组100mg/kg庆大霉素连续给药8天诱导肾损伤，并达到预期肾损伤效果。HE染色结果表明：不同剂量的庆大霉素组大鼠肾损伤明显，组织学上可见大量小管上皮细胞崩解、坏死，管腔内有大量由坏死脱落的上皮细胞形成的管型。为探讨组蛋白乙酰化修饰是否参与庆大霉素诱导的肾损伤，我们研究组蛋白去乙酰化酶抑制剂急性慢性处理，观察其对庆大霉素诱导肾损伤过程中，血清CRE和BUN及尿液中尿蛋白标记物Kim-1和NGAL水平的影响。结果表明：丁酸钠慢性处理明显降低庆大霉素诱导肾损伤时血清BUN和CRE水平（P<0.05）；而不同剂量丁酸钠急性处理对血清BUN和CRE水平无明显的影响。同时丁酸钠慢性处理后尿液中尿蛋白标记物Kim-1和NGAL水平明显降低。HE染色组织学观察表明组蛋白去乙酰化酶抑制剂慢性处理明显改善庆大霉素诱导肾损伤，而急性处理对庆大霉素诱导的肾损伤并没有明显的改善作用。我们研究表明组蛋白去乙酰化酶抑制剂慢性处理能明显改善庆大霉素诱导肾损伤。采用免疫组化方法检测庆大霉素诱导肾损伤过程中PHB蛋白表达，结果显示肾损伤过程中PHB蛋白表达明显降低。进一步研究发现组蛋白去乙酰化酶抑制剂慢性处理，在连续给药8天后，明显增加庆大霉素诱导肾损伤过程中PHB蛋白的表达；为了进一步证实我们的研究结果，我们采用Western blot方法检测组蛋白去乙酰化酶抑制剂对庆大霉素诱导肾损伤过程中PHB蛋白表达的影响。免疫印迹实验表明组蛋白去乙酰化酶抑制剂慢性处理，明显增加庆大霉素诱导肾损伤过程中PHB蛋白的表达，进一步表明组蛋白去乙酰化酶抑制剂可能通过增加PHB蛋白表达发挥其对肾损伤的保护作用，与免疫组织化学结果相一致。
结论：本研究结果显示，庆大霉素能够明显诱导肾脏损伤，组蛋白去乙酰化酶抑制剂能够改善庆大霉素诱导的肾损伤，其潜在机制可能是与提高PHB蛋白的表达有关。本研究为肾损伤的治疗提供了新的治疗策略和理论依据。
Background: Gentamicin is aminoglycoside antibiotic which hasbeen widely used for the clinical treatment of Gram-negative bacterialinfection. However, the major limitations in clinical use are partially dueto nephrotoxicity and ototoxicity. Among several side effects induced bygentamicin, nephrotoxicity has been reported widely. Although a largenumber of studies have been focused on the side effects induced bygentamicin, the mechanism of nephrotoxicity induced by gentamicin isnot completely known and remains to be studied further. It has beendemonstrated that gentamicin administration increases renal cortical lipidperoxidation, nitric oxide generation and mitochondria hydrogen peroxideproduction. Recent studies have postulated that reactive oxygen speciesparticularly superoxide anion radical are involved in this process.Prohibitin is a ubiquitous and highly conserved protein and has beenshown to play different functions by its special molecular chaperoneprotein. A large number of reports have been shown that prohibitin caninhibit tumor cell proliferation and apoptosis through regulating genetranscription and maintaining mitochondrial protein stability. In addition,studies have demonstrated that prohibitin plays an important role ininflammatory effects and myocardial ischemia reperfusion by protectedthe mitochondria from oxidative stress-induced injury. Recent studieshave indicated that prohibitin protein is involved in tubulointerstitialfibrosis and negatively correlated with the degrees of tubulointerstitiallesions, which suggested that prohibitin protein might be a potentialtherapeutic target for renal injury. However, there are few reports about its role in nephrotoxicity induced by gentamicin. Based on this, weevaluated the potential role of prohibitin in Gentamicin-inducednephrotoxicity in rats.
