柴半六合汤对慢性肾衰竭模型大鼠血清胃泌素、胃动素及生长抑素的影响(英文)

目的:观察柴半六合汤对慢性肾衰竭(CRF)模型大鼠血清胃泌素(GAS)、胃动素(MTL)、生长抑素(SS)水平的影响,探讨其作用机制。方法:采用5/6肾切除的方法复制CRF大鼠模型,设立假手术组、模型组、柴半六合汤高剂量组、低剂量组、尿毒清对照组,检测血肌酐(Scr)、尿素氮(BUN)、胃泌素(GAS)、胃动素(MTL)及生长抑素(SS),取胃粘膜行HE染色,光镜下观察其组织病理变化。结果:用药各组大鼠治疗后Scr、BUN低于模型组;柴半六合汤高剂量组大鼠Scr、BUN、GAS、MTL低于低剂量组、SS高于低剂量组;柴半六合汤高、低剂量组大鼠GAS、MTL低于尿毒清对照组、SS高于尿毒清对照组。结论:柴半六合汤通过降低CRF模型大鼠GAS、MTL水平、SS升高水平,改善胃肠道症状。     

广东虫草对腺嘌呤诱导的慢性肾衰竭大鼠的治疗作用

广东虫草Cordyceps guangdongensis是广东省微生物研究所近年发现并成功驯化的独有新品种,前期研究发现其具有抗氧化、抗疲劳、延缓衰老等药理作用,但其对慢性肾衰竭的治疗作用还未见报道。实验采用饲喂腺嘌呤诱导大鼠慢性肾衰竭（CRF）模型,观察比较了阴性对照组、阳性对照组、广东虫草子实体低、中、高剂量组CRF模型大鼠及正常健康大鼠对照组的血尿素氮、肌酐、24h尿量、尿蛋白量,以及肾组织病理变化。结果表明广东虫草子实体组能显著降低CRF大鼠血尿素氮和肌酐,能促进机体生成白蛋白和总蛋白,改善肾功能衰竭大鼠的临床症状及肾脏水肿、变大和病变程度。由此证明广东虫草子实体对大鼠的慢性肾衰竭有明显的治疗作用。     

益气化湿通络方对实验性肾功能衰竭大鼠肾脏氧化应激损伤及纤维化的改善作用

目的:观察益气化湿通络方对5/6肾切除肾衰竭模型大鼠残留肾脏氧化应激损伤及纤维化的改善作用。方法:采用Platt法建立5/6肾切除慢性肾衰竭大鼠模型。术后2周抽检大鼠确认造模成功后,将大鼠随机分为:模型组(Model)、益气化湿通络方组(YHT)、贝那普利组(BH)、假手术组(Sham),每组8只。每日灌胃治疗1次(YHT组免煎颗粒水溶液0.276 g/100 g;BH组盐酸贝那普利片剂水溶液0.09 mg/100 g灌胃;Sham及Model 1 ml/100 g生理盐水灌胃),连续治疗12周。12周末用代谢笼收集24 h尿液,检测尿蛋白含量。之后麻醉大鼠腹主动脉取血、摘取肾脏,检测血清血肌酐(Scr)、血尿素氮(BUN)含量;HE、Masson染色观察左肾病理改变;检测肾组织匀浆超氧化物歧化酶(SOD)的活性和丙二醛(MDA)的含量,检测肾组织中核因子NF-E2相关因子(Nrf2)、Kelch样环氧氯丙烷相关蛋白-1(Keap1)、NADPH氧化酶4(Nox4)、转化生长因子-β1(TGF-β1)、I型胶原蛋白(Collagen1)的表达以及Nrf2在肾组织细胞核内的表达。结果:与Sham组比较,Model组大鼠肾小球损伤较重,纤维化明显;Scr、BUN、MDA水平和24 h尿蛋白的排出量,Keap1、Nox4、TGF-β1、Collagen1的蛋白表达均明显升高(P＜0.01),SOD活性、Nrf2表达明显降低(P＜0.01);与Model组比较,经YHT或BH干预后肾小球病变程度减轻,纤维化较少,Scr、BUN、MDA水平和24 h尿蛋白的排出量,Keap1、Nox4、TGF-β1、Collagen1的蛋白表达均明显减少(P＜0.01),SOD活性、Nrf2表达明显升高(P＜0.01)。结论:益气化湿通络方通过影响Nrf2/Keap1信号通路、下调TGF-β1蛋白表达,从而改善肾衰竭模型大鼠残留肾脏的氧化应激损伤及纤维化程度。     

