The role of beta agonists in the treatment of chronic kidney disease

β受体激动剂在慢性肾脏病治疗中的作用

• 批准号: 10485842
• 负责人: JOSHUA H LIPSCHUTZ
• 金额: --
• 依托单位: RALPH H JOHNSON VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-10-01 至 2026-09-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10485842
• 关键词: ATP Synthesis Pathway; Acceleration; Address; Adrenergic Receptor; Adriamycin PFS; Affect; Agonist; Animal Experiments; Biogenesis; Bioinformatics; Biology; CD2-associated protein; Cardiovascular Diseases; Cell Culture Techniques; Cells; Cessation of life; Chronic Kidney Failure; Chronic Obstructive Pulmonary Disease; Clinical; Clinical Trials; Cohort Analysis; Data; Development; Diabetes Mellitus; Diabetic Nephropathy; Diabetic mouse; Diagnostic; Disease; Electron Transport; End stage renal failure; Event; Focal and Segmental Glomerulosclerosis; Functional disorder; Genes; Goals; Health; Hereditary nephritis; Homeostasis; Hour; Human; In Vitro; Injury; Investigation; Kidney; Kidney Diseases; Knockout Mice; Lupus Nephritis; Mediating; Mitochondria; Molecular Target; Mus; Mutation; NPHS2 protein; Non-Insulin-Dependent Diabetes Mellitus; Oral; Patients; Pharmaceutical Preparations; Plasma; Play; Proteinuria; Publishing; Puromycin; Recovery; Renal function; Renal glomerular disease; Research; Retrospective cohort; Retrospective cohort study; Role; Safety; South Carolina; Structure; System; Testing; Therapeutic; Validation; Veterans; beta-2 Adrenergic Receptors; drug discovery; efficacious treatment; efficacy evaluation; experimental study; formoterol; gene induction; glomerular filtration; glomerular function; improved; in vivo; in vivo Model; injured; injury recovery; intraperitoneal; kidney dysfunction; mitochondrial dysfunction; mouse model; new therapeutic target; novel; podocyte; pre-clinical assessment; premature; preservation; prevent; programs; prospective; randomized, clinical trials; repaired; slit diaphragm; therapeutic target

Diseases affecting podocytes and the glomerulus, such as diabetes, are the leading cause of end stage kidney disease (ESKD). Eleven percent of Veterans meet the established criteria for chronic kidney disease (CKD), which leads to ESKD and premature death from cardiovascular disease. The vast majority of research in the field of CKD has focused on the initiating events and causes of CKD; unfortunately, this approach does not represent what is seen clinically where CKD is identified after the injury occurs. Because therapeutic options for recovery from CKD are either severely limited or non-existent, there is a critical need for novel targets and therapeutics. The goal here is to validate a novel therapeutic target, the beta 2 adrenergic receptor (β2-AR), that we recently showed accelerates recovery of glomerular function following injury. Glomerular function is highly dependent on specialized cells known as podocytes, which are critical components of glomeruli. While podocyte injury is a common denominator in many glomerular diseases, there are no specific drugs that restore injury-induced loss of podocyte structure and function. Bioinformatics analysis following injury revealed induction of genes related to mitochondrial function. Mutations in mitochondrial genes are known to result in mitochondrial dysfunction and have been implicated in the loss of podocyte function. Since mitochondria are known to play a critical role in maintaining podocyte energy homeostasis, we hypothesized that podocytes could recover from injury by increasing mitochondrial biogenesis, and therapeutics that increase mitochondrial biogenesis would promote recovery from glomerular injury. To test this hypothesis, we investigated whether stimulation of the β2-AR by an agonist would induce mitochondrial biogenesis and restore glomerular filtration function in injured mice. Our recently published studies and preliminary data show a potent induction of mitochondrial biogenesis in podocytes by the long-acting β2-AR agonist formoterol. Importantly, using mouse models of podocyte injury, we demonstrated that oral and intraperitoneal administration of formoterol six hours following injury, when glomerular dysfunction is already established, restored glomerular structures, significantly reduced proteinuria, and accelerated recovery of glomerular function. We also show preliminary data indicating that Veterans with CKD and chronic obstructive pulmonary disease (COPD), who use β2-AR agonists, have a significantly slower decline of renal function. Since diabetes is the leading cause of CKD and ESKD, these clinical findings are most likely due to the effect of β2-AR agonists on diabetic nephropathy. Indeed, we have new data showing that formoterol use results in recovery from diabetic nephropathy in a mouse model of type II diabetes. Thus, we further hypothesize that treatment with formoterol accelerates the recovery of glomerular function following injury through the induction of podocyte mitochondrial biogenesis. To test this, we will investigate β2-AR-dependent mechanisms that participate in podocyte recovery by utilizing β2-AR knockout mice (β2-ARfl/fl;podocin-CreTg/+) and β2-AR-deficient podocytes derived from these mice. This will allow us to determine the mechanism of action of formoterol and possibly identify even more efficacious treatments (Aim 1). We will then assess the clinical value of using formoterol to molecularly target β2-AR-induced mitochondrial biogenesis to prevent or slow podocytopathy and CKD in a wide range of glomerular diseases, including Alport syndrome, loss of the podocyte slit diaphragm protein CD2AP, lupus nephritis, and diabetic nephropathy, the single most common cause of CKD and ESKD (Aim 2). Finally, we will perform a large retrospective cohort study to further evaluate the association between long- term β2-AR agonist use and decreased loss of renal function that we have identified in Veterans (Aim 3). Successful completion of this proposal, using a multifaceted approach that includes cell culture, animal experiments and human studies, will provide justification for a prospective randomized clinical trial to establish β2-AR agonists, which are both safe and inexpensive, as an efficacious treatment for CKD.

