Role of GSK3beta in diabetic kidney disease

GSK3beta 在糖尿病肾病中的作用

基本信息

批准号：
10700111
负责人：
Rujun Gong
金额：
$ 33.99万
依托单位：
UNIVERSITY OF TOLEDO HEALTH SCI CAMPUS
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-09 至 2027-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10700111
关键词：
Acceleration Acute Adriamycin PFS Affect Albuminuria Animals Antioxidants Attenuated Automobile Driving CDKN2A gene Cell Aging Chemicals Clinical Consensus Data Diabetic Nephropathy Diabetic mouse Disease Dose Ectopic Expression End stage renal failure Exposure to FDA approved Functional disorder Gene Delivery Genetic Glycogen Synthase Kinase 3 Glycogen Synthase Kinases Goals Health Healthcare Systems Histologic Hyperactivity Impairment In Vitro Injury Injury to Kidney Innovative Therapy Insulin Kidney Kidney Diseases Knock-in Knock-in Mouse Knock-out Lithium Mediator Modeling Molecular Mood stabilizers Mus Natural regeneration Nephrectomy Oxidative Stress Oxidative Stress Induction Pathogenesis Pathway interactions Persons Pharmaceutical Preparations Phase II Clinical Trials Phosphorylation Physiological Play Protein Isoforms Protein-Serine-Threonine Kinases Regulation Reporting Research Retinoic Acid Receptor Role Severities Signal Transduction Specificity Streptozocin Stress TP53 gene Techniques Testing Transducers Tretinoin Type 2 diabetic Work clinically relevant conditional knockout constitutive expression db/db mouse diabetic efficacy testing glycogen synthase kinase 3 beta glycogen synthase kinase 3 beta inhibitor improved in vivo inhibitor injured injury and repair insulin signaling knock-down men multitask novel organ injury overexpression oxidative damage pharmacologic podocyte premature preservation prevent repaired response retinoic acid receptor alpha senescence small molecule inhibitor synergism therapeutic target transcription factor type I diabetic

项目摘要

ABSTRACT Diabetic kidney disease (DKD) is the leading cause of end-stage renal disease with no definitive therapy yet available. Emerging evidence suggests that defective insulin signaling in podocytes plays a key role in the pathogenesis of DKD. In addition, the “final common molecular pathway” for glomerular degeneration contributes to DKD, involving oxidative damage and stress-induced premature senescence. Glycogen synthase kinase (GSK)3 is a critical transducer of insulin signaling, and also acts as a convergent point for myriad pathways implicated in organ injury, repair, and regeneration. In renal glomeruli, GSK3β rather than the α isoform is predominantly expressed and enriched in podocytes. Our latest studies demonstrated that GSK3β is hyperactive in glomerular podocytes in clinical and experimental DKD, correlating with the severity and progression of DKD and associated with accelerated podocyte senescence. However, the role of GSK3β in diabetic nephropathy (DN) is extremely controversial based on very few studies solely relying on chemical inhibitors or activators with specificity concerns. Preliminary data revealed that GSK3β catalyzes phosphorylation of p53 and p16INK4A, pivotal mediators of senescence signaling in podocytes, and that GSK3β-regulated Keap1-independent Nrf2 antioxidant defense is a new actionable target for podocyte protection. Furthermore, GSK3β inhibition promotes the expression and activity of retinoic acid (RA) receptor (RAR)α, a key transcription factor driving podocyte differentiation and repair. Building logically on previous work, this project aims to conclusively define the exact role of GSK3β in DN and test a novel hypothesis that targeting GSK3β in podocytes mimics or sensitizes insulin signaling, reinforces Nrf2 antioxidant response, mitigates senescence, and synergizes with RARα signaling, resulting in a beneficial effect in DN. Aim 1 will define the molecular mechanism underlying GSK3β regulation of diabetic podocyte injury. GSK3β activity will be manipulated in podocytes exposed to the diabetic milieu and its role in insulin signaling, Nrf2 response and accelerated podocyte senescence will be defined. Aim 2 will examine the role of podocyte-specific GSK3β in DN. In mice with type 1 DN elicited by streptozotocin plus uninephrectomy, or in db/db mice with type 2 DN, GSK3β activity will be promoted by GSK3β knockin or podocyte-specific GSK3β hyperactivity, or inhibited by inducible conditional knockout (icKO) of GSK3β. The rescue efficacy of small molecule inhibitors of GSK3β, including microdose lithium and tideglusib, on established DN will be further evaluated. Aim 3 will test the synergistic effect of GSK3β inhibition plus RA on DN. Mice with icKO of GSK3β and RARα in podocytes will be employed to determine if RARα contributes to GSK3β regulation of DN. The role of GSK3β in regulating RARα activity will be defined using podocytes with differing GSK3β activity and validated in GSK3βicKO mice with type 1 or 2 DN. The synergistic effect of RA plus GSK3β inhibitors on DN will be tested. Collectively, these studies will provide a mechanistic view of the role of GSK3β in the pathogenesis of DN and pave the way for trials of existing or novel medications with GSK3β inhibitory activities to treat DKD in men.