益肾和络合剂对慢性肾衰竭实验室指标的影响(英文)

目的:观察益肾和络合剂对慢性肾衰竭(CRF)实验室指标的影响。方法:将60例CRF患者随机分为两组,治疗组30例给予益肾和络合剂,对照组30例给予尿毒清颗粒,6个月后观察两组的实验室指标。结果:治疗组在用药后血肌酐(Scr)、尿素氮(BUN)、胆固醇(CH)、低密度脂蛋白(LDL)下降,高密度脂蛋白(HDL)、血清清蛋白(ALB)升高,与治疗前比较差异均有显著性(P0.05),与对照组比较差异均有显著性(P0.05)。结论:益肾和络合剂可以明显改善CRF患者的实验室指标,延缓CRF的进展。     

金樱子对糖尿病大鼠肾MCP-1表达的影响

目的:研究金樱子对糖尿病大鼠单核细胞趋化因子-1(MCP-1)表达的影响.方法:用STZ腹腔注射诱导建立SD大鼠糖尿病模型后,随机分为糖尿病模型组和金樱子干预组,同时另设正常对照组和金樱子对照组.测定大鼠血糖、血肌酐(Scr)、血尿素氮(BUN)、胆固醇(TC)、甘油三酯(TG)、24小时尿蛋白.HE染色观察肾组织病理改变、免疫组织化学、Western blot检测各组肾组织MCP-1表达情况.结果:金樱子能明显改善肾功能,降低实验性糖尿病大鼠血糖、血肌酐、血尿素氮、胆固醇、甘油三酯、24小时尿蛋白定量.形态学观察,糖尿病大鼠在金樱子干预后,肾小球硬化指数与肾小管损伤指数明显减小.免疫组织化学和Western bolt分析显示,MCP-1蛋白表达在糖尿病模型组中显著增强,而在金樱子干预组的表达显著减弱(P＜0.05),但仍较正常对照组蛋白表达升高.结论:金樱子对糖尿病肾病具有防治作用,其机制可能与降低MCP-1表达有关.     

BK通道对大鼠肾脏缺血再灌注损伤的作用及机制

目的:探讨缺血再灌注损伤早期肾脏皮质内大电导钙依赖性钾通道(BK)通道的表达及意义。方法:建立成年SD大鼠肾脏急性缺血再灌注损伤模型,快速收集24小时缺血大鼠与对照大鼠血和损伤侧肾脏皮质标本,使用ELISA方法检测血肌酐和尿素氮含量,实时荧光定量RT-PCR和蛋白免疫印迹方法检测肾脏组织中BK通道α亚基的m RNA表达水平和蛋白表达水平。结果:(1)急性缺血再灌注大鼠损伤侧肾脏皮质BK通道α亚基m RNA水平较对照大鼠同侧肾脏皮质的表达明显降低(P0.01)。(2)急性缺血再灌注大鼠损伤侧肾脏皮质BK通道α亚基蛋白水平较对照大鼠同侧肾脏皮质的表达也明显降低(P0.05)。(3)NS1619预处理缺血再灌注大鼠血尿素氮和血肌酐含量显著降低(P0.05)。结论:BK通道表达和功能的改变是参与大鼠肾脏缺血再灌注损伤的重要机制。     

