1O-羟基喜树碱和环孢素A诱导异基因大鼠心脏移植受者免疫耐受的实验研究

目的以中药制剂10-羟基喜树碱(HCPT)和环孢素A(CsA)诱导异基因大鼠心脏移植受者免疫耐受,并探讨免疫耐受的特异性和形成机制.方法以纯系SD大鼠为供者,纯系Wis-tar大鼠为受者行异体颈部心脏移植.将移植后50只受者大鼠随机分成5组,分别接受不同剂量HCPT、CsA或二者联合应用.A组接受安慰剂.B组接受HCPT 1.0mg·kg-1·d-1,腹腔注射.C组接受HCPT 2.0 mg·kg-1·d-1,腹腔注射.E组接受CsA10.0 mg·kg·d-1,导管灌胃.F组联合应用HCPT和CsA,方法剂量同B组和E组.心脏移植物长期存活受者术后60 d停用免疫抑制剂,120 d同时行供者来源(SD)大鼠和无关供者(SHR)大鼠皮肤移植.结果3只C组大鼠和5只F组大鼠心脏移植术后停用免疫抑制剂长期存活超过730 d.8块SD大鼠皮肤移植物长期存活超过610 d,而8块SHR大鼠皮肤均被排斥,平均存活时间(4.50±1.25)d.结论大剂量HCPT或小剂量HCPT与CsA联合应用可诱导异基因大鼠心脏移植受者免疫耐受,且形成的免疫耐受具有明确的抗原特异性.     

环孢素A对大鼠慢性肾毒性模型肾素-血管紧张素系统的影响

目的　探讨环孢素A (CsA)慢性肾毒性的发生机理。方法　采用放射免疫分析的方法 ,观察进低盐饮食的大鼠在灌服CsA 30mg·kg- 1 ·d- 1 2 8d后血浆肾素活性 (PRA)、血管紧张素Ⅱ(AngⅡ )、醛固酮水平的变化 ,以及复方丹参注射液、贝那普利对上述改变的防护作用。结果　CsA可引起大鼠血浆PRA、AngⅡ水平明显升高 ;丹参对这些改变影响不明显 ,而贝那普利对大鼠PRA、AngⅡ水平的升高有明显的抑制作用。血浆醛固酮水平 ,各组比较 ,只有给予贝那普利者明显下降 ,其余各组之间血浆醛固酮水平的差异无显著性 (P >0 .0 5)。结论　CsA的慢性肾毒性损伤可能与肾素 血管紧张素系统 (RAS)的激活 ,尤其是与AngⅡ的增加有关 ;CsA不引起血浆醛固酮水平的升高     

抗氧化剂茶多酚对环孢菌素A诱导慢性肾毒性时细胞凋亡的影响

目的　探讨抗氧化剂茶多酚 (teapolyphenols,TP)对环孢菌素A(cyclosporineA ,CsA)诱导慢性肾毒性时细胞凋亡的影响。　方法　采用大鼠CsA慢性肾毒性动物模型 ,分CsA溶剂oliveoil组(n =6)、TP组 (n=6)、CsA组 (n =8)与CsA +TP组 (n =8) ,处理 4周后观察肾功能与组织学改变 ,TUNEL法检测肾细胞凋亡 ,RT PCR检测肾组织caspase 3mRNA的表达 ,并测定caspase 3酶活性。结果　与CsA组相比较 ,CsA与TP联用显著改善CsA诱导的肾功能损伤与组织学改变 ;CsA与TP合用组肾小管及间质凋亡细胞数明显少于CsA组 (7 7± 1 4vs 1 8 9± 3 3 ,P <0 0 5) ,并明显减少CsA诱导的caspase 3mRNA的表达及其酶活性 (P <0 0 5)。　结论　抗氧化剂茶多酚具有抑制CsA诱导慢性肾毒性时肾小管和间质细胞凋亡的作用 ,提示减少CsA诱导的细胞凋亡是茶多酚保护肾功能与组织结构的机理之一。     

