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前言
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急性肾损伤（Acute Kidney Injury, AKI）是指一类在多种因素作用下导致肾功能突然急剧下降的临床综合征，表现为短期内进行性氮质血症、电解质紊乱和酸碱失衡以及波及各脏器的症状。AKI在临床上作为一种肾脏方面多发常见的急、危、重症，院内病死率高，医疗资源消耗大。根据中华人民共和国国家卫生和计划生育委员会( 现中华人民共和国国家卫生健康委员会) 的报告，参照改善全球肾脏病预后组织(Kidney Disease Improving Global Outcomes，KDIGO) 最新诊断标准，2013年全国有将近290万成年住院患者罹患AKI，高达70万患者死亡；AKI患者总体住院医疗费用达1 300万美元，占中国全年医疗总费用的10％。与没有AKI的患者相比，AKI患者的医疗保健支出增加了66％以上，为个人、家庭及社会均带来了沉重的经济负担 [1, 2]。
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既往的观点认为，AKI是可逆的急性病变，对患者长期预后并无影响，但近年来结合临床案例发现，即使是较快恢复的轻度AKI，患者随后发生慢性肾脏疾病(Chronic Kidney Disease, CKD)、肾纤维化、终末期肾病(End-stage Kidney Disease，ESRD) 的可能性仍大幅增高，死亡率也随之增大 [3-5]。研究发现，肾功能恢复的同时，肾脏通常会经历适应性不良的修复过程，发生肾脏纤维化，形成瘢痕，向CKD甚至ESRD进展 [6]。一项全球多个发达国家（美国、加拿大、西欧和澳大利亚）联合研究发现，每年约有15%~20%AKI患者进展为CKD，而在我国，AKI患者在出院时肾功能仍未完全恢复的高达67.5%，一半的患者进展为CKD[7, 8]。因此， AKI是CKD乃至ESRD的重要危险因素 [9]。基于这个认识，AKI在CKD发展中发挥的重要作用机制逐渐被研究。炎症损伤、细胞周期停滞、肾素血管紧张素(Renin-angiotensin，RAS) 系统激活、肾脏缺氧调控、细胞衰老和修复、细胞死亡调控以及表观遗传学修饰等均可能参与AKI向CKD进展的过程 [6]。研究AKI如何导致肾脏纤维化的机制，有助于预防及延缓AKI向CKD进展，也为制定医疗决策、研发新药提供了理论基础。
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继Yang等2010年首次揭示了肾小管上皮细胞G2/M期停滞是肾脏急性损伤后转为慢性纤维化的重要机制后，很多学者相继挖掘出细胞周期停滞在AKI适应性不良修复中的机制 [10-12]。本文将重点阐释细胞周期停滞在AKI向CKD转变过程中发挥的重要作用。
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1 细胞周期与细胞周期停滞
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细胞周期是指细胞从首次分裂产生新细胞到第二次分裂结束的全过程。细胞周期包括间期与分裂期。细胞间期分为三期：DNA合成前期（G1期）、DNA合成期（S期）和DNA合成后期（G2期）。G1期由G1早期（G0期）和G1晚期构成，主要合成细胞所需RNA和核糖体，为S期脱氧核糖核酸(Deoxyribo Nucleic Acid，DNA) 复制做好物质准备。在G0期，细胞上一周期分裂停止，处于静息状态。在G1晚期，细胞准备好合成DNA所需的前体物质、能量和酶类等待下一次分裂。细胞周期的完成时间主要由G1期长短决定，不同细胞G1期完成时间差异较大。G1期向S期过渡由细胞周期蛋白D(Cyclin D) 与细胞周期依赖性激酶4(Cyclin-dependent Kinase4, CDK4) 和CDK6形成的复合物共同调控，该复合物磷酸化进入S期所必须的成视网膜母细胞瘤相关基因(Retinoblastoma Gene，Rb gene)，磷酸化后失活的pRb释放结合在其上的转录因子E2F，上调细胞周期蛋白E(Cyclin E) 表达，令细胞度过R点，不可逆地进入S期。 S期是DNA复制，染色质分裂，复制中心粒，合成组蛋白的关键时期。 G2期为分裂期做最后准备，完成中心粒复制，并合成核糖核酸(Ribonucleic Acid，RNA) 和微管蛋白等。分裂期又称M期，历经前、中、后、末期的连续变化过程，从一个母细胞分裂变成两个子细胞。