达格列净对2型糖尿病大鼠肾脏葡萄糖转运蛋白2及葡萄糖转运蛋白4基因表达的影响*

目的:探讨达格列净对2型糖尿病大鼠肾脏葡萄糖转运蛋白2(GLUT2)和葡萄糖转运蛋白4(GLUT4)基因表达的影响。方法:使用高脂饲料和一次性注射40 mg/kg链脲佐菌素(STZ)建立2型糖尿病大鼠模型,造模大鼠以空腹血糖(FBG)含量≥16.7 mmol/L时视为造模成功。造模成功后随机分为模型组(B组,生理盐水)、达格列净低剂量组(C组,0.75 mg/kg)、达格列净中剂量组(D组,1.5 mg/kg)、达格列净高剂量组(E组,3.0 mg/kg),每组6只;另选取6只健康的SD大鼠作为正常对照组(A组,生理盐水)。各组均为灌胃给药,每天1次,连续7周。灌胃给药7周后测定大鼠的体重以及血清FBG、糖化血红蛋白(HbA1c)、血尿素氮(BUN)、血肌酐(Scr)的变化;采用酶联免疫吸附测定血清及肾组织丙二醛(MDA)、超氧化物歧化酶(SOD)和谷胱甘肽过氧化物酶(GSH-Px);采用HE观察肾脏病理学变化;采用Western blot检测肾脏组织中GLUT2、GLUT4蛋白表达;RT-qPCR检测肾脏组织中GLUT2、GLUT4 mRNA相对表达量。结果: 与A组比较,各组大鼠的体重及SOD、GSH-PX水平明显降低(P＜ 0.05),FBG、HbA1c、BUN、Scr、MDA水平明显升高(P＜0.05),肾脏病理损伤严重,肾组织GLUT2、GLUT4 mRNA相对表达量和蛋白表达均明显降低(P均＜0.05)。与B组比较,C组、D组和E组大鼠的体重、SOD、GSH-PX水平和肾组织GLUT2、GLUT4 mRNA相对表达量明显升高(P＜0.05),FBG、HbA1c、BUN、Scr、MDA水平明显降低(P＜ 0.05);D组和E组肾脏病理损伤明显减轻,肾组织GLUT2、GLUT4蛋白表达均明显升高(P均＜0.05)。结论:达格列净可缓解2型糖尿病模型大鼠的病情,并上调肾脏GLUT2及GLUT4基因的表达。     

霉酚酸酯对糖尿病大鼠肾组织单核细胞趋化蛋白-1表达和炎症细胞浸润的影响

目的观察霉酚酸酯(MMF)对糖尿病大鼠肾组织单核细胞趋化蛋白-1表达和炎症细胞浸润的影响,并探讨其对肾脏的保护作用及机制。方法SD大鼠随机分为三组:对照组(C组)、糖尿病组(D组)和糖尿病治疗组(M组,20mg.kg-1.d-1)。大鼠单侧肾脏切除后,腹腔注射链脲菌素(STZ)成糖尿病模型,对照组仅注射等量缓冲液。观察12周后,检测大鼠血糖(BG)、血尿素氮(BUN)、血肌酐(Scr)、肾脏肥大指数(肾重KW/体重BW)、肌酐清除率(Ccr)和24小时尿蛋白(24Upro)。肾组织做常规光镜和电镜检查,观察组织的形态结构。用免疫组织化学方法检测肾组织中巨噬细胞抗原(CD68)和增殖细胞核抗原(PCNA)的蛋白表达。用半定量RT-PCR的方法检测肾组织中单核细胞趋化蛋白-1(MCP-1)的mRNA的表达。结果与对照组相比,糖尿病组大鼠BG、KW/BW、24Upro、BUN、Scr、Ccr均显著上升(P<0.05或0.01);肾小球系膜区相对面积和肾小球基底膜厚度均显著增加(P<0.01);肾组织内CD68和PCNA的蛋白质表达和MCP-1的mRNA表达均显著上调(P<0.05或0.01)。在糖尿病治疗组,上述指标除血糖外都被显著抑制(P<0.05或0.01)。结论在糖尿病大鼠模型中,MMF能减少尿蛋白,对糖尿病肾病有保护作用,其机制可能与其抑制炎症因子-MCP-1的表达,下调CD68和PCNA的水平,减少肾组织单核/巨噬细胞的聚集有关。     