全反式维甲酸对5/6肾大部切除大鼠肾素-血管紧张素系统的影响

目的 观察全反式维甲酸（atRA）对残余肾肾素-血管紧张素系统（RAS）的影响。 方法 采用5/6肾大部切除大鼠模型，分别给予5 mg·kg-1·d-1（n＝8）、10 mg·kg-1·d-1（n＝8）、20 mg·kg-1·d-1（n＝8）的atRA灌胃。单纯肾大部切除非干预组（NX组，n＝8）和假手术组（sham组，n＝8）为对照。放射免疫法检测大鼠肾皮质肾素、血管紧张素水平。Western印迹检测肾组织血管紧张素1型受体（AT1R）水平。实时定量PCR方法检测激活蛋白1（AP-1）亚单位c-jun和c-fos mRNA的表达水平。 结果 atRA 灌胃10周时， 3种剂量atRA组收缩压明显低于NX组（P < 0.05），但不同剂量atRA组间差异无统计学意义。NX组大鼠肾皮质肾素和血管紧张素Ⅱ水平均显著高于sham组（P < 0.05）。atRA治疗组肾皮质肾素和血管紧张素Ⅱ水平均显著低于NX组，其中20 mg·kg-1·d-1组二者水平显著低于其他两个剂量组。atRA抑制残肾皮质AT1R表达约30％，而20 mg·kg-1·d-1剂量组AT1R表达水平最低。atRA组AP-1亚基c-jun和c-fos mRNA表达显著低于NX组（P < 0.05）。 结论 atRA能明显抑制5/6肾大部切除大鼠肾皮质RAS主要成分的高表达。     

雷公藤多甙及环孢素A在大鼠心脏移植中的协同作用

目的探讨心脏移植术后单用雷公藤多甙(TWHF)及与环孢素A(GsA)合用对大鼠心脏移植物生存期的影响.方法供体为雄性PVG(RT1C)大鼠,受体为雄性Lewis(LEW;RT11)大鼠.采用改良的Ono和Lindsey方法实施腹部异位心脏移植.根据术后处理不同将实验动物分为4组第1组(5只)对照组(非治疗组);第2组(7只)TWHF 60 mg·kg-1·d-1;第3组(6只)CsA 15 mg·kg-1·d-1;第4组(5只)TWHF 40 mg·kg-1·d-1+CsA1 mg·kg-1·d-1.用吐温80及蒸馏水将TWHF配制成1%悬液;CsA使用前以注射用水配成5g/L.术后当天即给药,TWHF为灌服,CsA为肌肉注射.直至发生排斥反应或最多给药14 d.每天通过触摸监测移植心脏的功能.结果4组移植大鼠心脏平均存活8.8、12.0、17.0、34.6 d.结论心脏移植术后给予雷公藤多甙及CsA联合治疗,能明显延长移植心脏的功能存活时间.     

大鼠肾上腺髓质增生模型的动态观察

目的　探讨利血平建立大鼠肾上腺髓质增生 (AMH)模型的最适剂量 ,观察其长期稳定性。方法　雄性Wistar大鼠 72只 ,随机分为A、B、C、D 4组各 18只 ,A组皮下注射利血平 0 .2mg·kg-1·d-1和 0 .9%生理盐水 0 .6mg·kg-1·d-1,B组皮下注射利血平 0 .4mg·kg-1·d-1和 0 .9%生理盐水 0 .4mg·kg-1·d-1,C组皮下注射利血平 0 .8mg·kg-1·d-1,D组皮下注射 0 .9%生理盐水0 .8mg·kg-1·d-1,每日 1次 ,持续 2个月后停药。分别于停药后 2周、2个月、6个月时测大鼠 2 4小时尿 3 甲氧基 4 羟基苦杏仁酸 (VMA )含量及血儿茶酚胺 (CA)水平 ,然后处死大鼠 ,取出肾上腺 ,作病理切片 ,测肾上腺髓质百分数 ,及AMH阳性率。结果　在各停药时段 ,B、C组与D组相比2 4h尿VMA含量、血浆CA水平和髓质百分数均有显著性升高 (P <0 .0 5 ) ,这三组各值与停药 2周相比差异均无显著性 (P >0 .0 5 ) ;在停药 6个月时 ,A组各值与停药 2周时相比有显著性下降( P <0 .0 5 ) ,与D组相比差异均无显著性 ( P >0 .0 5 )。结论　利血平所致大鼠AMH模型各生化指标稳定 ,但C组死亡率较高。     