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细胞周期停滞是在损伤作用下中断细胞周期，令细胞无法从当前阶段进入下一个阶段。细胞周期停滞可在DNA受损或生物能量资源不足的情况下，阻止细胞进入分裂期并发生灾难性的后果 [13]。细胞周期检查点相关的一套检查机制可以保证细胞周期中遗传物质的质量。当细胞周期进程中出现DNA损伤或DNA复制受阻等异常事件时，激活这套检查机制，诱发细胞周期停滞 [14]。待细胞修复或排除故障后，恢复细胞周期正常运转。目前发现的细胞周期检查点主要有G1/S期检查点， G2/M期检查点和有丝分裂期的M期检查点。G1/S期检查点决定细胞是否进行分裂，发生凋亡或进入G0期。G2/M期检查点阻止受损细胞进入有丝分裂，可防止细胞携带着受损的DNA和未复制的DNA进入有丝分裂。M期检查点又称纺锤体检查点，阻止受损细胞的分裂，监测姐妹染色单体是否已稳定地附着在纺锤体上，若未通过检查，细胞被阻止继续进行分裂。但研究发现，在细胞损伤发生后，未损伤的功能正常的细胞可在短时间细胞周期阻滞状态下代偿性增殖分裂或去分化替代坏死凋亡的细胞，完成损伤的正常修复 [15, 16]；但损伤严重或细胞较长时间甚至持续处于阻滞状态反而会使细胞发生适应性不良修复，趋向慢性纤维化，故细胞周期阻滞时长决定损伤后进入上皮细胞修复路径还是间质纤维化路径 [10]。
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2 细胞周期停滞与AKI、CKD的关系
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2.1 细胞周期停滞与AKI
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AKI病因众多，病理生理过程复杂，目前广泛认为肾小管上皮细胞及肾小球血管内皮细胞损伤、微循环功能障碍、炎症细胞浸润以及血栓形成等是AKI的主要致病机制 [10]，其中肾小管上皮细胞损伤被认为是主要的触发机制 [17]。肾小管上皮细胞生理性新陈代谢速率较低，相对较长时间地停留于细胞G1期，保证管状上皮细胞在遇到伤害或刺激时完成增殖去分化 [10, 18]。在经历内外界炎症、缺血、氧化应激、药物、毒物等多种不良因素刺激时，肾小管上皮Cyclin结合并激活CDK形成Cyclin-CDK复合物，通过蛋白激酶通路在CDK抑制因子共同调控下，控制细胞进程并且触发细胞周期检查点，使细胞处于停滞状态 [19]，加快新陈代谢去分化，介导非纤维性损伤修复以期恢复肾功能 [18, 20]。当细胞损伤难以修复时，ATM(Ataxia Telangiectasia Mutated) 基因编码产物ATM蛋白激酶/ATR(ATM-and RAD3-related) 及其介导的ATM-p53-p21、ATM-Chk1/Chk2( 细胞周期检查点激酶-1， Checkpoint Kinase1，Chk1/细胞周期检查点激酶-2， Checkpoint Kinase2，Chk2)、 PI3K/Akt(磷脂酰肌醇3激酶/蛋白激酶B，Phosphatidylinositol3-Kinases/Protein Kinase B，PI3K/Akt) 等信号通路被激活 [21]，CDK表达下调，使细胞长时间或持续处于细胞周期停滞状态 [22]，产生和释放各种细胞因子和炎症因子，发生适应性不良修复 [23-25]。目前多种动物模型均提示，ATM/ATR信号通路诱导下游G2/M期细胞停滞是AKI后适应性不良修复的一个重要特征，故G2/M期检查点是AKI后的细胞周期调控中重要的一环 [10]。
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2.2 细胞周期停滞与CKD
