Chen Bohan, Chen Mengxuan, Chang Mingyang, Ge Yan, Gunning William, Assaly Ragheb, Dworkin Lance D, Qiao Ying Jin, Gong Rujun
Division of Nephrology, Department of Medicine, University of Toledo College of Medicine, Toledo, Ohio, USA.
Division of Nephrology, Department of Medicine, University of Toledo College of Medicine, Toledo, Ohio, USA.
Kidney Int. 2025 May;107(5):835-851. doi: 10.1016/j.kint.2025.01.009. Epub 2025 Jan 23.
Melanocortin therapeutics, exemplified by adrenocorticotropic hormone, have a proven steroidogenic-independent anti-proteinuric and glomerular protective effect. The biological functions of melanocortins are mediated by melanocortin receptors (MCR), including MC1R, which recent studies have shown to protect against glomerular disease. However, the role of other MCRs like MC5R is unknown. Here, Mc5r knockout exacerbated glomerulopathy in mice injured by adriamycin (ADR) or nephrotoxic serum (NTS), as demonstrated by increased albuminuria and podocyte injury. Conversely, selective MC5R agonism using a peptidomimetic agonist improved outcomes of glomerulopathies. Mechanistically, MC5R is expressed in glomerular podocytes. Reconstitution of MC5R in podocytes attenuated glomerular injury and proteinuria in Mc5r knockout mouse models of glomerulopathies, indicating a direct podocyte protective effect. In vitro, MC5R agonism in primary wild-type podocytes attenuated ADR-elicited cytoskeleton disruption, hypermotility and apoptosis, associated with restored inhibitory phosphorylation of glycogen synthases kinase 3β (GSK3β), a signaling transducer downstream of MC5R and at the nexus of multiple podocytopathic pathways. In parallel, ADR-induced phosphorylation and activation of GSK3β substrates, such as paxillin and NF-κB Rela/p65, were abrogated, leading to improved actin cytoskeleton integrity and diminished expression of mediators of podocyte injury, like MCP-1, B7-1 and Cathepsin L. This protective effect of MC5R agonism was blunted in wild-type podocytes expressing constitutively active GSK3β and was mimicked in Mc5r knockout podocytes by ectopic expression of dominant negative GSK3β. Consistently in ADR-injured Mc5r knockout mice, worsened podocytopathy was associated with enhanced GSK3β hyperactivity. These findings suggest that MC5R signaling protects against podocyte injury and may serve as a novel therapeutic target for glomerular diseases.
以促肾上腺皮质激素为代表的黑素皮质素疗法具有已被证实的不依赖于类固醇生成的抗蛋白尿和肾小球保护作用。黑素皮质素的生物学功能由黑素皮质素受体（MCR）介导，包括MC1R，最近的研究表明其可预防肾小球疾病。然而，其他MCR如MC5R的作用尚不清楚。在此，Mc5r基因敲除加剧了阿霉素（ADR）或肾毒性血清（NTS）损伤小鼠的肾小球病变，表现为蛋白尿增加和足细胞损伤。相反，使用拟肽激动剂进行选择性MC5R激动改善了肾小球病变的结局。从机制上讲，MC5R在肾小球足细胞中表达。在肾小球病变的Mc5r基因敲除小鼠模型中，足细胞中MC5R的重建减轻了肾小球损伤和蛋白尿，表明其对足细胞有直接保护作用。在体外，原代野生型足细胞中的MC5R激动减弱了ADR引起的细胞骨架破坏、过度运动和细胞凋亡，这与糖原合酶激酶3β（GSK3β）抑制性磷酸化的恢复有关，GSK3β是MC5R下游的信号转导分子，处于多个足细胞病变途径的交汇点。同时，ADR诱导的GSK3β底物如桩蛋白和NF-κB Rela/p65的磷酸化和激活被消除，导致肌动蛋白细胞骨架完整性改善，足细胞损伤介质如MCP-1、B7-1和组织蛋白酶L的表达减少。MC5R激动的这种保护作用在表达组成型活性GSK3β的野生型足细胞中减弱，而在Mc5r基因敲除的足细胞中通过异位表达显性负性GSK3β得以模拟。在ADR损伤的Mc5r基因敲除小鼠中，足细胞病变恶化与GSK3β过度活性增强一致。这些发现表明MC5R信号传导可预防足细胞损伤，并可能成为肾小球疾病的新型治疗靶点。
