The Melanocortinergic pathway inglomerular disease

黑皮质素能通路肾小球疾病

• 批准号: 9677439
• 负责人: Rujun Gong
• 金额: $ 19.12万
• 依托单位: UNIVERSITY OF TOLEDO HEALTH SCI CAMPUS
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-15 至 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9677439
• 关键词: Melanocortinergic; pathway; inglomerular; disease

ABSTRACT Proteinuria, commonly caused by podocyte dysfunction or injury, is an invariable finding in patients with glomerular disease and is by itself a risk factor for long-term prognosis. Evidence suggests that the multi- tasking melanocortin hormone system plays a protective role in stress response in multiple organ systems, including the kidney. The clinical effectiveness of melanocortin therapy with adrenocorticotropin in inducing remission of steroid-resistant nephrotic syndrome points to a steroidogenic-independent anti-proteinuric activity of the melanocortinergic pathway. By harnessing the naturally occurring loss-of-function mutations in melanocortin 1 receptor (MC1R) in both humans and mice, our latest study demonstrated that MC1R is likely dispensable for the proteinuria-reducing and podocyte protective effect of melanocortin therapy. Rather, we found that MC5R is predominantly expressed in glomerular podocytes in vivo and in vitro, and MC5R agonists seem to confer a podocyte protective effect. Building on our previous work, this study will examine the role of the MC5R-mediated melanocortinergic pathway in regulating podocyte injury, explore the sites and modes of action and test an entirely novel strategy for treating proteinuric glomerulopathies based on targeting this pathway. Aim 1 will define and validate the role of MC5R versus MC1R in mediating the anti-proteinuric and podocyte protective effect by comparing the therapeutic efficacy of diverse melanocortins in wild-type, MC1R- null and MC5R knockout (MC5R-/-) mice with Adriamycin nephropathy or nephrotoxic serum nephritis. The contribution of hematopoietic MC5R to the beneficial effect of melanocortin therapy will be assessed in MC5R-/- mice receiving adoptive transfer of syngeneic wild-type bone marrow-derived cells. Furthermore, the podocyte autonomous effect of MC5R will be examined in MC5R-/- mice with podocyte specific MC5R reconstitution. Aim 2 will explore the mechanisms underlying the podocyte protective effect of MC5R signaling. How melanocortin treatment affects podocyte death, cytoskeleton disorganization and expression of NFB-dependent podocytopathic mediators will be assessed in conditionally immortalized and primary podocytes. The essential role of MC5R will be defined using primary MC5R-/- podocytes and those with MC5R reconstitution. Studies will further examine if the podocyte protective effect of MC5R signaling is conveyed by inhibitory phosphorylation of GSK3β, a key transducer of MC5R signaling and a point of convergence for multiple pathways involved in podocyte injury. Aim 3 will test the rescue effect of a novel and highly selective MC5R agonist on established podocyte injury elicited by Adriamycin or nephrotoxic serum in mice and by puromycin aminonucleoside in rats. The mechanisms responsible for the podocyte protective effect of melanocortinergic signaling will be validated in vivo. Collectively, these studies will provide a mechanistic view of the role of the melanocortinergic pathway in regulating podocyte injury and may pave the way for clinical trials of melanocortin based therapy to improve podocyte injury, induce proteinuria remission and slow progression of glomerulosclerosis in man.

抽象的 蛋白尿通常是由足细胞功能障碍或损伤引起的，是患者的不变发现 肾小球疾病本身就是长期预后的危险因素。有证据表明多数 任务黑素皮质素马酮系统在多器官系统中的压力反应中起保护作用， 包括肾脏。黑色素皮质素治疗在诱导中的临床有效性 耐药肾病综合征的缓解指向类固醇非依赖性抗蛋白尿活性 黑色皮质素能途径。通过利用自然发生的功能丧失突变 在人和小鼠中，黑色素皮质1受体（MC1R），我们的最新研究表明MC1R可能是MC1R 对于黑色素皮质素治疗的蛋白质症还原和足细胞保护作用的可分配。相反，我们 发现MC5R主要在体内和体外肾小球足细胞和MC5R激动剂中表达 似乎会遇到足细胞受保护的效果。在我们以前的工作的基础上，本研究将研究 在调节足细胞损伤中，MC5R介导的黑色皮质素能途径，探索 动作并测试一种完全新颖的策略，用于基于目标的蛋白尿肾小球病治疗蛋白尿 路径。 AIM 1将定义和验证MC5R与MC1R在介导抗蛋白尿和 通过比较野生型，MC1R-的细胞皮质素的治疗有效性，通过比较了足细胞保护作用。 NULL和MC5R敲除（MC5R - / - ）伴有阿霉素肾病或肾毒性血清肾炎的小鼠。这 造血MC5R对黑素性素治疗的有益作用的贡献将在MC5R - / - 中评估 接受合同性野生型骨髓衍生细胞的适应性转移的小鼠。此外，足细胞 MC5R的自主效应将在MC5R - / - 小鼠中检查具有Podocyte特异性MC5R重建。目的 2将探索MC5R信号传导的Podocyte受保护作用的基础机制。黑素皮质素如何 治疗会影响足细胞死亡，细胞骨架混乱和NFB依赖性的表达 足细胞病的介体将在有条件永生的和原发性co中评估。必不可少的 MC5R的作用将使用主要的MC5R - / - 足细胞和具有MC5R重建的那些定义。研究将 进一步检查是否通过抑制性磷酸化传达了MC5R信号的足细胞保护作用 GSK3β，MC5R信号的关键换能器，也是涉及多个途径的收敛点 足细胞损伤。 AIM 3将测试新颖和高度选择性的MC5R激动剂的救援效果 小鼠和大鼠呼吸霉素氨基核苷引起的足细胞损伤是由阿霉素或肾毒性血清引起的。 将验证黑色皮质素能信号传导的足细胞保护作用的机制 体内。总的来说，这些研究将提供对黑色皮质素能途径的作用的机械观点 在调节足细胞损伤中，可能为基于黑色皮质素治疗的临床试验铺平了道路 足细胞损伤，诱导蛋白尿缓解和人肾小球硬化的缓慢进展。