Sodium butyrate, a potent inhibitor of histone deacetylase, caninduce a nonspecific increase in gene expression. A large number ofreports have been demonstrated that it could provide antidepressant-likeeffect, improve memory function, protect against myocardial ischemiaand reperfusion injury and attenuate acute lung injury and reduceinflammatory cytokines. Recent studies indicated that enhancement ofhistone acetylation induced by sodium butyrate is correlated with increaseof the activities of several antioxidant enzymes, which has been revealedto result in gentamicin-induced nephrotoxicity. Moreover, it has beenreported that sodium butyrate decreases the activation of NF-κB in thekidney of rats subjected to contrast-induced nephropathy. However, theinformation on the effects of sodium butyrate on renal injury induced bygentamicin is lack. Thus, it is necessary to examine our hypothesis thatsodium butyrate may protect against gentamicin-induced renal injury.
Objective：The major purpose in our study was to investigate theeffects of sodium butyrate (NaBu) on renal injury induced by gentamicinin rats and determine further whether the protective effect is mediated bymodulation of prohibitin protein expression.
Method：Gentamicin was injected intraperitoneally (150mg/kg,100mg/kg,50mg/kg,25mg/kg,) once daily for8days to induce renal injury.To observe the effects of acute and chronic treatment of sodium butyrateon gentamicin-induced renal injury, rats received different doses ofsodium butyrate (50,100,200mg/kg, i.p.)30min prior to the gentamicin(100mg/kg, i.p.) injection on the last day and for8consecutive days,respectively.
Blood and urine were collected24h after the last gentamicininjection. Then animals were sacrificed by anesthesia and kidneys wereharvested and rinsed in saline for further serum biochemical andhistopathological analysis. In addition, for each group, food intake,drinking water and body weight were recorded daily, respectively. Theaverage and accumulative consumption amounts of food and drinkingwater of each rat were calculated.
Blood was collected24h after the last gentamicin injection fromdifferent treatment groups. Serum urea nitrogen and creatinine weremeasured by an automatic Clinical Analyzer.
Urine was collected under cooled conditions and stored untilmeasurement of the urinary NGAL and Kim-1. Urinary NGAL andKim-1were determined using the enzyme-linked immunosorbent assay(ELISA).
Kidneys were collected24h after the last gentamicin injection andfixed in10%formalin solution before being embedded in paraffin forsections (3μ mole thick). Sections were stained with hematoxylin andeosin (H&E). A semi-quantitative evaluation of renal tissues wasaccomplished by scoring the degree of severity. Tubular lesions andhyperplasia were observed under bright field using a Carl Zeiss Axioscopmicroscope.
Immunohistochemistry was performed as follows. Kidneys werecollected and processed by a standard pathology procedure. The tissuesections were deparaffinized by placing the slides in an oven at60°C for10min and then rinsed twice in xylene for10min each. The slides werethen hydrated in a graded ethanol series and then finally indouble-distilled water for10min. Next, endogenous peroxidase activitywas blocked using3%hydrogen peroxide solution (for10min at room temperature). Subsequently, the sections were incubated sequentially withthe primary antibody, rabbit antimouse prohibitin (Sigma;1:500dilution,overnight at4°C). After incubation, the tissue sections were rinsed withTBS containing0.05%Tween20twice and incubated with secondaryantibody (poly-HRP anti-rabbit IgG,1:2000dilution,1h at4°C.). Thetissue sections were observed for brown color formation under brightfield.
