Metabolic Reprogramming in Acute Kidney Injury

描述（由申请人提供）：由缺血再灌注损伤（IRI）引起的急性肾损伤（AKI）是一个经常遇到的临床问题，在重症监护环境中与高死亡率相关。此外，它也是慢性肾脏疾病（CKD）进展的重要因素。脯氨酸羟化酶(PHD)/缺氧诱导因子（HIF）氧感应途径是调控肾缺氧/缺血反应的一个中心途径。PHD蛋白是依赖铁和2-氧葡萄糖酸盐的加氧酶，其功能是氧传感器，并通过催化特定脯氨酸残基在其α -亚基的依赖氧降解区域内的羟基化来调节HIF活性。hif是多效异二聚体转录因子，在缺氧/缺血条件下的细胞适应和存活中起关键作用。所有三个主要hif - phd， PHD1， -2和-3，都在肾脏中表达。虽然PHD2调节肾上皮细胞中HIF-1的活性，并已被证明可控制肾间质细胞中促红细胞生成素的产生，但PHD1和PHD3在肾缺氧反应和病理生理中的作用尚不清楚。我们的实验室和其他小组已经在临床前动物模型中证明，肾脏博士的短期药物失活对于预防急性缺血性损伤及其长期后遗症具有很大的治疗潜力。为了了解单个博士在肾脏生理学中的功能作用，并深入了解博士/ hif介导的肾保护的分子和细胞基础，我们已经开始使用遗传学和药理学方法来解剖细胞类型特异性的博士功能及其在肾脏代谢调节中的作用。在这里，我们假设PHD/ hif控制的肾上皮细胞代谢重编程在决定缺血性肾损伤的生物学结果中起着核心作用。在这项资助下，我们使用基因工程小鼠来研究肾脏急性PHD失活的代谢后果。提出了三个具体目标。目的1研究PHD2在肾脏能量代谢中的作用，目的2研究小管上皮PHD1和PHD3在肾脏生理和IRI中的功能作用，目的3研究IRI中与细胞保护相关的特定代谢途径。

DESCRIPTION (provided by applicant): Acute kidney injury (AKI) resulting from ischemia-reperfusion injury (IRI) is a frequently encountered clinical problem and associates with high mortality in a critical care setting. It is furthermore an important contributor to the progressionof chronic kidney disease (CKD). A central pathway in the regulation of renal hypoxia/ischemia responses is the prolyl-hydroxylase (PHD)/hypoxia-inducible factor (HIF) oxygen-sensing pathway. PHD proteins are iron- and 2-oxoglutarate-dependent oxygenases that function as oxygen sensors and regulate HIF activity by catalyzing the hydroxylation of specific proline residues within the oxygen-dependent degradation domain of it's alpha-subunit. HIFs are pleiotropic heterodimeric transcription factors that play key roles in cellular adaptation and survival under hypoxic/ischemic conditions. All three main HIF-PHDs, PHD1, -2 and -3, are expressed in the kidney. While PHD2 regulates HIF-1 activity in renal epithelial cells and has been shown to control erythropoietin production in renal interstitial cells, the role of PHD1 and PHD3 in renal hypoxia responses and pathophysiology is unknown. Our laboratory and other groups have demonstrated in preclinical animal models that short-term pharmacologic inactivation of renal PHDs has great therapeutic potential for the prevention of acute ischemic injuries and their long-term sequelae. In order to understand the functional role of individual PHDs in renal physiology and to gain insight into the molecular and cellular basis of PHD/HIF-mediated renoprotection, we have begun to use genetic and pharmacologic approaches to dissect cell type-specific PHD functions and their role in the regulation of renal metabolism. Here we hypothesize that PHD/HIF-controlled re-programming of metabolism in renal epithelial cells plays a central role in determining the biological outcome of ischemic kidney injuries. Under this grant we use genetically engineered mice to investigate the metabolic consequences of acute PHD inactivation in the kidney. Three specific aims are proposed. Aims 1 investigates the role of PHD2 in renal energy metabolism, aim 2 examines the functional role of tubular epithelial PHD1 and PHD3 in renal physiology and IRI, and aim 3 examines specific metabolic pathways that associate with cytoprotection in IRI.