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.

影响足细胞和肾小球的疾病，例如糖尿病，是终末期肾病的主要原因 11% 的退伍军人符合慢性肾脏病 (CKD) 的既定标准， 这会导致 ESKD 和心血管疾病导致的过早死亡。 CKD 领域一直关注 CKD 的起始事件和原因，但不幸的是，这种方法并没有做到这一点； 代表了损伤发生后因治疗选择而被诊断为 CKD 的临床情况。 CKD 的康复要么严重有限，要么根本不存在，因此迫切需要新的靶点和 这里的目标是验证一种新的治疗靶点，β2 肾上腺素受体 (β2-AR)， 我们最近表明可以加速损伤后肾小球功能的恢复。 高度依赖于称为足细胞的特殊细胞，足细胞是肾小球的关键组成部分。 豆荚细胞损伤是许多肾小球疾病的共同点，目前尚无特效药物可以恢复 损伤后的生物信息学分析揭示了损伤引起的足细胞结构和功能的丧失。 已知诱导与线粒体功能相关的基因突变。 线粒体功能障碍并与足细胞功能丧失有关。 已知在维持足细胞能量稳态中发挥关键作用，我们突袭了足细胞 可以通过增加线粒体生物发生和增加线粒体的治疗来从损伤中恢复 为了检验这一假设，我们研究了是否会促进肾小球损伤的恢复。 激动剂刺激 β2-AR 将诱导线粒体生物发生并恢复肾小球滤过 我们最近发表的研究和初步数据显示了对受伤小鼠的有效诱导。 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，使用小鼠。 在足细胞损伤模型中，我们证明口服和腹腔注射福莫特罗六小时 损伤后，当肾小球功能障碍已经建立时，恢复肾小球结构， 我们还初步显示，蛋白尿明显减少，肾小球功能加速恢复。 数据表明患有 CKD 和慢性阻塞性肺疾病 (COPD) 的退伍军人使用 β2-AR 激动剂可以显着减缓肾功能的下降，因为糖尿病是 CKD 的主要原因。 ESKD，这些临床发现很可能是由于β2-AR激动剂对糖尿病肾病的作用所致。 事实上，我们有新的数据表明，使用福莫特罗可以使糖尿病肾病康复。 因此，我们进一步研究了福莫特罗治疗的加速作用。 通过诱导足细胞线粒体恢复损伤后的肾小球功能 为了测试这一点，我们将研究参与足细胞的 β2-AR 依赖性机制。 利用 β2-AR 敲除小鼠 (β2-ARfl/fl;podocin-CreTg/+) 和 β2-AR 缺陷型足细胞衍生的恢复 这将使我们能够确定福莫特罗的作用机制，并可能鉴定出福莫特罗的作用机制。 然后我们将评估使用福莫特罗治疗的临床价值。 分子靶向 β2-AR 诱导的线粒体生物合成，以预防或减缓足细胞病和 CKD 多种肾小球疾病，包括阿尔波特综合征、足细胞裂隙隔膜蛋白缺失 CD2AP、狼疮性肾炎和糖尿病肾病是 CKD 和 ESKD 的最常见原因（Aim 2）.最后，我们将进行一项大型回顾性队列研究，以进一步评估长期 术语 β2-AR 激动剂的使用和我们在退伍军人中发现的肾功能丧失的减少（目标 3）。 使用多方面的方法成功完成了该提案，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 β2-AR激动剂既安全又便宜，是治疗慢性肾病的有效方法。