Kidney was homogenized and then centrifuged as described(Manikandan et al.,2011). The concentration of protein extracts wasdetermined using BCA kit (Pierce, Rockford, IL, USA) and30μg proteinlysates were separated on12%SDA-PAGE followed by being transferredto nitrocellular membrane. After mounting with TBST (Tris-bufferedsaline+0.05%Tween) containing non-fat dry milk (5%w/v) for2h, themembrane was incubated with the primary antibody, rabbit antimouseprohibitin (Sigma;1:500dilution, overnight at4°C). After washing withTBST3times, the membrane was incubated with secondary antibody(poly-HRP anti-rabbit IgG,1:2000dilution,1h at4°C.). After washing3times with TBST, the blots were developed using a chemiluminescencedetection kit. The image was scanned using a gel image analysis system,and the grey scale values of the experimental points were compared withthat of the internal reference β-actin, and statistically were analyzed withKodak Software.
Result：The present study demonstrated that gentamicin treatmentfor8consecutive days significantly increased in the levels of blood ureanitrogen (BUN), creatinine (CRE), kidney injury molecule (KIM-1) andneutrophil gelatinase-associated lipocalin (NGAL) which indicated renalinjury induced by gentamicin. In addition, chronic treatment with NaBusignificantly attenuated gentamicin-induced renal injury. Our results showed that it was not acute treatment of sodium butyrate on the last day,but systematic administration of sodium butyrate for8consecutive dayssignificantly decreased the gentamicin-induced increase of blood ureanitrogen and creatinine when compared to gentamicin/saline treatmentgroup. Urinary NGAL and Kim-1levels in rat with gentamicin-inducedrenal injury were attenuated after chronic treatment of sodium butyrate.Moreover, chronic treatment of sodium butyrate improves the bodyweight, food and water intake in rats with gentamicin-induced renalinjury.
To study whether the protective effects of sodium butyrate ongentamicin-induced renal injury could be related to the activation ofprohibitin protein, the expression of prohibitin in the kidney of rats incontrol and experimental group is examined by immunohistochemistryand western blot analysis. The immunohistochemistry and western blotanalysis revealed that sodium butyrate prevented gentamicin-inducedrenal injury by increasing prohibitin expression.
Conclusion：We have confirmed that sodium butyrate plays aprotective role against renal injury induced by gentamicin exposure.According to our biochemical findings, which were supported by westernblot and immunohistochemistry analysis, chronic administration ofsodium butyrate reduced gentamicin-induced renal injury. Therefore, wepropose that sodium butyrate might be a potential candidate agent againstgentamicin-induced renal injury.
目的：本研究应用庆大霉素慢性给药诱导大鼠肾损伤，观察组蛋白去乙酰化酶抑制剂对肾损伤的影响，并进一步研究prohibitin蛋白在肾损伤中的作用。