霉酚酸酯对糖尿病大鼠肾组织单核细胞趋化蛋白-表达和炎症细胞浸润的影响

目的观察霉酚酸酯(MMF)对糖尿病大鼠肾组织单核细胞趋化蛋白-1表达和炎症细胞浸润的影响,并探讨其对肾脏的保护作用及机制。方法SD大鼠随机分为三组:对照组(C组)、糖尿病组(D组)和糖尿病治疗组(M组,20mg.kg-1.d-1)。大鼠单侧肾脏切除后,腹腔注射链脲菌素(STZ)成糖尿病模型,对照组仅注射等量缓冲液。观察12周后,检测大鼠血糖(BG)、血尿素氮(BUN)、血肌酐(Scr)、肾脏肥大指数(肾重KW/体重BW)、肌酐清除率(Ccr)和24小时尿蛋白(24Upro)。肾组织做常规光镜和电镜检查,观察组织的形态结构。用免疫组织化学方法检测肾组织中巨噬细胞抗原(CD68)和增殖细胞核抗原(PCNA)的蛋白表达。用半定量RT-PCR的方法检测肾组织中单核细胞趋化蛋白-1(MCP-1)的mRNA的表达。结果与对照组相比,糖尿病组大鼠BG、KW/BW、24Upro、BUN、Scr、Ccr均显著上升(P<0.05或0.01);肾小球系膜区相对面积和肾小球基底膜厚度均显著增加(P<0.01);肾组织内CD68和PCNA的蛋白质表达和MCP-1的mRNA表达均显著上调(P<0.05或0.01)。在糖尿病治疗组,上述指标除血糖外都被显著抑制(P<0.05或0.01)。结论在糖尿病大鼠模型中,MMF能减少尿蛋白,对糖尿病肾病有保护作用,其机制可能与其抑制炎症因子-MCP-1的表达,下调CD68和PCNA的水平,减少肾组织单核/巨噬细胞的聚集有关。     

歼击飞行员血清胱抑素C、血肌酐、尿素氮检测的临床意义

目的:了解歼击飞行员血清胱抑素C(Cys C)、血肌酐(Scr)、尿素氮(BUN)水平及其临床意义。方法:采用乳胶增强比浊法、苦味酸法、酶两点动力法测定歼击飞行员及地勤人员血清Cys C、Scr、BUN浓度。结果:歼击飞行员与地勤人员各项指标比较,差异无统计学意义(P0.05);二代机飞行员与三代机飞行员各项指标比较,血清Cys C及Scr差异无统计学意义(P0.05),三代机飞行员BUN比二代机高,差异有统计学意义(P0.05)。结论:+Gz对高性能战斗机飞行员的肾脏有一过性功能损害,血肌酐尿素氮联合血清胱抑素C检测对评价歼击飞行员的肾功能有积极意义。     

骨化三醇联合补气口服液对慢性肾功能衰竭患者血清瘦素及睾酮水平的影响

目的:探究骨化三醇联合补气口服液对慢性肾功能衰竭患者血清瘦素及睾酮水平的影响。方法:选取我院诊治慢性肾功能衰竭患者116例为研究对象,根据随机数字对照表分为对照组(58例)与试验组(58例)。两组患者均常规给予血管紧张素酶抑制剂或β受体阻滞剂,对照组给予口服骨化三醇胶丸,试验组在对照组的基础上联合给予补气口服液。治疗结束后,比较两组患者肾功能指标、血清瘦素及睾酮水平、营养生化指标。结果:治疗结束后,两组患者血清肌酐(Cr)、血尿素氮(BUN)及瘦素水平均较治疗前显著降低(P0.05),睾酮、血钙水平较治疗前升高(P0.05),血磷水平降低(P0.05)。与对照组相比,试验组血Cr、BUN及瘦素水平较低(P0.05),而血清睾酮、血钙水平较高,血磷水平较低(P0.05)。结论:骨化三醇联合补气口服液能够更有效改善慢性肾功能衰竭患者的肾功能,纠正患者体内电解质紊乱,改善患者食欲不振营养不良症状,推测其与降低血清瘦素水平及升高睾酮水平有关。     

