Klotho: Therapeutic Agent for Ischemia Reperfusion Induced Acute Kidney Injury

Klotho：缺血再灌注引起的急性肾损伤的治疗剂

• 批准号: 8918590
• 负责人: Ming-Chang Hu
• 金额: $ 34.58万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-20 至 2017-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8918590
• 关键词: Ablation; Acute; Acute Renal Failure with Renal Papillary Necrosis; Address; American; Animals; Apoptosis; Attenuated; Biological Markers; Body Fluids; Brain; Cell Culture Techniques; Cell Line; Cells; Cessation of life; Chronic Kidney Failure; Clinical; Clinical Research; Complex; Critical Illness; Cytoprotection; Data; Databases; Dependence; Development; Diagnosis; Diagnostic; Dialysis procedure; Dose; Epithelial Cells; Erythropoiesis; Erythropoietin; Fibrosis; Functional disorder; Genes; Healed; Heart; Heart Injuries; Hospitals; Hypoxia; Hypoxia Inducible Factor; Hypoxic Brain Damage; In Vitro; Incidence; Inflammation; Injury; Investigational Therapies; Ischemia; Kidney; Knock-in Mouse; Knockout Mice; Metabolic; Modality; Modeling; Mus; Natural regeneration; Outcome; Oxidative Stress; Pathway interactions; Patients; Play; Population; Prevalence; Process; Proteins; RNA Interference; Rattus; Recording of previous events; Recovery; Reperfusion Injury; Reperfusion Therapy; Resistance; Rodent Model; Role; Staging; Testing; Therapeutic; Therapeutic Agents; Therapeutic Studies; Time; Translating; Tubular formation; Uncertainty; Work; aging gene; anti aging; base; clinical practice; efficacy testing; fibrogenesis; functional loss; healing; hypoxia inducible factor 1; in vivo; insight; interest; kidney cell; klotho protein; mortality; mutant; novel; novel strategies; outcome forecast; overexpression; oxygen transport; pre-clinical; prevent; protective effect; receptor; receptor expression; renal ischemia; repaired; research clinical testing; research study; response; senescence; success; tissue regeneration; transcription factor; tubular necrosis

DESCRIPTION (provided by applicant): Acute kidney injury (AKI) is a critical clinical problem. The annual prevalence of AKI is 22-620 per million populations in the USA. In particular, the AKI incidence is extremely high in critically ill patients with high mortality. Current overall mortality is still unacceptably high at ~ 30%. Even if patients survive the acute insult, long-term prognosis after AKI is still far from optimal. Of surviving patients, 5-20% are still dialysis-dependent at hospital discharge. The prevalence chronic kidney disease (CKD) is currently estimated at 26 million (16.5%) Americans. Of note, a significant number of CKD patients have a history of AKI. Furthermore, patients with pre-existing CKD are more susceptible to renal insults and have a poorer outcome and higher mortality when they develop AKI. Thus, efficient treatment of AKI is an effective modality to block the development of CKD. Hypoxia-inducible factor (HIF) is a heterodimeric transcription factor that regulate(s) many genes involved in angiogenic, metabolic, and oxygen transport functions. HIF1/2 activation protects the kidney from IRI. Erythropoietin (EPO) has also been used for treatment of ischemic injury in the brain, heart, and kidney. Mice null for either EPO or EpoR have delayed tissue regeneration post ischemia, which suggests that EPO-EpoR is protective against hypoxic brain injury and heart injury. But the EpoR effect on AKI is relatively poorly documented. Moreover, the relationship of Klotho to HIF(s) and EpoR in the kidney is not defined. To date, renal replacement remains the sole treatment for AKI and improvement in outcome has been modest. Dialysis, though effective in maintaining body fluid composition and volume, is not able to ameliorate kidney damage and promote kidney regeneration. We found that Klotho is not only an early biomarker for AKI patients, but also confers renoprotection to attenuate kidney injury, and potentially promote recovery and prevent CKD development. Klotho protein may turn out to be a most promising protein for clinical AKI, but a lot of work still needs to be done. In this proposal, we propose a hypothesis that encompasses the existing database including our own preliminary data; and put it to test. Doubtlessly, this therapeutic study will provide more interesting and encouraging results to inspire to use Klotho protein as a novel strategy. We will also explore whether the mechanism of renoprotection by Klotho is through HIF(s) and EpoR. This data will set the stage for therapeutics as we are at an advanced stage of preclinical experimentation, placing us at a very close proximity to clinical testing.

描述（由申请人提供）：急性肾损伤（阿基）是一个严重的临床问题。在美国，阿基的年患病率为22-620/百万人口。特别是，在死亡率高的危重患者中，阿基发生率极高。目前的总体死亡率仍然高得令人无法接受，约为30%。即使患者在急性损伤后存活，阿基后的长期预后仍然远非最佳。在存活的患者中，5-20%在出院时仍依赖透析。据估计，目前美国慢性肾脏病（CKD）的患病率为2600万（16.5%）。值得注意的是，相当多的CKD患者有阿基病史。此外，既存CKD患者更容易受到肾损害，当他们发生阿基时，结局更差，死亡率更高。因此，阿基的有效治疗是阻断CKD发展的有效方式。缺氧诱导因子（Hypoxia-inducible factor，HIF）是一种异源二聚体转录因子，其调节涉及血管生成、代谢和氧转运功能的许多基因。HIF 1/2激活可保护肾脏免受IRI的影响。促红细胞生成素（EPO）也已用于治疗脑、心脏和肾脏中的缺血性损伤。EPO或EpoR缺失的小鼠在缺血后具有延迟的组织再生，这表明EPO-EpoR对缺氧性脑损伤和心脏损伤具有保护作用。但EpoR对阿基的影响相对较少。此外，Klotho与肾脏中HIF和EpoR的关系尚未确定。迄今为止，肾脏替代仍然是阿基的唯一治疗方法，结局改善不大。透析虽然能有效维持体液成分和体积，但不能改善肾损伤和促进肾再生。我们发现Klotho不仅是阿基患者的早期生物标志物，而且还提供肾保护以减轻肾损伤，并可能促进恢复和预防CKD发展。Klotho蛋白可能是临床阿基最有前途的蛋白质，但仍有许多工作要做。在这个提议中，我们提出了一个假设，包括现有的数据库，包括我们自己的初步数据;并将其进行测试。毫无疑问，这项治疗研究将提供更多有趣和令人鼓舞的结果，以启发使用Klotho蛋白作为一种新的策略。我们还将探讨Klotho的肾保护机制是否是通过HIF（s）和EpoR。这些数据将为治疗奠定基础，因为我们正处于临床前实验的高级阶段，使我们非常接近临床测试。