Stimulation of the calcium-sensing receptor stabilizes the podocyte cytoskeleton, improves cell survival, and reduces toxin-induced glomerulosclerosis
Stimulation of the calcium-sensing receptor stabilizes the podocyte cytoskeleton, improves cell survival, and reduces toxin-induced glomerulosclerosis
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DOI：
10.1038/ki.2011.105
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发表时间：
2011-09-01
影响因子：
19.6
通讯作者：
Schmitt, Claus P.
中科院分区：
文献类型：
--
作者：
Oh, Jun;Beckmann, Julia;Schmitt, Claus P.
拟钙剂增加甲状旁腺钙敏感受体对细胞外钙的敏感性，有效控制甲状旁腺功能亢进。最近的研究表明，除了控制骨和矿物质稳态外，拟钙剂还具有有益的作用。在这里，我们测试了钙敏感受体是否也在足细胞中表达和功能相关。使用基因集富集分析的微阵列数据的分析发现，拟钙R-568影响与氧化应激，细胞骨架调节，细胞增殖和在培养的足细胞中的存活相关的各种途径。R-568诱导ERK 1/2-P90 RSK-CREB信号级联的剂量和时间依赖性磷酸化，并诱导BAD和Bcl-xl的促存活磷酸化，从而使嘌呤霉素氨基糖苷（PAN）诱导的足细胞凋亡减少一半。此外，R-568保留了暴露于PAN的足细胞中的肌动蛋白细胞骨架，并改善了暴露于细胞松弛素D（一种肌动蛋白聚合的可逆抑制剂）的恢复。在大鼠中，R-568联合给药可预防PAN单次给药引起的蛋白尿，并减轻重复嘌呤霉素治疗引起的肾小球硬化和GFR丧失。因此，拟钙剂通过抗凋亡和细胞凋亡稳定作用限制足细胞损伤，并可能构成肾小球疾病预防和治疗的新方法。Kidney International（2011）80，483-492; doi：10.1038/ki.2011.105; 2011年4月20日在线发表
Calcimimetics increase the sensitivity of the parathyroid calcium-sensing receptor to extracellular calcium for efficient control of hyperparathyroidism. Recent studies suggest that there are beneficial effects of calcimimetics beyond the control of bone and mineral homeostasis. Here, we tested whether the calcium-sensing receptor is also expressed and functionally relevant in podocytes. Analysis of microarray data using Gene Set Enrichment Analysis found that the calcimimetic R-568 influenced various pathways related to oxidative stress, cytoskeletal regulation, cell proliferation, and survival in cultured podocytes. R-568 induced a dose-and time-dependent phosphorylation of the ERK1/2-P90RSK-CREB signaling cascade, and induced pro-survival phosphorylation of BAD and Bcl-xl, thus reducing puromycin aminonucleoside (PAN)-induced podocyte apoptosis by half. Moreover, R-568 preserved the actin cytoskeleton in podocytes exposed to PAN and improved recovery from exposure to cytochalasin D, a reversible inhibitor of actin polymerization. In rats, co-administration of R-568 prevented the proteinuria caused by a single dose of PAN and attenuated the glomerulosclerosis and loss of GFR caused by repetitive puromycin treatment. Hence, calcimimetics limit podocyte damage by antiapoptotic and cytoskeleton-stabilizing effects and may constitute a new approach in the prevention and treatment of glomerular disease. Kidney International (2011) 80, 483-492; doi:10.1038/ki.2011.105; published online 20 April 2011