Role of GSK3beta in diabetic kidney disease

GSK3beta 在糖尿病肾病中的作用

• 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
• 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

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 摘要糖尿病肾病(DKD)是导致终末期肾病的主要原因，目前尚无明确的治疗方法。 可用。新的证据表明，足细胞中有缺陷的胰岛素信号在 DKD的发病机制。此外，肾小球退行性变的“最终共同分子途径”也有助于 对于DKD，涉及氧化损伤和应激诱导的早衰。糖原合成酶激酶 (GSK)3是胰岛素信号转导的关键途径，也是多种途径的汇聚点 与器官损伤、修复和再生有关。在肾小球中，Gsk3β而不是α亚型是 主要在足细胞中表达和丰富。我们最新的研究表明Gsk3β是多动的。 临床和实验性DKD患者肾小球足细胞中与DKD严重程度和进展的相关性 并与足细胞加速衰老有关。然而，GSK3β在糖尿病肾病中的作用 (DN)极具争议性，因为仅依靠化学抑制剂或激活剂的研究很少。 专一性问题。初步数据显示，GSK3β催化P53和p16INK4A的磷酸化， 足细胞衰老信号的关键介体，以及Gsk3β调控的Keap1非依赖性NRF2 抗氧化防御是足细胞保护的一个新的可操作的靶点。此外，抑制GSK3的β促进 足细胞关键转录因子维甲酸受体α的表达及活性 分化和修复。建立在以前工作的逻辑基础上，这个项目的目的是最终定义 Gsk3β在糖尿病肾病中的作用及验证一种新的假说，即靶向足细胞中的Gsk3β可模拟或增敏胰岛素 信号转导，增强NRF2抗氧化反应，延缓衰老，并与RARα信号转导协同， 从而在糖尿病肾病中产生有益的效果。目标1将定义Gsk3β调控的分子机制 糖尿病足细胞损伤。GSK3β活性将在暴露于糖尿病环境和它的足细胞中被操纵 在胰岛素信号、Nrf2反应和足细胞加速衰老中的作用将被定义。Aim 2将检查 足细胞特异性β在糖尿病肾病中的作用。在链脲佐菌素加单肾切除术诱发1型糖尿病肾病的小鼠中， 在患有2型糖尿病肾病的db/db小鼠中，gsk3β活性将被gsk3β敲门蛋白或足细胞特异性gsk3β所促进 多动，或被Gsk3β的可诱导条件敲除(ICKO)抑制。Small的救援效果 Gsk3β的分子抑制剂，包括微剂量锂和替地西布，对已建立的糖尿病肾病将进一步 已评估。目的3检测GSK3β抑制与维甲酸联合治疗糖尿病肾病的协同作用。Gsk3β的icKO小鼠 足细胞中的RARα将被用来确定RARα是否参与了β对糖尿病肾病的调节。角色 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验证 在患有1型或2型糖尿病肾病的GSK3βICKO小鼠中。将测试RA和GSK3β抑制剂对糖尿病肾病的协同作用。 总之，这些研究将提供Gsk3β在糖尿病肾病和糖尿病肾病发病机制中的作用的机制观点。 为试验现有或新型具有GSK3GSK3β抑制活性的药物治疗男性弥漫性肾病铺平道路。