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病症，其特征在于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215，000例死亡，医疗负担约为170亿美元。多达50%的脓毒症患者发生急性肾损伤（阿基），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，临床医生必须仅依赖于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，肾微循环衰竭和肾线粒体超氧化物（O2在诱导脓毒症后4小时，小鼠中发生了-）生成，并且这些事件先于肾功能的下降。重要的是，抗氧化剂可以使微循环恢复，防止肾损伤。现在我们有数据显示，肾脏中主要的线粒体O2- 清除剂锰超氧化物歧化酶（MnSOD）在脓毒症后4 h下降约50%，线粒体复合物II/III在脓毒症后6 h下降约30%。此外，脓毒症诱导的线粒体损伤刺激线粒体自噬（线粒体的安全去除）;然而，线粒体生物发生（有丝分裂）受损。基于这些数据，我们推测，在败血症增加线粒体超氧化物是由于MnSOD活性的损失和复合物II/III活性降低。由此产生的线粒体损伤触发线粒体自噬，但过量的超氧化物抑制功能性线粒体生物合成。因此，减少线粒体超氧化物的试剂将允许功能性有丝分裂并改善脓毒症诱导的阿基。使用体内CLP模型以及原代细胞体外模型的三个特定目的将检验该假设。目的1建立脓毒症小鼠MnSOD失活与呼吸链功能障碍（损伤期）、线粒体自噬和有丝分裂发生（恢复期）的时间关系。目的2探讨脓毒症时肾上皮MnSOD活性变化的分子机制。最后，目标3中的研究将使用临床相关的给药模式评估靶向抗氧化剂在脓毒症期间减少肾线粒体功能障碍和促进修复的治疗潜力。该提案不仅从公共卫生的角度，而且从药理学的角度来看都是重要和创新的。它将为靶向修复提供科学依据，这是脓毒症研究的一个被忽视的领域，在肾脏中至关重要，因为即使是轻度阿基也被认为是慢性阿基的重要风险因素。

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.