方法：本研究首先建立庆大霉素诱导肾损伤模型。对照组大鼠腹腔注射生理盐水。庆大霉素组大鼠腹腔注射不同剂量的庆大霉素（高剂量组150mg/kg、中剂量组100mg/kg和两个低剂量组50mg/kg与25mg/kg），连续给药8天，建立庆大霉素诱导肾损伤模型。大鼠用戊巴比妥钠麻醉后，腹主动脉取血，检测血清尿素氮和肌酐水平。代谢笼中收集尿液，检测Kim-1和NGAL含量。大鼠麻醉后取肾脏，放入预先配好的10％福尔马林固定液中，进行HE染色，观察庆大霉素诱导肾损伤的组织学改变。组蛋白的去乙酰化能到抑制转录因子与相关基因特异性结合，从而影响基因的转录。为研究组蛋白去乙酰化酶在庆大霉素诱导肾损伤中的作用，我们采用组蛋白去乙酰化酶抑制剂丁酸钠为研究对象。研究表明丁酸钠可有效增加转录活跃区组蛋白的乙酰化，促进转录因子与相关基因特异性结合，诱导非特异性基因表达的增加。在本研究中我们探讨了丁酸钠急慢性处理对100mg/kg庆大霉素诱导肾损伤的影响。100mg/kg庆大霉素连续给药8天，建立庆大霉素诱导肾损伤模型，在每日给庆大霉素前30分钟腹腔注射不同剂量的丁酸钠（高剂量组200mg/kg、中剂量组100mg/kg和低剂量组50mg/kg），研究丁酸钠慢性处理对庆大霉素诱导肾损伤的作用。在连续给庆大霉素后的第八天给一次丁酸钠，研究丁酸钠急性处理对庆大霉素诱导肾损伤的影响。并应用HE染色方法观察庆大霉素诱导肾损伤过程中，组蛋白乙酰基转移酶对庆大霉素诱导肾损伤的影响。本研究使用免疫组化、Western blot等法检测庆大霉素诱导肾损伤时prohibitin蛋白的表达情况及组蛋白去乙酰化酶抑制剂丁酸钠对肾损伤时prohibitin蛋白的影响。
结果：不同剂量的庆大霉素在连续给药8天后，血清中的BUN和CRE明显增高，表明庆大霉素能够诱导肾损伤。具体表现为：庆大霉素高剂量组150mg/kg和中剂量组100mg/kg明显增加了肾脏损伤时血清BUN水平（P<0.01，P<0.01）；两个低剂量组25mg/kg和50mg/kg也看到了类似的BUN升高（P<0.05，P<0.05）。同样不同剂量的庆大霉素明显增加了血清中的CRE水平，与生理盐水组比较具有显著地统计学意义。低剂量组25mg/kg无统计学意义（P>0.05）。
不同剂量的庆大霉素在连续给药8天后，尿液中尿蛋白标记物Kim-1和NGAL明显增高。与生理盐水比较，具有显著的统计学意义。此外，肾损伤大鼠的每日平均进食量进水量，体重明显降低，与正常组大鼠比较具有显著的统计学意义。通过观察不同剂量庆大霉素对肾损伤过程中血清中的BUN和CRE变化，及尿液中尿蛋白标记物Kim-1和NGAL水平的变化，我们选取中剂量组100mg/kg庆大霉素连续给药8天诱导肾损伤，并达到预期肾损伤效果。HE染色结果表明：不同剂量的庆大霉素组大鼠肾损伤明显，组织学上可见大量小管上皮细胞崩解、坏死，管腔内有大量由坏死脱落的上皮细胞形成的管型。为探讨组蛋白乙酰化修饰是否参与庆大霉素诱导的肾损伤，我们研究组蛋白去乙酰化酶抑制剂急性慢性处理，观察其对庆大霉素诱导肾损伤过程中，血清CRE和BUN及尿液中尿蛋白标记物Kim-1和NGAL水平的影响。结果表明：丁酸钠慢性处理明显降低庆大霉素诱导肾损伤时血清BUN和CRE水平（P<0.05）；而不同剂量丁酸钠急性处理对血清BUN和CRE水平无明显的影响。同时丁酸钠慢性处理后尿液中尿蛋白标记物Kim-1和NGAL水平明显降低。HE染色组织学观察表明组蛋白去乙酰化酶抑制剂慢性处理明显改善庆大霉素诱导肾损伤，而急性处理对庆大霉素诱导的肾损伤并没有明显的改善作用。我们研究表明组蛋白去乙酰化酶抑制剂慢性处理能明显改善庆大霉素诱导肾损伤。采用免疫组化方法检测庆大霉素诱导肾损伤过程中PHB蛋白表达，结果显示肾损伤过程中PHB蛋白表达明显降低。进一步研究发现组蛋白去乙酰化酶抑制剂慢性处理，在连续给药8天后，明显增加庆大霉素诱导肾损伤过程中PHB蛋白的表达；为了进一步证实我们的研究结果，我们采用Western blot方法检测组蛋白去乙酰化酶抑制剂对庆大霉素诱导肾损伤过程中PHB蛋白表达的影响。免疫印迹实验表明组蛋白去乙酰化酶抑制剂慢性处理，明显增加庆大霉素诱导肾损伤过程中PHB蛋白的表达，进一步表明组蛋白去乙酰化酶抑制剂可能通过增加PHB蛋白表达发挥其对肾损伤的保护作用，与免疫组织化学结果相一致。
结论：本研究结果显示，庆大霉素能够明显诱导肾脏损伤，组蛋白去乙酰化酶抑制剂能够改善庆大霉素诱导的肾损伤，其潜在机制可能是与提高PHB蛋白的表达有关。本研究为肾损伤的治疗提供了新的治疗策略和理论依据。
Background: Gentamicin is aminoglycoside antibiotic which hasbeen widely used for the clinical treatment of Gram-negative bacterialinfection. However, the major limitations in clinical use are partially dueto nephrotoxicity and ototoxicity. Among several side effects induced bygentamicin, nephrotoxicity has been reported widely. Although a largenumber of studies have been focused on the side effects induced bygentamicin, the mechanism of nephrotoxicity induced by gentamicin isnot completely known and remains to be studied further. It has beendemonstrated that gentamicin administration increases renal cortical lipidperoxidation, nitric oxide generation and mitochondria hydrogen peroxideproduction. Recent studies have postulated that reactive oxygen speciesparticularly superoxide anion radical are involved in this process.Prohibitin is a ubiquitous and highly conserved protein and has beenshown to play different functions by its special molecular chaperoneprotein. A large number of reports have been shown that prohibitin caninhibit tumor cell proliferation and apoptosis through regulating