Role of GSK3beta in diabetic kidney disease

GSK3beta 在糖尿病肾病中的作用

• 批准号: 10501151
• 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
• 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/10501151
• 关键词: Acute; Adriamycin PFS; Affect; Albuminuria; Animals; Antioxidants; Attenuated; Automobile Driving; CDKN2A gene; Cell Aging; Chemicals; Clinical; Consensus; Data; Diabetic Nephropathy; Diabetic mouse; Disease; Ectopic Expression; End stage renal failure; Exposure to; FDA approved; Functional disorder; Gene Delivery; Genetic; Glycogen Synthase Kinase 3; 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; Knockout Mice; Lithium; Mediator of activation protein; Modeling; Molecular; Moods; Mus; Natural regeneration; Nephrectomy; Oxidative Stress; Pathogenesis; Pathway interactions; Persons; Pharmaceutical Preparations; Pharmacology; Phase II Clinical Trials; Phosphorylation; Physiological; Play; Protein Isoforms; Protein-Serine-Threonine Kinases; Receptor Signaling; Regulation; Reporting; Research; Role; Severities; Signal Transduction; Specificity; Streptozocin; Stress; TP53 gene; Techniques; Testing; Transducers; Tretinoin; Type 2 diabetic; Work; base; clinically relevant; conditional knockout; 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 sensitizing drugs; insulin signaling; knock-down; men; multitask; novel; organ injury; overexpression; oxidative damage; podocyte; premature; preservation; prevent; receptor; repaired; response; retinoic acid receptor alpha; senescence; small molecule inhibitor; therapeutic target; transcription factor; type I diabetic

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.

摘要 糖尿病肾病（Diabetic kidney disease，DKD）是终末期肾病的主要病因，目前尚无明确的治疗方法 available.新出现的证据表明，足细胞中的胰岛素信号传导缺陷在糖尿病的发病中起着关键作用。 DKD的发病机制此外，肾小球变性的“最后共同分子途径”有助于 DKD，涉及氧化损伤和应激诱导的早衰。糖原合成酶激酶 （GSK）3是胰岛素信号传导的关键转换器，并且还充当无数途径的汇聚点 与器官损伤、修复和再生有关。在肾小球中，GSK 3 β而不是α亚型是 主要在足细胞中表达和富集。我们最新的研究表明，GSK 3 β是一种高活性的 在临床和实验性DKD的肾小球足细胞中，与DKD的严重程度和进展相关 并与加速的足细胞衰老有关。然而，GSK 3 β在糖尿病肾病中的作用 (DN)是非常有争议的，因为很少有研究仅仅依赖于化学抑制剂或活化剂， 特殊性问题。初步数据显示，GSK 3 β催化p53和p16 INK 4A的磷酸化， 足细胞衰老信号传导的关键介质，以及GSK 3 β调节的Keap 1非依赖性Nrf 2 抗氧化防御是足细胞保护的一个新的可操作目标。此外，GSK 3 β抑制促进 足细胞关键转录因子视黄酸受体α的表达和活性 分化和修复。建立在以前的工作逻辑上，这个项目的目的是最终确定确切的 目的：研究GSK 3 β在糖尿病肾病中的作用，并验证一种新的假设，即在足细胞中靶向GSK 3 β模拟或增敏胰岛素 信号传导，增强Nrf 2抗氧化反应，减轻衰老，并与RARα信号传导协同作用， 导致对DN的有益效果。目的1将明确GSK 3 β调控的分子机制， 糖尿病足细胞损伤将在暴露于糖尿病环境的足细胞中操纵GSK 3 β活性， 将定义在胰岛素信号传导、Nrf 2应答和加速足细胞衰老中的作用。目标2将检查 足细胞特异性GSK 3 β在DN中的作用在链脲佐菌素加单侧肾切除术诱发的1型DN小鼠中， 而在db/db 2型DN小鼠中，GSK 3 β基因敲入或足细胞特异性GSK 3 β基因敲入均能促进GSK 3 β活性， 过度活跃，或通过GSK 3 β的诱导型条件性敲除（icKO）抑制。抢救疗效小 GSK 3 β的分子抑制剂，包括微剂量锂和tideglusib，将进一步用于已建立的DN 评估。目的3探讨抑制GSK 3 β与RA联合治疗DN的协同作用。GSK 3 β icKO小鼠 将采用足细胞中的RARα来确定RARα是否有助于DN的GSK 3 β调节。的作用 将使用具有不同GSK 3 β活性的足细胞来定义GSK 3 β在调节RARα活性中的作用，并验证 在1型或2型DN的GSK 3 βicKO小鼠中。将测试RA加GSK 3 β抑制剂对DN的协同作用。 总的来说，这些研究将为GSK 3 β在DN发病机制中的作用提供一个机制观点， 为具有GSK 3 β抑制活性的现有或新型药物治疗男性DKD的试验铺平了道路。