糖尿病等影响足细胞和肾小球的疾病是终末期肾脏的主要原因。 疾病(ESKD)。11%的退伍军人符合慢性肾脏疾病(CKD)的既定标准， 这会导致ESKD和心血管疾病的过早死亡。世界上绝大多数的研究都是 CKD领域关注的是CKD的启动事件和原因；不幸的是，这种方法没有 表示在损伤发生后发现的CKD的临床表现。因为治疗选择 因为CKD的恢复要么严重有限，要么根本不存在，迫切需要新的目标和 治疗学。这里的目标是验证一种新的治疗靶点，即β2肾上腺素能受体(β2-AR)， 我们最近发现可以加速损伤后肾小球功能的恢复。肾小球功能是 高度依赖被称为足细胞的特殊细胞，足细胞是肾小球的关键组成部分。而当 足细胞损伤是许多肾小球疾病的共同特征，目前还没有特效药可以恢复 损伤导致足细胞结构和功能的丧失。损伤后的生物信息学分析显示 线粒体功能相关基因的诱导。已知线粒体基因突变会导致 线粒体功能障碍，并与足细胞功能的丧失有关。因为线粒体是 众所周知，足细胞在维持足细胞能量平衡方面起着关键作用，我们假设足细胞 可以通过增加线粒体的生物生成和增加线粒体的治疗方法来从损伤中恢复 生物发生可促进肾小球损伤的恢复。为了验证这一假设，我们调查了 激动剂刺激β-2-AR可诱导线粒体生物发生并恢复肾小球滤过 在受伤的小鼠中发挥作用。我们最近发表的研究和初步数据表明， 长效β2-AR激动剂福莫特罗在足细胞中的线粒体生物发生。重要的是，使用鼠标 足细胞损伤模型，我们证明口服和腹腔注射福莫特罗6小时 损伤后，当肾小球功能障碍已经确立时，恢复肾小球结构， 显著减少蛋白尿，加速肾小球功能恢复。我们还展示了初步的 数据表明，患有慢性肾脏病和慢性阻塞性肺疾病的退伍军人使用β2-AR 激动剂的肾功能下降速度明显较慢。由于糖尿病是慢性肾脏病的主要原因， 这些临床表现很可能是由于β-2-AR激动剂对糖尿病肾病的影响。 事实上，我们有新的数据表明，福莫特罗的使用有助于糖尿病肾病的康复。 2型糖尿病小鼠模型的建立。因此，我们进一步假设福莫特罗可加速治疗。 足细胞线粒体诱导肾损伤后肾小球功能的恢复 生物发生学。为了测试这一点，我们将研究参与足细胞的β2-AR依赖机制 利用β2-AR基因敲除小鼠(β2-ARFL/FL；Podocin-CreTg/+)和β2-AR缺陷足细胞的恢复 从这些老鼠身上。这将使我们能够确定福莫特罗的作用机制，并可能确定 更有效的治疗方法(目标1)。然后我们将评估使用福莫特罗的临床价值 分子靶向β-AR诱导的线粒体生物发生预防或延缓小鼠足细胞病变和慢性肾功能不全 广泛的肾小球疾病，包括Alport综合征、足细胞裂隙隔膜蛋白丢失 CD2AP、狼疮性肾炎和糖尿病肾病，是CKD和ESKD最常见的单一原因(AIM 2)。最后，我们将进行一项大型的回溯性队列研究，以进一步评估长期和长期的 术语β2-AR激动剂的使用和我们在退伍军人中发现的减少肾功能损失(目标3)。 成功完成这项提案，使用多方面的方法，包括细胞培养、动物 实验和人体研究，将为前瞻性随机临床试验提供理由，以建立 β-2-AR激动剂是治疗慢性肾功能不全的有效药物，既安全又廉价。