genetranscription and maintaining mitochondrial protein stability. In addition,studies have demonstrated that prohibitin plays an important role ininflammatory effects and myocardial ischemia reperfusion by protectedthe mitochondria from oxidative stress-induced injury. Recent studieshave indicated that prohibitin protein is involved in tubulointerstitialfibrosis and negatively correlated with the degrees of tubulointerstitiallesions, which suggested that prohibitin protein might be a potentialtherapeutic target for renal injury. However, there are few reports about its role in nephrotoxicity induced by gentamicin. Based on this, weevaluated the potential role of prohibitin in Gentamicin-inducednephrotoxicity in rats.
Sodium butyrate, a potent inhibitor of histone deacetylase, caninduce a nonspecific increase in gene expression. A large number ofreports have been demonstrated that it could provide antidepressant-likeeffect, improve memory function, protect against myocardial ischemiaand reperfusion injury and attenuate acute lung injury and reduceinflammatory cytokines. Recent studies indicated that enhancement ofhistone acetylation induced by sodium butyrate is correlated with increaseof the activities of several antioxidant enzymes, which has been revealedto result in gentamicin-induced nephrotoxicity. Moreover, it has beenreported that sodium butyrate decreases the activation of NF-κB in thekidney of rats subjected to contrast-induced nephropathy. However, theinformation on the effects of sodium butyrate on renal injury induced bygentamicin is lack. Thus, it is necessary to examine our hypothesis thatsodium butyrate may protect against gentamicin-induced renal injury.
Objective：The major purpose in our study was to investigate theeffects of sodium butyrate (NaBu) on renal injury induced by gentamicinin rats and determine further whether the protective effect is mediated bymodulation of prohibitin protein expression.
Method：Gentamicin was injected intraperitoneally (150mg/kg,100mg/kg,50mg/kg,25mg/kg,) once daily for8days to induce renal injury.To observe the effects of acute and chronic treatment of sodium butyrateon gentamicin-induced renal injury, rats received different doses ofsodium butyrate (50,100,200mg/kg, i.p.)30min prior to the gentamicin(100mg/kg, i.p.) injection on the last day and for8consecutive days,respectively.
Blood and urine were collected24h after the last gentamicininjection. Then animals were sacrificed by anesthesia and kidneys wereharvested and rinsed in saline for further serum biochemical andhistopathological analysis. In addition, for each group, food intake,drinking water and body weight were recorded daily, respectively. Theaverage and accumulative consumption amounts of food and drinkingwater of each rat were calculated.
Blood was collected24h after the last gentamicin injection fromdifferent treatment groups. Serum urea nitrogen and creatinine weremeasured by an automatic Clinical Analyzer.
