脯氨酸羟化酶(PHD)在大鼠肾脏中的表达及PHD抑制剂对5/6肾切除大鼠的作用  

Expression of prolyl hydroxylase domain enzyme(PHD)in rat kidney and the effect of PHD inhibitor on rats with 5/6 remnant kidney

作　　者：俞小芳[1] 蔡洁茹[1] 崔萌[1] 刘少鹏[1] 方艺[1] 邹建洲[1] 丁小强[1] 

机构地区：[1]复旦大学附属中山医院肾内科,上海200032

出　　处：《复旦学报（医学版）》2014年第2期191-197,共7页Fudan University Journal of Medical Sciences

基　　金：上海市科委基础研究重大项目(12DJ1400200);国家自然科学基金(81000307;81100524)~~

摘　　要：目的观察脯氨酸羟化酶(prolyl hydroxylase domain enzyme,PHD)在肾脏内的生理性表达及在慢性肾脏病(chronic kidney disease,CKD)进程中的动态表达变化,探讨不同时机PHD抑制剂治疗对CKD的作用。方法雄性SD大鼠行5/6肾切除后(以下简称RK大鼠),分别于术前及术后第1、2、4、6、8和12周处死大鼠。不同时机给予RK大鼠PHD抑制剂L-mimosine(L-Mim)治疗:早期治疗组,治疗时间为术后第2周至第12周;进展期治疗组,治疗时间为术后第4周至第12周;晚期治疗组,治疗时间为术后第8周至第12周。结果生理情况下PHD2和PHD3在肾脏内均有一定程度的表达。PHD2和PHD3在肾切除术后表达逐渐增加,至术后第6周PHD2达到峰值,此后表达明显减少,至12周时降为基线水平;至第4周PHD3达到峰值,此后维持较高水平。与对照组相比,早期治疗组的肾功能障碍加重;进展期治疗组的肾功能障碍有所改善;晚期治疗组与对照组相比差异无统计学意义(P>0.05)。与对照组相比,早期治疗组低氧诱导因子1α(hypoxia-inducible factor-1α,HIF-1α)蛋白表达升高(P<0.05),而进展期和晚期治疗组与对照组HIF-1α蛋白表达的差异无统计学意义(P>0.05)。相反,早期治疗组HIF-2α蛋白表达高于对照组(P<0.05),进展期治疗组HIF-2α蛋白表达则明显高于对照组(P<0.01),而晚期治疗组HIF-2α蛋白表达与对照组相比差异无统计学意义(P>0.05)。结论 PHD2和PHD3在RK进展过程中呈差异性表达;在RK病程进展的不同阶段给予PHD抑制剂L-Mim治疗可以对大鼠肾功能产生有利或有害作用,这可能与PHD抑制剂选择性地活化HIF-α亚型有关。Objective To characterize prolyl hydroxylase domain enzyme （PHD） expression in physiologic state and during the development of chronic kidney disease （CKD）,and to investigate the effect of PHD inhibitor on CKD.Methods Rats with remnant kidney （RK rats） were sacrificed at week 0,1,2,4,6,8,12 after subtotal nephrectomy.An additional group of RK rats were randomized and each received special administration of PHD inhibitor L-mimosine （L-Mim） as follows：early long-term L-Mim treatment group were administered at weeks 2-12; advanced medium-term L-Mim treatment group were administered at weeks 4-12,and end-stage L-Mim treatment group were administered at weeks 8-12.Results Moderate amount of PHD2 and PHD3 were physiologically expressed in distal tubules of the cortex and tubules of the medulla.PHD2 and PHD3 expressions were gradually increased during the early stage after nephrectomy.PHD2 level peaked at week 6,and then gradually decreased until the baseline at week 12.PHD3 level peaked at week 4,and then maintained at a high level.Compared with control group,renal dysfunction was exacerbated by early long-term L-Mim treatment,and improved by advanced medium-term L-Mim treament.End-stage L-Mim treatment had no effect on RK rats.Compared with control group,early long-time L-Mim treatment up-regulated hypoxia-inducible factor-1α （HIF-1α） level （P〈0.05）,while advanced medium-term and end-stage L-Mim treatment had no effect on HIF-1α expression.Campared with control group,early long-term L-Mim treatment up-regulated HIF-2α level （P〈0.05）,and advanced medium-term L-Mim treatment also upregulated HIF2α level significantly （P〈0.01）,while end-stage L-Mim treatment had no effect on HIF-2α expression.Conclusions The expression of PHD2 and PHD3 were different during the progression of RK.PHD inhibitor L-Mim has dual roles in the development of CKD depending on the timing of the administration and possibly the activated isoform of HIF-α.

关 键 词：脯氨酸羟化酶(PHD) 低氧诱导因子α(HIF-α) 肾切除 SD大鼠 

分 类 号：R692[医药卫生—泌尿科学]