肾移植患者应用他克莫司的临床观察

目的　评价肾移植术后应用他克莫司 (FK5 0 6 )的有效性、安全性。方法　将肾移植术后的 70例患者按使用不同的基础免疫抑制剂分为两组 :FK5 0 6组 30例 ,环孢素A(CsA)组 40例。FK5 0 6按 0 .1～ 0 .2mg·kg-1·d-1、CsA按 6～ 8mg·kg-1·d-1给药 ,并动态连续检测全血FK5 0 6和CsA谷值浓度并观察临床治疗效果 ,两组进行比较。结果　FK5 0 6组达稳态浓度时间短于CsA组 ,分别为 4和 10d ,糖尿病发生率 ( 2 0 % )高于CsA组 ( 7.5 % ) ;肝毒性 ( 3 .3 % )、排斥反应 ( 6 .6 % )发生率低于CsA组 ( 17.5 %、2 5 % )。结论　FK5 0 6是一种强效的免疫抑制剂。但在使用过程中 ,需定期检测血浓度以指导用药剂量。     

延长大鼠异种心脏移植后存活时间的实验研究

目的　研究如何延长大鼠异种心脏移植后的存活时间。方法　实验分为A、B、C、D四组。A组 :移植术前 12、8、4、0d及 10、6、2、0d分别将脾细胞 1× 10 8个 ,抗血清 0 .2ml静脉注入受体大鼠 ;B组 :在A组的基础上 ,加用中华眼镜蛇毒 (CCV) 0 .2mg·kg-1·d-1,术前 3d至术日腹腔注射。C组 :在B组的基础上 ,加用环孢素A(CsA) 10mg·kg-1·d-1、环磷酰胺 (Cy) 2 0mg·kg-1·d-1,术前 12d开始至术日腹腔注射。D组 :在C组的基础上 ,加用抗巨噬细胞和抗自然杀伤细胞单克隆抗体 2 5 0 μg·kg-1·d-1,术前 12d开始至术日腹腔注射。结果　A、B、C、D四组移植心脏分别存活 (0 .32± 0 .12 )h ,(2 5 .6± 9.6 )h、(48.6± 10 .4)h和 (72 .4± 2 1.7)h ;术日各组IgG均下降 ,尤以C、D组下降明显 ,与A、B组比较 ,差异有显著性 (P <0 .0 5 )。结论　术前静脉注射供体脾细胞及抗血清 ,尤其与CCV、CsA、Cy合用 ,能显著抑制IgG的产生 ,延长移植心脏的存活时间。     

10-羟基喜树碱对异基因大鼠心脏移植物急性排斥反应的抑制作用

目的　探讨 10 羟基喜树碱 (HCPT)对移植物急性排斥反应的免疫抑制作用。方法　以SD大鼠为供者 ,Wistar大鼠为受者 ,行大鼠同种异体异位心脏移植。用中药制剂 10 羟基喜树碱(HCPT)预防和治疗移植物急性排斥反应。结果　HCPT 1.0mg·kg-1·d-1组与对照组比较 ,移植物存活时间明显延长 (6.0 5d/ 11.45d ,P <0 .0 0 1) ;HCPT 2 .0mg·kg-1·d-1组作用更为显著 (>2 41.6d) ,其中 3只大鼠于术后 60d停用HCPT ,移植心脏长期存活 ,超过 73 0d ,并经证实已形成免疫耐受。大鼠心脏移植物发生急性排斥反应时 ,HCPT 10 .0mg·kg-1·d-1能使排斥反应完全逆转 ,移植心脏功能完全恢复正常。较大剂量HCPT可导致轻微的胃肠道反应 ,但未观察到明显的肝、肾、心、脾、睾丸和造血系统损害。结论　HCPT对大鼠移植心脏急性排斥反应具有显著的抑制作用 ,且具有剂量相关性     