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肾间质纤维化是CKD发生的主要病变，是判断CKD发生的主要病理表型 [26]，细胞G2/M期持续停滞，导致非适应性修复及肾纤维化的发生 [27]。 Cyclin-B在细胞G2-M期调控进程不可或缺，细胞外调节蛋白激酶(Extracellular Regulated Protein Kinases, ERK) 信号激活使细胞处于G2/M期停滞状态，Cyclin-B/Cyclin-D比率增加，细胞停滞在G1期或G2期延长 [28, 31]，使得上皮细胞肥大和间质纤维化表现增多 [32]。细胞外各种刺激作用于细胞时或近端小管上皮细胞发生G2/M期细胞停滞时，激活小G蛋白Ras介导应激活化蛋白激酶( 亮氨酸拉链家族成员转录调节因子c-Jun氨基末端激酶，c-Jun N-terminal Kinase，JNK) 信号通路，促进细胞基质变化、生长因子分泌及炎症反应等多种过程，介导细胞依赖JNK/c-Jun凋亡途径的凋亡反应[29, 31, 34]，加速近端小管上皮细胞G2/M期阻滞[33]，增加结缔组织生长因子(Connective Tissue Growth Factor, CTGF)[34] 和转化生长因子-β(Transforming Growth Factor-β, TGF-β) 的生成和释放 [35]，加快肾间质纤维化进展 [10, 29, 36]。Zhao等构建了很多细胞发生单一的G2/M期阻滞改变的模型，证明管状上皮细胞G2/M期停滞在决定纤维化反应中起主要作用 [37]。在增加G2/M期运动的模型中，肾纤维化则明显减少 [36]。另外，抑制ATM的激活、抑制ATM-p53-p21途径减弱G2/M期的阻滞作用，很大程度上减少了肾脏间质纤维化病理表型 [29]。上述体外和体内研究结果均表明，管状上皮细胞G2/M期阻滞与纤维化之间存在明显的相关性，且加快向CKD进展。
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2.3 细胞周期停滞是AKI-CKD进展的重要驱动因素
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AKI向纤维化进展与肾小管上皮细胞周期停滞之间存在很多值得研究的联系。多种小鼠AKICKD肾脏损伤的模型提示，确定细胞G2/M期停滞是很多疾病导致进行性纤维化肾病进展的共同特征 [38]。Con-等构建了重复近端肾小管受损的体内肾小管损伤模型，发现小管上皮细胞反复发生G2/M期停滞，CTGF过度扩增并参与AKI后适应不良修复和慢性纤维化转变。与处于G0/G1期的细胞相比，特异性抑制剂诱导的停滞于G2/M期的小管上皮细胞促纤维化基因表达明显上调。 Yoshihara等实验证明增加G0/G1期细胞运动使上皮细胞发生相对性G2/M期阻滞会阻断TGF-β 信号传导，然后减少小鼠纤维化的发生 [39]。这些都证明细胞周期停滞参与并促进AKI-CKD进展，尤其是G2/M期细胞停滞扮演着AKI-CKD转变的其中一个重要阀门的角色。
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3 细胞周期阻滞导致AKI-CKD进展的可能机制
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AKI发生后，大量调控细胞周期停滞的生物分子被释放并诱导调控损伤部位邻近的细胞发生细胞周期停滞，继而引起持续性炎症状态、周细胞/间质肌成纤维细胞的转化发生上皮间充质转分化(Epithelial-mesenchymal Transition, EMT)、细胞器应激/串扰尤其是线粒体损伤、各种细胞因子及炎症因子的异常增多和分泌、衰老激活、肾小管周围毛细血管(Peritubular Capillary, PTC) 稀疏等共同协调作用发生适应性不良修复，通过阻碍肾脏的形态和功能恢复进一步介导AKI向CKD的进展，发生间质纤维化、肾小管萎缩和PTC稀疏，最终进展至ESRD（见图1）。
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图1 细胞周期停滞在AKI-CKD转变中的作用机制
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3.1 细胞周期阻滞诱导炎症持续存在