抽象的糖尿病肾病（DKD）是终末期肾病的主要原因，目前尚无明确的治疗方法新出现的证据表明，足细胞中的胰岛素信号传导缺陷在这一过程中发挥着关键作用。此外，肾小球变性的“最终共同分子途径”也有贡献。 DKD，涉及氧化损伤和应激诱导的过早衰老。 (GSK)3 是胰岛素信号转导的关键转导器，也是多种途径的汇聚点在肾小球中，GSK3β 而不是 α 亚型参与器官损伤、修复和再生。我们最新的研究表明 GSK3β 高度活跃。临床和实验性 DKD 中的肾小球足细胞中存在，与 DKD 的严重程度和进展相关然而，GSK3β 在糖尿病肾病中的作用。（DN）极具争议性，因为很少有研究仅依赖于化学抑制剂或激活剂初步数据显示 GSK3β 催化 p53 和 p16INK4A 的磷酸化，足细胞衰老信号传导的关键介质，以及 GSK3β 调节的 Keap1 独立 Nrf2 抗氧化防御是足细胞保护的一个新的可行目标此外，GSK3β 抑制可促进足细胞的生长。视黄酸（RA）受体（RAR）α的表达和活性，这是驱动足细胞的关键转录因子该项目以先前工作的逻辑为基础，旨在最终定义准确的差异和修复。 GSK3β 在 DN 中的作用并测试一个新的假设：针对足细胞中的 GSK3β 模拟或使胰岛素敏感信号传导，增强 Nrf2 抗氧化反应，减轻衰老，并与 RARα 信号传导协同作用，目标 1 将确定 GSK3β 调节的分子机制。糖尿病足细胞损伤 GSK3β 活性将在暴露于糖尿病环境及其的足细胞中受到影响。目标 2 将确定胰岛素信号传导、Nrf2 反应和加速足细胞衰老中的作用。足细胞特异性 GSK3β 在 DN 中的作用在链脲佐菌素加单肾切除术引起的 1 型 DN 小鼠中，或者在具有 2 型 DN 的 db/db 小鼠中，GSK3β 活性将通过 GSK3β 敲入或足细胞特异性 GSK3β 得到促进多动症，或通过诱导条件敲除（icKO）抑制 GSK3β 的拯救功效较小。 GSK3β的分子抑制剂，包括微剂量锂和tigeglusib，对已确定的DN的治疗将进一步目标 3 将测试 GSK3β 抑制加 RA 对 GSK3β icKO 小鼠的协同作用。足细胞中的RARα将用于确定RARα是否有助于GSK3β对DN的调节作用。 GSK3β 在调节 RARα 活性中的作用将使用具有不同 GSK3β 活性的足细胞来定义并经过验证将在患有 1 型或 2 型 DN 的 GSK3βicKO 小鼠中测试 RA 与 GSK3β 抑制剂对 DN 的协同作用。总的来说，这些研究将为 GSK3β 在 DN 发病机制中的作用提供机制观点。为试验具有 GSK3β 抑制活性的现有或新型药物治疗男性 DKD 铺平道路。