肝细胞生长因子在环孢素A肾病大鼠肾组织中的表达意义

目的　探讨肝细胞生长因子 (HGF)在环孢素A(CsA)肾病大鼠肾组织中的表达及意义。　方法　 2 8只SD大鼠低盐饮食饲养 7d后 ,随机分为对照组、CsA组、CsA加维拉帕米组、CsA加依那普利组。每组 7只。除对照组外 ,其余 3组大鼠皮下注射CsA 15mg·kg-1·d-1,采用放射免疫法检测各组动物血管紧张素Ⅱ (AngⅡ )水平 ;Northernblot、原位杂交检测肾组织HGFmRNA的表达。对各组动物肾小管损伤进行半定量计分。　结果　CsA处理组肾组织AngⅡ水平均明显高于对照组 :(2 9.8± 6.0 )vs (8.7± 1.7)ng/g肾组织 ,P <0 .0 0 1,HGFmRNA表达也明显减少。依那普利组肾组织AngⅡ水平明显降低 ,HGFmRNA表达增加 ,P <0 .0 5。依那普利能明显减轻CsA引起的肾小管损伤 ,异博定对肾小管损伤无显著改善。肾组织HGFmRNA表达与肾小管损伤呈负相关 ,P <0 .0 5。　结论　肾素血管紧张素系统 (RAS)的激活使HGFmRNA表达下调 ,阻断RAS可以使HGFmRNA表达增加 ,减轻CsA引起的肾小管损伤     

Synergistic effects of mycophenolate mofetil and losartan in a model of chronic cyclosporine nephropathy

BACKGROUND: Combined treatments of mycophenolate mofetil (MMF) and losartan (LSRT) have synergistic effects on various renal diseases through their hemodynamic and anti-inflammatory effects. This study investigated whether MMF treatment is effective in inhibiting inflammatory processes in chronic cyclosporine A (CsA) nephrotoxicity, and whether combined treatment using MMF and LSRT affords superior protection compared with the respective monotherapies. METHODS: Rats on a low-salt diet were given vehicle (VH group, olive oil, 1 mg/kg per day), CsA (15 mg/kg per day), CsA and LSRT (CsA+LSRT group, 100 mg/L per day), CsA and MMF (CsA+MMF group; 40 mg/kg per day), or CsA, LSRT and MMF (CsA+LSRT MMF group). Control groups received each drug without CsA treatment. Renal function, histologic parameters (arteriolopathy, tubulointerstitial fibrosis, and inflammatory cell infiltration), and mediators of CsA-induced nephrotoxicity (angiotensin-II, osteopontin, and transforming growth factor [TGF]-beta1) were studied. RESULTS: The CsA-treated rats showed decreased renal function and increased histologic parameters compared with the VH-treated rats. The CsA+MMF treatment significantly improved renal function and histopathologic parameters compared with the CsA group, and combined treatment with MMF and LSRT further improved those parameters compared with the CsA+LSRT and CsA+MMF groups. At a molecular level, increased expression of angiotensin II protein, osteopontin, and TGF-beta1 mRNAs in the CsA group were significantly decreased with MMF, and further decrease was observed with the combined treatment using MMF and LSRT. CONCLUSIONS: MMF treatment decreases CsA-induced nephrotoxicity, and combined treatment with LSRT has a synergistic effect in preventing chronic CsA nephrotoxicity.     

Attenuation of Cyclosporine-Induced Renal Dysfunction by Catechin: Possible Antioxidant Mechanism