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AKI后，细胞处于G2/M期停滞，激活TGF-β，诱导炎症反应及体内免疫细胞聚集浸润于损伤部位，后者分泌释放各种细胞因子介导炎症损伤，使小管反复受损，甚至发生肾小管坏死，启动坏死性路径，诱导一些细胞坏死通路重要信号蛋白丝氨酸/苏氨酸激酶3(Receptor Interacting Serine/Threonine Kinase3，RIPK3) 和混合谱系蛋白激酶样假激酶(Mixed Lineage Kinase Domain Like Pseudokinase，MLKL) 的释放，激活炎性小体NLRP3(NLR Family Pyrin Domain Containing3， NLRP3) 和肾脏中白介素IL-1β 的释放，促进炎症因子的分泌，以正反馈方式导致坏死和炎症发生甚至持续存在，通过炎症修复路径，发生纤维化 [6, 17, 40, 41]。而持续存在的炎症状态诱导活性氧释放，加速衰老进程，前者通过诱导核因子κB信号传导、表达炎性因子、激活p53检查点和激活衰老反过来抑制CKD1-pRb-E2F1通路，使细胞处于阻滞状态；后者使得小管上皮细胞对炎症反应更加易感，互相促进，向纤维化进展 [27, 42, 43]。据Huang等研究，RIPK3和MLKL缺失后在一定程度上抑制了炎症小体的激活，尽管结果未能完全阻止AKI进展为CKD，但显著减轻了细胞周期停滞后持续地炎症状态对AKI-CKD进展的不良影响 [44, 45]。这进一步验证了细胞周期停滞后持续性炎症状态对AKICKD进展的促进作用。
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3.2 细胞周期阻滞促使上皮间充质转分化
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AKI可激活独立于p53的p21路径中的抑癌基因Waf1/Cip1，引起细胞G1期阻滞，一方面，诱导生长因子例如表皮生长因子和TGF-β 的释放增多，介导PI3K/Akt/mTOR（ 雷帕霉素靶蛋白， mammalian Target of Rapamycin, mTOR）和Ras/ERK的丝裂原活化蛋白激酶(Mitogen-activated Protein Kinases，MAPK) 信号通路，前者诱导Akt/PKB( 蛋白激酶B，Protein Kinase B，PKB) 磷酸化，抑制凋亡调节因子BCL2相关促细胞凋亡因子(BCL2Associated Agonist of Cell Death，BAD) 和含半胱氨酸的天冬氨酸蛋白水解酶(Cysteinyl Aspartate Specifi c Proteinase，Caspase9) 的活性，诱导内皮细胞增生移行，发生EMT[46, 47]；后者p38丝裂原活化蛋白激酶(p38-MAPK) 活化促丝裂原活化蛋白激酶蛋白酶(MAPK Activated Protein Kinase2/3，MAPKAPK2/3)，磷酸化热休克蛋白27，诱导肌动蛋白骨架重构，上皮细胞粘附能力减低，管状基底膜的破坏，增强细胞迁移和间质的侵袭 [48, 49]，发生EMT，使血管周细胞、间质肌成纤维细胞及上皮细胞不同程度的转分化为肌成纤维细胞 [50, 51]。另一方面，激活上皮状态下沉默或部分沉默的核糖体DNA操纵子的转录，显著增加转录因子Snail1与核糖体DNA操纵子的结合，这一结合有利于EMT相关的核糖体生物完成向间充质细胞状态转化所需的基因表达程序，将上皮细胞去分化为干细胞样间质表型，以促进发育和疾病中的细胞迁移 [52-54]。综上所述，AKI后细胞周期阻滞通过生长因子介导的信号转导和EMT相关转录因子介导的核糖体生成，诱导启动EMT，促进肌成纤维细胞和细胞外基质蛋白生成，导致间质纤维化 [20, 53, 55]。由此可见，细胞周期阻滞促使EMT的发生在AKICKD进展中扮演着极其重要的作用。
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3.3 细胞周期阻滞引起细胞器应激/串扰
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AKI后部分小管上皮细胞坏死凋亡进入停滞阶段，小管上皮细胞中密集存在的线粒体减少并出现功能障碍，无法将高能三磷酸腺苷转化为能量，导致细胞及细胞器功能无法正常维持，进一步激活其下游未折叠蛋白反应(Unfolded Protein Response, UPR) 信号通路，促进刺激因子分泌，诱发线粒体自噬 [56]，细胞缺氧，内质网功能障碍，细胞器出现应激、功能紊乱、串扰 [57-59] 等反应，后者特异性地触发肾小管炎症途径，通过炎症途经修复，导致纤维化 [60]；同时发出转录活化因子ATF4-p16(Activating Transcription Factor 4-P16) 信号诱导UPR信号通路促进内质网应激进一步发生 [61]。而细胞器应激又可调节小管上皮细胞进入衰老凋亡，促进细胞永久停滞，减慢对促纤维化因子和促炎症因子的抑制作用，导致肾间质纤维化 [62]。总体来说，细胞周期阻滞导致细胞器应激/串扰引起细胞功能障碍，与缺氧、炎症、衰老等共同调控发生小管间质纤维化表型，加速AKI-CKD进展。