Urine was collected under cooled conditions and stored untilmeasurement of the urinary NGAL and Kim-1. Urinary NGAL andKim-1were determined using the enzyme-linked immunosorbent assay(ELISA).
Kidneys were collected24h after the last gentamicin injection andfixed in10%formalin solution before being embedded in paraffin forsections (3μ mole thick). Sections were stained with hematoxylin andeosin (H&E). A semi-quantitative evaluation of renal tissues wasaccomplished by scoring the degree of severity. Tubular lesions andhyperplasia were observed under bright field using a Carl Zeiss Axioscopmicroscope.
Immunohistochemistry was performed as follows. Kidneys werecollected and processed by a standard pathology procedure. The tissuesections were deparaffinized by placing the slides in an oven at60°C for10min and then rinsed twice in xylene for10min each. The slides werethen hydrated in a graded ethanol series and then finally indouble-distilled water for10min. Next, endogenous peroxidase activitywas blocked using3%hydrogen peroxide solution (for10min at room temperature). Subsequently, the sections were incubated sequentially withthe primary antibody, rabbit antimouse prohibitin (Sigma;1:500dilution,overnight at4°C). After incubation, the tissue sections were rinsed withTBS containing0.05%Tween20twice and incubated with secondaryantibody (poly-HRP anti-rabbit IgG,1:2000dilution,1h at4°C.). Thetissue sections were observed for brown color formation under brightfield.
Kidney was homogenized and then centrifuged as described(Manikandan et al.,2011). The concentration of protein extracts wasdetermined using BCA kit (Pierce, Rockford, IL, USA) and30μg proteinlysates were separated on12%SDA-PAGE followed by being transferredto nitrocellular membrane. After mounting with TBST (Tris-bufferedsaline+0.05%Tween) containing non-fat dry milk (5%w/v) for2h, themembrane was incubated with the primary antibody, rabbit antimouseprohibitin (Sigma;1:500dilution, overnight at4°C). After washing withTBST3times, the membrane was incubated with secondary antibody(poly-HRP anti-rabbit IgG,1:2000dilution,1h at4°C.). After washing3times with TBST, the blots were developed using a chemiluminescencedetection kit. The image was scanned using a gel image analysis system,and the grey scale values of the experimental points were compared withthat of the internal reference β-actin, and statistically were analyzed withKodak Software.
Result：The present study demonstrated that gentamicin treatmentfor8consecutive days significantly increased in the levels of blood ureanitrogen (BUN), creatinine (CRE), kidney injury molecule (KIM-1) andneutrophil gelatinase-associated lipocalin (NGAL) which indicated renalinjury induced by gentamicin. In addition, chronic treatment with NaBusignificantly attenuated gentamicin-induced renal injury. Our results showed that it was not acute treatment of sodium butyrate on the last day,but systematic administration of sodium butyrate for8consecutive dayssignificantly decreased the gentamicin-induced increase of blood ureanitrogen and creatinine when compared to gentamicin/saline treatmentgroup. Urinary NGAL and Kim-1levels in rat with gentamicin-inducedrenal injury were attenuated after chronic treatment of sodium butyrate.Moreover, chronic treatment of sodium butyrate improves the bodyweight, food and water intake in rats with gentamicin-induced renalinjury.
To study whether the protective effects of sodium butyrate ongentamicin-induced renal injury could be related to the activation ofprohibitin protein, the expression of prohibitin in the kidney of rats incontrol and experimental group is examined by immunohistochemistryand western blot analysis. The immunohistochemistry and western blotanalysis revealed that sodium butyrate prevented gentamicin-inducedrenal injury by increasing prohibitin expression.
Conclusion：We have confirmed that sodium butyrate plays aprotective role against renal injury induced by gentamicin exposure.According to our biochemical findings, which were supported by westernblot and immunohistochemistry analysis, chronic administration ofsodium butyrate reduced gentamicin-induced renal injury. Therefore, wepropose that sodium butyrate might be a potential candidate agent againstgentamicin-induced renal injury.
引文
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