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: 8843837
• 负责人: LEAH J SISKIND
• 金额: $ 32.52万
• 依托单位: UNIVERSITY OF LOUISVILLE
• 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 2017-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8843837
• 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（由申请人提供）：急性肾损伤（阿基）是一种具有高死亡率的毁灭性疾病。细胞凋亡和坏死在阿基中起主要作用，但对阿基中调控其诱导的因素存在基本的知识空白。这种差距的持续存在代表了一个重要的问题，因为阿基具有高死亡率，并且很少有治疗干预来改变这种疾病的临床病程。长期目标是揭示阿基的相关机制，以开发保护肾脏的新疗法。神经酰胺调节细胞凋亡和坏死，并且在几种阿基模型中在肾脏中升高。在肾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细胞凋亡与坏死性肾细胞死亡是完全未知的。同样，存在许多不同的神经酰胺种类，并且尚未确定特定神经酰胺种类在阿基中的作用。该提案将回答这些问题，以实现开发神经酰胺作为治疗阿基的新型治疗方法的目标。初步数据表明：（i）长链神经酰胺（ii）促凋亡BCL-2蛋白巴克是肾细胞凋亡期间神经酰胺酶（CerS）和长链神经酰胺生成的关键调节剂;（iii）酸性鞘磷脂酶（aSMase）产生非常长链的神经酰胺（C24-C26-神经酰胺）发生在肾细胞坏死;（iv）在阿基的体内啮齿动物模型中，肾皮质CerS和酸性SMase被激活，并且特异性神经酰胺升高数倍（顺铂肾毒性和横纹肌溶解诱导的阿基）;和（v）给予负责神经酰胺合成的酶的抑制剂的小鼠被保护免于顺铂诱导的阿基。这种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介导的途径升高特定种类的肾神经酰胺，诱导肾细胞死亡并最终导致肾衰竭。这一假设将用三个 具体目标：（1）确定巴克在肾细胞凋亡期间调节CerS活性和特异性长链神经酰胺生成的机制;（2）确定SMase生成的神经酰胺对肾细胞坏死的贡献;（3）确定CerS和aSMase对顺铂诱导的小鼠阿基的体内贡献。该方法是创新的，因为它将确定巴克调节神经酰胺脱氢酶的机制以及单个神经酰胺种类在阿基中的体内特定作用。这项研究意义重大，因为它推进了我们目前对肾细胞死亡机制的认识。最终，这些知识有可能极大地改善阿基的治疗。