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3.4 细胞周期阻滞上调各种细胞因子的分泌
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AKI导致管状上皮细胞G2/M期停滞后，一方面，激活DNA修复路径，促使生成和分泌纤维化因子，刺激成纤维细胞增殖和胶原生成，导致纤维化和肾小球硬化 [27]。另一方面，激活JNK，分泌CTGF和TGF-β1的分泌，通过TGF-β1依赖性和非依赖性途径，增加体外促纤维化基因的表达和增多体内胶原细胞外基质的合成，刺激成纤维细胞增殖并抑制胶原酶活性，向间质纤维化进展 [63]。抑制JNK活性使得细胞因子的释放减少可保护肾脏免受纤维化的发展 [64]。可见细胞周期阻滞上调各种细胞因子的分泌与AKI-CKD进展有相关性，促进AKI后纤维化，向CKD进展。
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3.5 细胞周期停滞诱发衰老激活
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AKI使细胞处于停滞状态，以p12为主的细胞周期蛋白激酶抑制剂表达增加、Klotho表达下调和端粒缩短，增加细胞衰老速度 [65]，激活衰老相关分泌表型(Senescence-associated Secretory Phenotype， SASP)，介导环鸟苷酸-腺苷酸合成酶/干扰素刺激基因(cyclic GMP-AMP Synthase/Stimulator of Interferon Genes, cGAS-STIN) 通路，加速疾病表型，促进衰老细胞IL-8、CTGF和TGF-β 等许多生长因子、细胞因子和趋化因子的分泌，增加对损伤、炎症、纤维化和血管稀疏等的易感性，加速衰老细胞的衰老凋亡、炎症反应及加快纤维化，进展为CKD[43, 66, 67]。证实了细胞周期停滞诱发的衰老激活在加速AKI-CKD进展中有重要作用。
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3.6 细胞周期阻滞加重肾周微血管稀疏
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肾周毛细血管(Peritubular Capillary，PTC) 是由从中皮层和外皮层的肾小球发出的传出小动脉沿近端小管和远端小管( 皮质肾单位) 延伸构成的，流入内髓，且其正常PTC数量与肾小球滤过率(Glomerular Filtration Rate，GFR) 呈正相关 [68]。当机体受到各种体内外刺激引起促血管生成因子和抗血管生成因子之间失衡导致血管结构和功能发生障碍时，PTC稀疏，减少灌注，内皮糖萼不稳定并导致血管损伤加重进一步促进PTC的减少，出现炎症、缺氧及肾排泄障碍，进展为CKD[69, 70]。 Menshikh等构建了顺铂诱导损伤、横纹肌溶解和再灌注损伤三种不同的AKI-CKD动物模型，通过比较三者的病变程度与GFR的相关度，发现PTC稀疏比纤维化更能体现出CKD的进展 [71]。PTC稀疏不仅是CKD的组织学特征，亦可作为CKD进展的一个促进因素，并提示CKD的严重程度 [72]。
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AKI发生导致细胞周期停滞时，一方面，刺激p53再表达，抑制血管内皮生长因子(Vascular Endothlial Growth Factor, VEGF)及血管内皮生长因子受体2(Vascular Endothlial Growth Factor Receptor， VEGF-R2) 介导的信号级联通路磷酸化，磷脂酶Cγ（PLCγ）无活性，细胞内Ca2+ 释放减少，血管通透性降低，无法刺激血管新生，导致PTC稀疏 [73, 74]。