One of great use of immunosuppressant, Cyclosporine-A (CsA) is in the solid organ transplantation; however the extensive use of this is cautionable due to its toxic effect in renal tissue, characterized by the tubular atrophy, interstitial fibrosis, and progressive renal impairment. However, there are many mediators are associated with pathogenesis of nephrotoxicity of CsA, the exact mechanism is still in debate. Recent studies indicate that Reactive Oxygen Species (ROS) induced oxidative stress and lipid peroxidations are the important mechanisms implicated in the pathophysiology of nephrotoxicity with CsA. In the present study we examined effect of dietary flavonoid catechin on oxidative damage in cyclosporine-A induced nephrotoxicity. Chronic administration of CsA (20 mg/kg/day) subcutaneously for 21 days significantly decreased the body weight as compared with vehicle treated rats. CsA (20 mg/kg/day) administration for 21 days significantly decreased the renal function by increase in the serum creatinine, blood urea nitrogen, and decrease in the creatinine and urea clearance as compared with vehicle treated rats. Catechin (100 mg/kg/day) for 21 days along with CsA significantly reversed the changed renal parameters, however lower dose of catechin (50 mg/kg/day) restored only increased serum creatinine levels as compared with CsA alone treated group. Biochemical analysis revealed that chronic administration of CsA (20 mg/kg/day) for 21 days significantly induced lipid peroxidation and decreased the glutathione levels in the kidney homogenate of rats. It is also observed that chronic CsA administered rats showed decrease in antioxidant defense enzyme superoxide dismutase and increase in the catalase activity as compared with vehicle treated rats. Co-administration of catechin (100 mg/kg/day) orally along with CsA for 21 days significantly reduced the lipid peroxidation and restored the decreased glutathione levels as compared with CsA alone group, but lower dose of catechin (50 mg/kg/day) restored only decreased glutathione levels induced by CsA. Co-administration of only higher dose of catechin (100 mg/kg/day) along with CsA significantly increased the superoxide dismutase (SOD) levels as compared with CsA alone treated group. It is also observed that catechin (100 mg/kg/day) along with CsA further increased the catalase levels as compared with CsA alone treated group, but not with lower dose of catechin. Animals administered with catechin (100 mg/kg/day) alone for 21 days showed significant increase in the catalase levels as compared with vehicle treated group. The major findings of the present study suggest that oxidative stress might play a significant role in CsA-induced nephrotoxicity. In conclusion, dietary administration of flavonoid catechin could be a useful component for the prevention/treatment of CsA-induced nephrotoxicity.     

Attenuation of cyclosporine-induced renal dysfunction by catechin: possible antioxidant mechanism

One of great use of immunosuppressant, Cyclosporine-A (CsA) is in the solid organ transplantation; however the extensive use of this is cautionable due to its toxic effect in renal tissue, characterized by the tubular atrophy, interstitial fibrosis, and progressive renal impairment. However, there are many mediators are associated with pathogenesis of nephrotoxicity of CsA, the exact mechanism is still in debate. Recent studies indicate that Reactive Oxygen Species (ROS) induced oxidative stress and lipid peroxidations are the important mechanisms implicated in the pathophysiology of nephrotoxicity with CsA. In the present study we examined effect of dietary flavonoid catechin on oxidative damage in cyclosporine-A induced nephrotoxicity. Chronic administration of CsA (20 mg/kg/day) subcutaneously for 21 days significantly decreased the body weight as compared with vehicle treated rats. CsA (20 mg/kg/day) administration for 21 days significantly decreased the renal function by increase in the serum creatinine, blood urea nitrogen, and decrease in the creatinine and urea clearance as compared with vehicle treated rats. Catechin (100 mg/kg/day) for 21 days along with CsA significantly reversed the changed renal parameters, however lower dose of catechin (50 mg/kg/day) restored only increased serum creatinine levels as compared with CsA alone treated group. Biochemical analysis revealed that chronic administration of CsA (20 mg/kg/day) for 21 days significantly induced lipid peroxidation and decreased the glutathione levels in the kidney homogenate of rats. It is also observed that chronic CsA administered rats showed decrease in antioxidant defense enzyme superoxide dismutase and increase in the catalase activity as compared with vehicle treated rats. Co-administration of catechin (100 mg/kg/day) orally along with CsA for 21 days significantly reduced the lipid peroxidation and restored the decreased glutathione levels as compared with CsA alone group, but lower dose of catechin (50 mg/kg/day) restored only decreased glutathione levels induced by CsA. Co-administration of only higher dose of catechin (100 mg/kg/day) along with CsA significantly increased the superoxide dismutase (SOD) levels as compared with CsA alone treated group. It is also observed that catechin (100 mg/kg/day) along with CsA further increased the catalase levels as compared with CsA alone treated group, but not with lower dose of catechin. Animals administered with catechin (100 mg/kg/day) alone for 21 days showed significant increase in the catalase levels as compared with vehicle treated group. The major findings of the present study suggest that oxidative stress might play a significant role in CsA-induced nephrotoxicity. In conclusion, dietary administration of flavonoid catechin could be a useful component for the prevention/treatment of CsA-induced nephrotoxicity.     

