Calcium, TRPC channels, and regulation of the actin cytoskeleton in podocytes: towards a future of targeted therapies.
Calcium, TRPC channels, and regulation of the actin cytoskeleton in podocytes: towards a future of targeted therapies.
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钙，TRPC通道和足细胞中肌动蛋白细胞骨架的调节：迈向靶向疗法的未来。
DOI：
10.1007/s00467-015-3224-1
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发表时间：
2016-07
期刊：
影响因子：
--
通讯作者：
Greka A
中科院分区：
文献类型：
--
作者：
Wieder N;Greka A
仅在美国，每年就有6000多名新儿科患者患有治疗抵抗性肾病综合征，因此对新型足细胞特异性治疗的需求尚未得到满足。最近，血管紧张素转换酶（ACE）抑制剂和血管紧张素受体阻滞剂（ARB）的治疗益处被用作了解原发性足细胞病变的病理机制的起点。已经确定了钙（Ca2+）介导的途径，将血管紧张素1型受体（AT1R）连接到足细胞细胞骨架动力学，这对于肾小球滤过屏障的功能至关重要。这一发现为我们理解滤膜屏障损伤的病理机制提供了重要的缺失部分，揭示了Ca2+信号对足细胞健康和疾病的关键作用。两个Ca2+渗透通道TRPC5和TRPC6作为该途径的介质的鉴定不仅加强了足细胞细胞骨架动力学的重要性，而且揭示了治疗耐药肾病综合征的有希望的药物靶点。本文将重点讨论原发性足细胞病变中这种新的信号通路及其对肾小球疾病新一代治疗方法的影响。
With more than 6,000 new pediatric patients with treatment-resistant nephrotic syndrome in the US each year alone, the unmet need for novel, podocyte-specific therapies is substantial. Recently, the established therapeutic benefit of angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARB) was used as a starting point to gain insight into the pathomechanism of primary podocytopathies. A calcium (Ca2+)-mediated pathway has been identified that connects the angiotensin type 1 receptor (AT1R) to podocyte cytoskeletal dynamics, essential for a functioning glomerular filtration barrier. This discovery provided an important missing piece in our understanding of the pathomechanism of filter barrier damage, revealing Ca2+ signaling as critical for podocyte health and disease. The identification of the two Ca2+ permeant channels TRPC5 and TRPC6 as mediators of this pathway not only bolstered the importance of podocyte cytoskeleton dynamics but also revealed promising drug targets for treatment-resistant nephrotic syndrome. This review will focus on this novel signaling pathway in primary podocytopathies and its implications for next-generation therapies for glomerular disease.