同时Akt磷酸化受抑制，增加真核起始因子4E(eukaryotic Translation Initiation Factor 4E， eIF4E) 与真核翻译起始因子4E结合蛋白1(Eukaryotic Initiation Factor 4E-binding Protein1， 4E-BP1) 的相互作用，使得基因c-Myc、VEGF、 VEGFR等相关生长因子的表达减少，促血管生成因子和抗血管生成因子失衡，发生PTC稀疏。另一方面，细胞周期阻滞调节硫氧还蛋白(Thioredoxin-interacting Protein, TNXIP) 的水平进一步通过糖基化VEGFR2的赖氨酸(Lysine, Lys) 1 270部位诱导VEGFR2在高尔基体积聚，阻断VEGFR2磷酸化和其向细胞表面的信号转导 [75]。 Xiao等人体外敲除TNXIP后VEGF明显减少，血管形成和增殖明显被抑制 [75]。对再灌注损伤行肾切除术阻滞PTC稀疏，在很大程度上减少了肾脏间质纤维化的表型 [76]。综上所述，细胞周期阻滞加重PTC稀疏并加重损伤内皮加快CKD进展。
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4 细胞周期停滞关于AKI-CKD进展的前景
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AKI诱导肾小管上皮细胞发生细胞周期停滞后，其作为一种重要的导致AKI-CKD进展的因素，引起不可逆的肾脏损伤，降低了肾脏的生存时间。理论上，靶向抑制细胞周期阻滞可抑制炎症、EMT、细胞器应激、细胞因子增多、衰老激活、 PTC稀疏等多方面损伤因素。目前已经有学者构建了p53缺乏或者p53-p21途径受阻的细胞周期停滞阻滞体外模型，间质纤维化明显减少 [77]；通过体外抑制复制检查点激酶的激活，阻断ATR对细胞周期阻滞的诱导调节，对减慢AKI向CKD进展有所帮助，但其阻断阈值目前难以界定 [78]；更有通过使用特发性肺纤维化抑制剂尼替达尼来减少PTC稀疏，可明显缓解动物模型纤维化，但其临床中的具体疗效仍需后期多次验证 [79]。这些都证明了抑制细胞周期阻滞在控制CKD进展中具备一定的有效性，这作为潜在的治疗靶点，将成为未来预防和减少人类AKI-CKD转变中有价值的治疗策略之一。
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摘要
急性肾损伤（Acute Kidney Injury, AKI）向慢性肾脏病（Chronic Kidney Disease, CKD）的进展过程严重影响肾脏预后及患者生存质量，是目前研究热点之一，其中细胞周期停滞是 AKI 向 CKD 进展中一个重要的致病机制。其可能通过持续增加细胞因子及炎症因子生成和释放、上皮间充质转分化、细胞器应激 / 串扰、衰老激活、管周微血管稀疏等一系列适应性不良修复过程，加速 AKI 向 CKD 转变。故调控细胞周期有望成为预防、减缓甚至阻断 AKI-CKD 进展的新的靶点机制。
Abstract
As the major threat of poor renal outcome and survival quality, the mechanism of acute kidney injury (AKI) progressing to chronic kidney disease (CKD) has aroused much attention. The cell cycle arrest, one of the major culprits, accelerates the AKI-to-CKD transition through maladaptive repair that involved overwhelming cytokines excretion and inflammation storm, epithelial-mesenchymal transition, organelles stress/crosstalk, aging activation as well as peritubular capillary rarefaction. Therefore, the cell cycle regulation can serve as a novel potential therapeutic target for the prevention, alleviation and even interruption of AKI -to- CKD transition.