Biochemical mechanisms underlying cyclosporine-induced nephrotoxicity. Effect of concomitant administration of prednisolone

Biochemical mechanisms underlying cyclosporine (CsA)-induced nephrotoxicity and the effect of concomitant administration of prednisolone (Pr) on the nephrotoxicity were studied. Male Wistar rats were treated with the vehicles used for CsA and Pr administration (group 1), Pr alone (group 2), CsA alone (group 3), or CsA plus Pr (group 4), respectively. The dose of CsA was 5 mg/kg/day, i.p. for the initial 7 days, and was decreased to 2.5 mg/kg/day i.p. thereafter. The dose of Pr was always maintained at one-tenth of that of CsA. At 10, 30, and 90 days after the initiation of these treatments, blood urea nitrogen (BUN) and serum levels of creatinine and CsA were determined. The syntheses of DNA, RNA, and protein, Na+, K+-adenosine triphosphate (ATP)ase activity, and ATP content were measured using homogenates of the renal cortex obtained from each experimental group. At an early stage (at 10 and 30 days) of CsA administration, the impairment of renal function and inhibition of the synthesis of DNA and RNA appeared in groups 3 and 4. The magnitude of these changes was found to be greater in group 3 (CsA alone) than in group 4 (CsA plus Pr). Group 3 also showed a significant reduction of Na+, K+-ATPase activity as well as ultrastructural abnormalities. At a later stage (at 90 days), however, such differences in nephrotoxicity between groups 3 and 4 were not detected. These results strongly suggest that inhibition of the synthesis of DNA and RNA and the activity of enzymes related to the functions of cell membrane, such as Na+, K+-ATPase, may be involved in the occurrence of CsA-induced nephrotoxicity. The present results also suggest that the concomitant administration of Pr with CsA may reduce the nephrotoxicity of CsA at early stages of CsA administration, but this preventive effect of Pr may disappear if the administration of CsA is prolonged.     

Mercury exacerbates cyclosporin nephrotoxicity in rats

Background The use of cyclosporin (CsA) in the presence of other nephrotoxic drugs poses a great challenge to physicians. This study was designed to address the effect of concomitant administration of mercury and cyclosporin on nephrotoxicity of rats. Methods Male Sprague-Dawley rats (weighing 230±20 g) were divided into the following 8 groups of 7 animals each: group 1, control; group 2, mercury alone; group 3, cyclosporin 12.5 mg/kg; group 4, cyclosporin 25 mg/kg; group 5, CsA 50 mg/kg; group 6, CsA 12.5 mg/kg+mercury; group 7, CsA 25 mg/kg+mercury; and group 8, CsA 50 mg/kg+mercury. Mercury (1 mg/kg) was given by subcutaneous injection, and CsA, by oral gavage; drugs were given once a day for 7 days. Twenty-four hours after the last dose of drugs, the animals were killed, and blood samples were assayed for BUN, serum creatinine, and CsA levels. The left kidney was analyzed for malondialdehyde, lipid hydroperoxides, vitamin E, and glutathione levels, and histopathologic analysis was done on the right kidney. Results Mercury significantly exacerbated CsA-induced nephrotoxicity. There was a highly significant increase in oxidative stress in animals treated with the combination of CsA and mercury. Mercury also increased the bioavailability of CsA in rats. Conclusions Concomitant treatment of mercury with CsA produced severe nephrotoxicity. The enhanced nephrotoxicity may be attributed to the increased bioavailability of CsA and an increase in lipid peroxidation after concomitant use of these drugs.     

