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.

抽象的 糖尿病性肾脏疾病（DKD）是终末期肾脏疾病的主要原因，尚无明确治疗 可用的。新兴的证据表明，足细胞中有缺陷的胰岛素信号传导在 DKD的发病机理。此外，肾小球变性的“最终公共分子途径”有助于 到DKD，涉及氧化损伤和应力诱导的过早感应。糖原合酶激酶 （GSK）3是胰岛素信号传导的关键传感器，也是无数途径的收敛点 在器官损伤，维修和再生中实施。在肾肾小球中，GSK3β而不是α同工型为 主要表达并富含足细胞。我们的最新研究表明GSK3β是多动症 在临床和实验DKD中的肾小球足细胞中，与DKD的严重程度和进展相关 并与加速的足细胞感应相关。但是，GSK3β在糖尿病性肾病中的作用 （DN）基于仅依靠化学抑制剂或活化剂的非常有争议的引起争议 特殊性问题。初步数据表明，GSK3β催化p53和p16ink4a的磷酸化， 足细胞中的感应信号传导的关键介体，并且GSK3β调节的Keap1无依赖性NRF2 抗氧化剂防御是podocyte保护的新的可行目标。此外，GSK3β促进 视黄酸（RA）受体（RAR）α的表达和活性，驱动足细胞的关键转录因子 分化和维修。该项目以先前的工作为逻辑，旨在最终定义确切的 GSK3β在DN中的作用并检验了一个新的假设，即针对足细胞中的GSK3β模拟或敏感性胰岛素 信号传导，增强NRF2抗氧化剂反应，减轻感受并与RARα信号传导合成，， 导致DN产生有益效果。 AIM 1将定义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的足细胞中操纵 将定义胰岛素信号，NRF2反应和加速足细胞感应的作用。 AIM 2将检查 足细胞特异性GSK3β在DN中的作用。在由链蛋白酶蛋白酶和单次切除术引起的1型DN的小鼠中， 或在具有2型DN的DB/DB小鼠中，GSK3β活性将由GSK3β敲击素或足细胞特异性GSK3β促进 多动症或被GSK3β的有条件敲除（ICKO）抑制。小的救援效率 GSK3β的分子抑制剂，包括微溶锂和潮汐，在已建立的DN上将进一步 评估。 AIM 3将测试GSK3β抑制和RA对DN的协同作用。 GSK3β的ICKO小鼠 将进行足细胞中的RARα，以确定RARα是否有助于DN的GSK3β调节。角色 在调节RARα活性中的GSK3β将使用具有分化GSK3β活性的足细胞定义并验证 在具有1型或2型DN的GSK3βICKO小鼠中。将测试RA PlusGSK3β抑制剂对DN的协同作用。 总的来说，这些研究将为GSK3β在DN和DN的发病机理中的作用提供机械观点 为使用GSK3β抑制活性的现有或新型药物试验以治疗男性DKD的现有或新型药物铺平道路。