脂代谢异常对肾病的影响

肾脏疾病发展为慢性肾衰竭是个不可逆的过程,脂质代谢的异常,对肾病患者具有重要的影响。多项实验已经证实,即使在肾病的早期阶段,也会出现不同程度的脂质及脂类代谢的异常,高密度脂蛋白(HDL)、低密度脂蛋白(LDL)、脂联素、瘦素等脂类代谢相关物质发生改变,不仅对血浆脂代谢产生影响,对于肾小球及肾小管的结构及功能也会有一定的损伤作用。肾病患者,如肾病综合征、慢性肾衰竭等疾病,多数有肾小球及肾小管间质的损伤,肾脏的脂毒性加重肾单位的破坏。随着人们对于慢性肾脏病认识的逐渐深入,降脂治疗的普遍应用,人们普遍认为改善血浆中脂类的水平,对于肾病的治疗,尤其对于慢性肾衰竭的预防具有重要作用。     

Soluble leptin receptor levels in patients with chronic renal failure

Soluble leptin receptor (SLR) is the extracellular part of the leptin receptor. This protein is released into circulation and constitutes the main circulating leptin-binding protein. The aim of our study was to measure SLR concentrations in patients with chronic renal failure (CRF) and healthy subjects and to explore the relationship of SLR to other hormones and cytokines. The patients with CRF had significantly higher serum leptin, TNF-alpha and insulin levels than healthy subjects (25.1+/-23.5 vs. 9.4+/-7.6 ng.ml(-1) (S.D.); 14.2+/-4.2 vs. 4.55+/-2.5 ng.ml(-1); 39.8+/-36.1 vs. 20.3+/-11.1 mU.l(-1)). Serum soluble leptin receptor levels did not differ between these groups (19.1+/-11.3 vs. 19.6+/-6.1 U.ml(-1)). An inverse relationship between serum SLR and leptin levels was found in both groups. In patients with CRF the inverse relationship between SLR and insulin, body fat content and total protein levels were also found, while in healthy subjects only inverse relationship of SLR with insulin and albumin concentrations were detected. We conclude that soluble leptin receptor levels in patients with chronic renal failure do not differ from those of healthy subjects despite higher serum leptin levels in CRF patients. The physiological consequences of this finding require further investigation.     

Mechanism of increased renal prostaglandin E2 in uranyl nitrate-induced acute renal failure

We have previously demonstrated that decreased cortical prostaglandin metabolism can contribute significantly to an increase in renal tissue levels and activity of prostaglandin E2 in bilateral ureteral obstruction, a model of acute renal failure. In the present study, we have further investigated whether alterations in prostaglandin metabolism can occur in a nephrotoxic model of acute renal failure. Prostaglandin synthesis, prostaglandin E2 metabolism (measured as both prostaglandin E2-9-ketoreductase and prostaglandin E2-15-hydroxydehydrogenase activity), and tissue concentration of prostaglandin E2 were determined in rabbit kidneys following an intravenous administration of uranyl nitrate (5 mg/kg). No changes in the rates of cortical microsomal prostaglandin E2 and prostaglandin F2 alpha synthesis were noted at the end of 1 and 3 days, while medullary synthesis of prostaglandin E2 fell by 47% after 1 day and 43% after 3 days. Cortical cytosolic prostaglandin E2-9-ketoreductase activity was found to be decreased by 36% and 76% after 1 and 3 days respectively. No significant changes were noted in cortical cytosolic prostaglandin E2-15-hydroxydehydrogenase activity after 3 days. Cortical tissue levels of prostaglandin E2 increased by 500% at the end of 3 days. These data demonstrate that in nephrotoxic acute renal failure, decreased prostaglandin metabolism (i.e., prostaglandin E2-9-ketoreductase activity) can result in increased tissue levels of prostaglandin E2 in the absence of increased prostaglandin synthesis and suggest that alterations in prostaglandin metabolism may be an important regulator of prostaglandin activity in acute renal failure.     