Protective effect of Epo on oxidative renal injury in rats with cyclosporine nephrotoxicity

The aim of our study was to determine the effect of recombinant human erythropoietin (rhEPO) on cyclosporine (CsA) nephrotoxicity. Twenty-six female Wistar rats were injected with 15 mg/kg subcutaneous CsA and intraperitoneal saline/rhEPO for 28 days. Four groups were formed: Group 1 (n = 5), a control group; Group 2 (n = 7), CsA + saline; Group 3 (n = 7), CsA + low dose (20 U/kg per day) rhEPO; Group 4 (n = 7), CsA + high dose (100 U/kg per day) rhEPO. Body weights, creatinine clearance, urinary protein/creatinine, hematocrit, serum creatinine levels, histopathological parameters, apoptosis and lipid peroxidation tests were compared between the three groups. Body weights and renal functions were similar in Groups 2, 3 and 4 rats but significantly lower than the values found for the control group at the end of the study. The hematocrit was significantly different between the four groups, showing a positive association with the strength of the injected rhEPO doses. Tubular and arteriolar damage was significantly lower in Groups 3 and 4 rats than in Group 2 rats, while chronic changes were similar between the three groups. TUNEL-positive cells and thiobabarbituric acid reacting substance (TBARS) levels were significantly higher in Group 2 rats, whereas superoxide dismutase levels were significantly lower in Group 2 rats than in those of the other three groups. Low or high dose rhEPO had no significant protective effects on body weight, renal functions, chronic fibrotic changes, but both doses reduced tubular and arteriolar changes, apoptotis and oxidative stress.     

Sirolimus increases transforming growth factor-beta1 expression and potentiates chronic cyclosporine nephrotoxicity

BACKGROUND: Sirolimus (SRL) is increasingly being used to decrease cyclosporine (CsA) exposure. SRL is not known to be nephrotoxic and has a mechanism of action distinct from CsA. We investigated the effect of combining CsA and SRL on renal structure and function and on transforming growth factor-beta1 (TGF-beta1) and extracellular matrix (ECM) proteins in a model of chronic CsA nephrotoxicity. METHODS: Rats treated with vehicle, SRL 0.3 mg/kg/day, CsA 5 or 10 mg/kg/day, or CsA5+SRL were sacrificed at 7 or 28 days. Physiologic and histologic changes were studied in addition to TGF-beta1 mRNA and protein expressions, and mRNA expression of plasminogen activator inhibitor-1 (PAI-1) and ECM proteins biglycan and types I and IV collagen. RESULTS: While SRL alone did not alter renal function and structure, it potentiated the nephrotoxic actions of CsA when used in combination with low-dose CsA5 and resulted in significant changes similar to high-dose CsA10. In addition, SRL alone increased TGF-beta1 by 44% to 49% (P < 0.05 vs. VH). When used in combination with low-dose CsA5, SRL potentiated TGF-beta1 mRNA and protein by 121% and 176%, respectively (P < 0.05 vs. VH and CsA5), to levels achieved with high-dose CsA10. The expression of the ECM proteins followed that of TGF-beta1; a similar effect was observed with PAI-1, suggesting a decrease in ECM degradation. CONCLUSION: Because SRL augments nephrotoxicity, caution should be exercised when it is used in combination with CsA. More studies are needed to determine the long-term clinical impact of SRL on nephrotoxicity and allograft function.     

Telmisartan attenuates chronic ciclosporin A nephrotoxicity in a pig model.

