Mitochondrial injury and repair in sepsis-induced acute kidney injury

描述(由申请人提供)： 脓毒症是一种严重的医学状况，其特征是由微生物感染引起的严重全身炎症反应。在美国，败血症每年导致约21.5万人死亡，医疗保健负担约170亿美元。多达50%的脓毒症患者发生急性肾损伤(AKI)，这使死亡率从25%增加到75%。目前，没有有效的治疗方法来治疗脓毒症，临床医生只能依靠通常在出现症状后开始的支持性护理。我们的实验室最近报道，在脓毒症诱导后4h，小鼠出现肾脏微循环衰竭和肾脏线粒体超氧化物歧化酶(O2-)生成，这些事件发生在肾功能下降之前。重要的是，清除氧化剂的药物可以恢复微循环，防止肾脏损伤。目前已有资料表明，脓毒症后4h，肾脏线粒体的主要氧清除剂--锰超氧化物歧化酶(MnSOD)活性下降~50%，线粒体复合体II/III活性在6h下降~30%。此外，脓毒症引起的线粒体损伤刺激线粒体吞噬(安全移除线粒体)；然而，线粒体生物发生(有丝分裂)受到损害。根据这些数据，我们推测在脓毒症期间线粒体超氧化物歧化酶的增加是MnSOD活性丧失和复合体II/III活性降低的结果。由此产生的线粒体损伤会触发有丝分裂，但过量的超氧化物会抑制线粒体的功能生物发生。因此，减少线粒体超氧化物歧化的药物将允许有丝分裂功能的发生，并改善脓毒症诱导的AKI。使用体内CLP模型和体外原代细胞模型的三个特定目标将检验这一假设。目的1建立脓毒症小鼠呼吸链功能障碍(损伤期)到有丝分裂和有丝分裂(恢复期)的时间关系。目的2探讨脓毒症时肾上皮细胞MnSOD失活的分子机制。最后，AIM 3的研究将评估线粒体靶向抗氧化剂的治疗潜力，以减少肾线粒体功能障碍并促进脓毒症期间的修复，使用临床相关的剂量范例。这项提议不仅从公共卫生角度，而且从药理学角度来看，都具有重大意义和创新性。这将为靶向修复提供科学依据，这是败血症研究中一个被忽视的领域，在肾脏中至关重要，因为即使是轻微的AKI也被认为是慢性AKI的重要危险因素。

DESCRIPTION (provided by applicant): Sepsis is a serious medical condition characterized by a severe systemic inflammatory response caused by a microbial infection. In the US, sepsis causes ~ 215,000 deaths annually and a healthcare burden of ~ $17 billion. As many as 50% of septic patients develop acute kidney injury (AKI) and this increases mortality from 25% to 75%. Currently, there are no effective therapies to treat sepsis and clinicians must rely only on supportive care usually initiated after the presence of symptoms. Our laboratories recently reported that renal microcirculatory failure and renal mitochondrial superoxide (O2-) generation occur in the mouse by 4h after induction of sepsis, and these events precede the decline in renal function. Importantly, agents that scavenge oxidants allowed the microcirculation to recover and prevented renal injury. Now we have data showing that activities in the kidney of the major mitochondrial O2- scavenger, manganese superoxide dismutase (MnSOD) is decreased ~50% by 4h post sepsis and mitochondrial complex II/III is decreased ~30% at 6h. Also, sepsis induced mitochondrial damage stimulates mitophagy (safe removal of mitochondria); however, mitochondrial biogenesis (mitogenesis) is impaired. Based on these data, we hypothesize that during sepsis increased mitochondrial superoxide is a result of both the loss of MnSOD activity and reduced Complex II/III activity. The resulting mitochondrial damage triggers mitophagy but excessive superoxide dampens functional mitochondrial biogenesis. Consequently, agents, which reduce mitochondrial superoxide will allow for functional mitogenesis and improve sepsis-induced AKI. Three Specific Aims using both the in vivo CLP model as well as a primary cell in vitro model will test this hypothesis. Aim 1 will establish the temporal relationships between MnSOD inactivation and respiratory chain dysfunction (damage phase) to mitophagy and mitogenesis (attempted recovery phase) during sepsis in mice. Aim 2 will investigate the molecular mechanisms that inactivate renal epithelial MnSOD during sepsis. Finally, studies in Aim 3 will evaluate the therapeutic potential of mitochondria-targeted antioxidants to reduce renal mitochondrial dysfunction and promote repair during sepsis using a clinically relevant dosing paradigm. The proposal is significant and innovative from not just a public health perspective but also from a pharmacological perspective. It will provide the scientific basis for targeting repair, a neglected area of sepsis research and critically important in the kidney because even mild AKI is recognized as a significant risk factor for chronic AKI.