Time-dependent effect of leptin on renal Na+,K+-ATPase activity

Leptin, secreted by adipose tissue, is involved in the pathogenesis of arterial hypertension, however, the mechanisms through which leptin increases blood pressure are incompletely elucidated. We investigated the effect of leptin, administered for different time periods, on renal Na(+),K(+)-ATPase activity in the rat. Leptin was infused under anesthesia into the abdominal aorta proximally to the renal arteries for 0.5-3 h. Leptin administered at doses of 1 and 10 microg/min per kg for 30 min decreased the Na(+),K(+)-ATPase activity in the renal medulla. This effect disappeared when the hormone was infused for > or =1 h. Leptin infused for 3 h increased the Na(+),K(+)-ATPase activity in the renal cortex and medulla. The stimulatory effect was abolished by a specific inhibitor of Janus kinases (JAKs), tyrphostin AG490, as well as by an NAD(P)H oxidase inhibitor, apocynin. Leptin increased urinary excretion of hydrogen peroxide (H(2)O(2)) between 2 and 3 h of infusion. The effect of leptin on renal Na(+),K(+)-ATPase and urinary H(2)O(2) was augmented by a superoxide dismutase mimetic, tempol, and was abolished by catalase. In addition, infusion of H(2)O(2) for 30 min increased the Na(+),K(+)-ATPase activity. Inhibitors of extracellular signal regulated kinases (ERKs), PD98059 or U0126, prevented Na(+),K(+)-ATPase stimulation by leptin and H(2)O(2). These data indicate that leptin, by acting directly within the kidney, has a delayed stimulatory effect on Na(+),K(+)-ATPase, mediated by JAKs, H(2)O(2) and ERKs. This mechanism may contribute to the abnormal renal Na(+) handling in diseases associated with chronic hyperleptinemia such as diabetes and obesity.     

A TLR5 agonist inhibits acute renal ischemic failure

Reperfusion of ischemic organs induces a potent inflammatory response initiated by the generation of reactive oxygen species that directly damage tissue and promote leukocyte infiltration and activation that also mediate tissue injury. We recently found that radiation-induced tissue injury, which is caused by radiation-induced reactive oxygen species, is attenuated by administration of CBLB502, a pharmacologically optimized derivative of the TLR5 agonist flagellin. Therefore, we tested the ability of CBLB502 to attenuate injury in a murine model of acute ischemic renal failure. CBLB502 given 30 min before imposition of bilateral renal pedicle occlusion provided marked protection against the renal dysfunction and inflammation that follows reperfusion of ischemic kidneys, including marked decreases in leukocyte infiltration, proinflammatory cytokine production, and tubular injury. Importantly, CBLB502 given within 30 min after ischemic kidney reperfusion reproduced the protective effects of pretreatment with the TLR5 agonist, indicating a window following reperfusion in which CBLB502 administration abrogates acute renal ischemic failure. Bone marrow-reconstituted chimeras were used to show that the protective effects of CBLB502 could be delivered by intact MyD88 signaling on renal parenchymal cells. Consistent with this, Ab staining of kidney sections indicated that cells lining the renal vasculature expressed TLR5. Overall, these results indicate the use of TLR5 agonists as mitigators and protectants of acute renal ischemic failure.     

Effect of leptin on renal ischemia-reperfusion damage in rats

Tumor necrosis factor-alpha (TNF-alpha) has been established as an important mediator in renal ischemia-reperfusion (I/R) injury. Leptin, a product of the ob gene, has been known to exhibit cytoprotective effects on renal tissue, but its effect on renal tissue TNF-alpha level after renal I/R injury in rats remains unknown. The purpose of the study was to evaluate the effects of leptin on renal tissue TNF-alpha, malondialdehyde (MDA), protein carbonyls (PCs) and total sulfydryl group (SH) levels, and plasma nitrite levels after renal I/R injury in rats. The animals were divided into three groups: control, I/R and I/R+leptin. Rats were subjected to renal ischemia by clamping the left pedicle for 45 min, and then reperfused for 1 h. The I/R+leptin group was pretreated intraperitoneally with leptin (10 microg/kg) 30 min before the induction of ischemia. Our results indicate that MDA, TNF-alpha levels, and PCs were significantly higher in the I/R group than those in the control group (p < 0.05). The administration of leptin decreased these parameters (p < 0.05) significantly. The SH level was observed to significantly decrease after I/R injury when compared to the control group (p < 0.05). Leptin treatment significantly increased tissue SH and plasma nitrite levels when compared to the I/R group (p < 0.05). Plasma nitrite levels did not change significantly in I/R when compared to the control. These results suggest that leptin could exert a protective effect on I/R induced renal damage by decreasing TNF-alpha levels and increasing nitrite level.     

