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.

摘要 蛋白尿通常由足细胞功能障碍或损伤引起， 肾小球疾病，本身是长期预后的危险因素。有证据表明，多- 任务黑皮质激素系统在多器官系统的应激反应中起保护作用， 包括肾脏促肾上腺皮质激素联合黑素皮质素治疗急性脑梗死的临床疗效观察 激素抵抗性肾病综合征的缓解表明具有非类固醇生成依赖性抗蛋白尿活性 黑皮质素途径的一部分通过利用自然发生的功能丧失突变， 黑素皮质素1受体（MC 1 R）在人类和小鼠，我们的最新研究表明，MC 1 R可能是 黑皮质素治疗的蛋白尿减少和足细胞保护作用的研究。而是 发现MC 5 R在体内和体外主要在肾小球足细胞中表达，并且MC 5 R激动剂 似乎赋予足细胞保护作用。在我们之前工作的基础上，本研究将研究 MC 5 R介导的黑素皮质素能信号通路在足细胞损伤中的作用，探讨黑素皮质素能信号通路在足细胞损伤中的作用部位和方式。 作用和测试一个全新的策略，用于治疗蛋白尿性肾小球病的基础上，针对这一点， 通路目的1将定义和验证MC 5 R与MC 1 R在介导抗蛋白尿和抗糖尿病中的作用。 通过比较不同黑皮质素在野生型、MC 1 R- 空和MC 5 R敲除（MC 5 R-/-）小鼠阿霉素肾病或肾毒性血清肾炎。的 造血MC 5 R对黑皮质素治疗的有益作用的贡献将在MC 5 R-/- 接受同基因野生型骨髓衍生细胞过继转移的小鼠。此外，足细胞 将在具有足细胞特异性MC 5 R重建的MC 5 R-/-小鼠中检查MC 5 R的自主作用。目的 2将探讨MC 5 R信号转导对足细胞保护作用的机制。黑皮质素 治疗影响足细胞死亡、细胞骨架解体和NF-κ B依赖性 将在条件永生化和原代足细胞中评估足细胞病变介质。的基本 将使用原代MC 5 R-/-足细胞和具有MC 5 R重建的足细胞来定义MC 5 R的作用。研究将 进一步检查MC 5 R信号传导的足细胞保护作用是否通过抑制性磷酸化来传达 GSK 3 β是MC 5 R信号传导的关键转导子，也是参与MC 5 R信号传导的多种途径的汇聚点。 足细胞损伤目的3将测试一种新的和高选择性的MC 5 R激动剂对建立的 阿霉素或肾毒血清引起的小鼠足细胞损伤和嘌呤霉素氨基糖苷引起的大鼠足细胞损伤。 黑皮质素能信号传导对足细胞保护作用的机制将得到验证 in vivo.总的来说，这些研究将提供一个机制的看法，黑皮质素途径的作用， 在调节足细胞损伤，并可能铺平了道路，为临床试验的黑皮质素为基础的治疗，以改善 足细胞损伤，诱导蛋白尿缓解和肾小球硬化的缓慢进展。