BACKGROUND: We have previously demonstrated renal enlargement in pigs treated with ciclosporin A (CsA) 10 mg/kg/day orally for 6 months. The aim of the study was to investigate the effect of oral CsA (10 mg/kg/day) for 12 months on kidney structure and function and the potential renoprotective role of angiotensin II (Ang II) receptor blocker telmisartan on chronic CsA nephrotoxicity in pigs. METHODS: Fourteen G?ttingen minipigs aged 12-14 months were included: pigs received either CsA 10 mg/kg/day (n = 7) or CsA 10 mg/kg/day + telmisartan 40 mg/day (n = 7) orally for 12 months. At week 0, 12, 31, 38, 47 and 54, we measured body weight, mean arterial blood pressure (MAP), serum creatinine, whole blood trough CsA, plasma Ang II, haemoglobin and liver function parameters. Magnetic resonance imaging was used to estimate kidney length, volume, relative glomerular filtration rate (rGFR) and renal blood flow (RBF). Kidney tissue biopsies were used for conventional histological examination. RESULTS: Plasma Ang II levels were significantly higher during telmisartan treatment. Interstitial fibrosis and glomerulosclerosis occurred in both groups, but were attenuated in the telmisartan-treated pigs (P = 0.064). A significant increase in renal volume was seen in both groups, but tended to be lower in the CsA + telmisartan pigs at 54 weeks (P = 0.097). Telmisartan did not reduce MAP, RBF or rGFR. CONCLUSIONS: Long-term CsA treatment causes histopathological changes in the porcine kidney similar to those observed in humans and results in renal enlargement. Telmisartan attenuates the CsA-induced histopathological changes and enlargement in the pig kidney.     

Peritransplant treatment with cobalt protoporphyrin attenuates chronic renal allograft rejection

Allogen-independent injury contributes to chronic rejection in renal allografts and heme oxygenase-1 (HO-1) has been shown to be protective in a number of settings. This study evaluated the effect of renal allograft recipient HO-1 up-regulation on chronic rejection in a rat model. Rat (F344 to Lewis) renal transplantation recipients were grouped: (i) cyclosporine (CsA) alone (0.75 mg/kg s.c. x 10 day; n = 5); (ii) CsA + low dose cobalt protoporphyrin (CoPP) an HO-1 inducer (0.5 mg/kg i.p. on days -5,0,5; n = 13) and (iii) CsA + high dose CoPP (5.0 mg/kg i.p. on days -5,0,5; n = 8). Renal function was assessed by serum creatinine levels on day 140. Histopathologic changes in allografts were graded. Morphometric analyses performed to objectively quantify the vascular changes and glomerulosclerosis. HO-1 expression quantified by Western blot and both HO-1 and endothelin (ET-1) localized using immunohistochemistry. Recipients treated with CsA + high dose CoPP had significantly decreased cortical scarring, vascular hyalinization and intimal thickness. They also had a significant, dose-dependent, reduction in luminal obliteration and glomerulosclerosis by morphometric analyses. This freedom from chronic rejection in recipients treated with CoPP translated into quiescent grafts at postoperative day 140 with immunostaining and Western blot demonstrating decreased level of HO-1 versus controls (P = 0.012). In summary, the peritransplant up-regulation of HO-1 in renal allograft recipients significantly attenuates chronic rejection in rat renal allografts by inhibiting transplant vasculopathy.     

氨基胍与环孢素A联用对大鼠心脏移植后急性排斥反应的影响

目的：探讨氨基胍与环孢素A联用对同种大鼠心脏移植后急性排斥反应的影响。方法：受体SD大鼠心脏移植后分为4组：（1）对照组：术后不作任何处理;（2）低剂量环孢素A（CsA)组;术后0－7d肌肉注射CsA2mg.kg^-1.d^-1;（3）氨基胍（AG）组：术后0－7d皮下注射AG600mg.kg^-1.d^-1;（4）低剂量CsA加AG组;术后0－7d肌肉注射CsA2mg.kg^-1.d^-1及皮下注射AG600mg.kg^-1.d^-1。术后4d测定急性排斥反应时移植心的诱生型一氧化氮合酶（iNOS)的表达及血清一氧化氮（NO）含量,并观察移植心存活时间。结果与低剂量环孢素A组相比较,低剂量环孢素A与氨基胍联用组不仅显著地抑制移植心iNOS表达与NO产生（P＜0．05）;而且显著地减轻急性排斥反应（P＜0．01）,延长了移植心存活时间（P＜0．05）。结论低剂量环孢素A与氨基胍联用,协同抑制急性排斥反应时移植心iNOS活性及NO产生;显著地延长移植物存活时间。