Role of Ceramide-induced Kidney Cell Death in Acute Kidney Injury

神经酰胺诱导的肾细胞死亡在急性肾损伤中的作用

• 批准号: 8546378
• 负责人: LEAH J SISKIND
• 金额: $ 5.73万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-17 至 2013-06-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8546378
• 关键词: Acids; Acute Renal Failure with Renal Papillary Necrosis; Apoptosis; Apoptotic; BAX gene; BCL-2 Protein; Bioenergetics; Biological Assay; Cell Death; Cells; Ceramides; Cisplatin; Clinical Course of Disease; Data; Development; Disease; Enzyme Inhibitor Drugs; Enzyme Inhibitors; Enzymes; Figs - dietary; Generations; Glycerol; Goals; In Vitro; Individual; Injury; Intervention; Kidney; Kidney Failure; Knockout Mice; Knowledge; Lead; Measures; Mediating; Modeling; Mus; N-palmitoylsphingosine; Necrosis; Nephrotoxic; Pathway interactions; Play; Production; Protein Isoforms; Proximal Kidney Tubules; Public Health; Research; Rhabdomyolysis; Rodent Model; Role; Sphingolipids; Stimulus; Supportive care; Testing; Therapeutic Intervention; Time; acid sphingomyelinase; base; dihydroceramide desaturase; improved; in vivo; inhibitor/antagonist; innovation; kidney cell; mortality; nephrotoxicity; new therapeutic target; novel; novel therapeutic intervention; novel therapeutics; research study; therapeutic development

DESCRIPTION (provided by applicant): Acute kidney injury (AKI) is a devastating disease with a high mortality rate. Apoptosis and necrosis play major roles in AKI, but there is a fundamental knowledge gap of the factors regulating their induction in AKI. Continued existence of this gap represents a significant problem as AKI has a high mortality rate and there are very few therapeutic interventions to alter the clinical course of this disease. The long-term goal is t uncover mechanisms involved in AKI for the development of novel therapeutics to protect the kidney. Ceramides regulate apoptosis and necrosis and are elevated in the kidney in several models of AKI. The factors that regulate production of ceramides during kidney apoptosis and necrosis and whether ceramides lead to apoptotic versus necrotic kidney cell death are completely unknown. Likewise, there are many different ceramide species and the roles for particular ceramide species in AKI have not been determined. This proposal will answer these questions to achieve the objective of developing ceramides as novel therapeutic approaches for the treatment of AKI. Preliminary data demonstrate that: (i) long-chain ceramides (C16 - C20- ceramides) are generated via de novo synthesis during kidney cell apoptosis and blocking their generation inhibits apoptosis; (ii) the pro-apoptotic BCL-2 protein BAK is a key regulator of ceramide synthases (CerS) and long-chain ceramide generation during kidney cell apoptosis; (iii) acid sphingomyelinase (aSMase) generated very long-chain ceramides (C24-C26-ceramides) occurs in kidney cell necrosis; (iv) kidney cortical CerS and acid SMase are activated and specific ceramides elevated several-fold in in vivo rodent models of AKI (cisplain nephrotoxicity and rhabdomyolysis-induced AKI); and (v) mice given inhibitors of enzymes responsible for ceramide synthesis are protected from cisplatin-induced AKI. This expanding and developing body of work has led us to propose the following hypothesis: nephrotoxic stimuli elevate specific species of kidney ceramides through CerS and SMase-mediated pathways, inducing kidney cell death and ultimately kidney failure. This hypothesis will be tested with three specific aims: (1) determine the mechanism by which BAK regulates CerS activity and generation of specific long-chain ceramides during kidney cell apoptosis; (2) determine the contribution of SMase-generated ceramide to kidney cell necrosis; and (3) determine the in vivo contribution of CerS and aSMase to cisplatin-induced AKI in mice. The approach is innovative because it will identify the mechanism by which BAK regulates ceramide synthases as well as the specific role of individual ceramide species in vivo in AKI. The proposed research is significant as it advances our current knowledge of mechanisms of kidney cell death AKI. Ultimately such knowledge has the potential to greatly improve the treatment of AKI.

描述(申请人提供)：急性肾损伤(AKI)是一种高死亡率的破坏性疾病。细胞凋亡和坏死在AKI中起主要作用，但对它们在AKI中诱导的调控因素还存在基本的认识空白。这一差距的持续存在是一个重大问题，因为AKI的死亡率很高，而且很少有治疗干预措施来改变这种疾病的临床进程。长期目标是为了发现AKI中涉及的机制，以开发保护肾脏的新疗法。神经酰胺调节细胞凋亡和坏死，并在几种AKI模型的肾脏中升高。在肾脏细胞凋亡和坏死过程中调节神经酰胺产生的因素，以及神经酰胺是否导致肾细胞的凋亡性和坏死性死亡是完全未知的。同样，有许多不同的神经酰胺种类，特定神经酰胺种类在AKI中的作用尚未确定。这项建议将回答这些问题，以实现开发神经酰胺作为治疗AKI的新治疗方法的目标。初步研究表明：(1)肾细胞凋亡过程中通过从头合成产生长链神经酰胺(C16-C20-神经酰胺)，阻断其合成可抑制细胞凋亡；(2)促细胞凋亡的bcl2蛋白BAK是神经酰胺合成酶(CERs)和长链神经酰胺生成的关键调节因子；(3)肾细胞坏死中存在酸性鞘磷脂酶(ASMase)生成的超长链神经酰胺(C24-C26-神经酰胺)；(Iv)在AKI(顺铂肾毒性和横纹肌溶解诱导的AKI)啮齿动物模型中，肾脏皮质CERs和酸性SMase被激活，特异性神经酰胺增加数倍；(V)给予神经酰胺合成酶抑制剂的小鼠可免受顺铂诱导的AKI的影响。这一不断扩大和发展的工作使我们提出了以下假设：肾毒性刺激通过CERs和sMase介导的途径增加特定种类的肾神经酰胺，诱导肾细胞死亡，最终导致肾功能衰竭。这一假设将通过三个方面进行检验 具体目标：(1)确定BAK在肾细胞凋亡过程中调节CERs活性和特定长链神经酰胺生成的机制；(2)确定sMase产生的神经酰胺对肾细胞坏死的贡献；以及(3)确定CERs和aSMase在顺铂诱导的小鼠急性肾损伤中的体内贡献。这种方法是创新的，因为它将确定BAK调节神经酰胺合成酶的机制以及体内单个神经酰胺物种在AKI中的特定作用。这项拟议的研究具有重要意义，因为它促进了我们目前对肾脏细胞死亡机制的了解。归根结底，这些知识有可能极大地改善AKI的治疗。