Effects of retinoic acid administration and dietary vitamin A supplementation on leptin expression in mice: lack of correlation with changes of adipose tissue mass and food intake

Retinoic acid (RA) administration and chronic vitamin A supplementation were reported to inhibit adipose tissue leptin expression in rodents, but the impact of this effect on food intake and its relationship with changes of body adiposity was not analyzed. Here, we have studied the effects of RA administration at three different doses on body weight, adipose tissue mass, food intake, adipose tissue leptin expression and circulating leptin levels in NMRI mice; the effects of chronic vitamin A supplementation with a 40-fold excess retinyl palmitate on the same parameters in NMRI and C57BL/6J mice; and the effects of RA and retinoid receptors agonists on leptin expression in brown and white adipocyte cell model systems. The results show that vitamin A down-regulates leptin expression in white and brown adipose tissue and circulating leptin levels independently of changes of adipose tissue mass and, for the first time to our knowledge, that this effect does not correlate with increased food intake. They also demonstrate a direct inhibitory effect of RA on leptin expression in both white and brown adipocyte cell cultures, and constitute first proof of the involvement of both RA receptors (RARs) and rexinoid receptors (RXRs) in this effect. Reduction of leptin levels by specific nutrients is of potential interest from a clinical point of view.     

The role of oxygen free radicals in the development of chronic renal failure.

This study examined whether there is increased production of oxygen free radicals during chronic renal failure. Rats subjected to 3/4 nephrectomy and sham operated controls were killed after 3 weeks. Lipid extracts of plasma and renal tissue were examined by HPLC and kidney specimens were also analyzed by EPR spectroscopy. The redox capacity of blood was assessed using nitroblue tetrazolium and plasma ascorbate levels were measured with HPLC. There was no detectable renal production of oxygen free radicals in rats with chronic renal failure. Kidney parenchymal content of other oxidants and the oxidant:reductant ratio were similar in control and uremic animals. The plasma redox capacity and ascorbate levels were elevated in uremic rats. We conclude that early in the course of chronic renal failure, there is not excessive production of oxygen free radicals. There is accumulation of reductants, primarily ascorbate, in the plasma of uremic animals.     

Bioengineered 3D Human Kidney Tissue,a Platform for the Determination of Nephrotoxicity

The staggering cost of bringing a drug to market coupled with the extremely high failure rate of prospective compounds in early phase clinical trials due to unexpected human toxicity makes it imperative that more relevant human models be developed to better predict drug toxicity. Drug–induced nephrotoxicity remains especially difficult to predict in both pre-clinical and clinical settings and is often undetected until patient hospitalization. Current pre-clinical methods of determining renal toxicity include 2D cell cultures and animal models, both of which are incapable of fully recapitulating the in vivo human response to drugs, contributing to the high failure rate upon clinical trials. We have bioengineered a 3D kidney tissue model using immortalized human renal cortical epithelial cells with kidney functions similar to that found in vivo. These 3D tissues were compared to 2D cells in terms of both acute (3 days) and chronic (2 weeks) toxicity induced by Cisplatin, Gentamicin, and Doxorubicin using both traditional LDH secretion and the pre-clinical biomarkers Kim-1 and NGAL as assessments of toxicity. The 3D tissues were more sensitive to drug-induced toxicity and, unlike the 2D cells, were capable of being used to monitor chronic toxicity due to repeat dosing. The inclusion of this tissue model in drug testing prior to the initiation of phase I clinical trials would allow for better prediction of the nephrotoxic effects of new drugs.