Tacrolimus ameliorates podocyte injury by restoring FK506 binding protein 12 (FKBP12) at actin cytoskeleton
Tacrolimus ameliorates podocyte injury by restoring FK506 binding protein 12 (FKBP12) at actin cytoskeleton
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DOI：
10.1096/fj.202101052r
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发表时间：
2021-11-01
期刊：
影响因子：
4.8
通讯作者：
Kawachi，Hiroshi
中科院分区：
文献类型：
--
作者：
Yasuda，Hidenori;Fukusumi，Yoshiyasu;Kawachi，Hiroshi
FKBP 12是他克莫司（Tac）的结合蛋白。Tac与FKBP 12结合并在T细胞中表现出免疫抑制作用。虽然有报道称Tac治疗可直接改善肾病综合征足细胞功能障碍，但其确切的药理学机制尚不清楚。还已知FKBP 12独立于Tac发挥功能。然而，FKBP 12的定位和生理功能尚未得到很好的阐明。在本研究中，我们观察到FKBP 12在肾小球中高度表达，并且肾小球中的FKBP 12仅限于足细胞。FKBP 12在培养的足细胞中沿着肌动蛋白细胞骨架表达，并与丝状肌动蛋白（F-肌动蛋白）相关。FKBP 12与肌动蛋白相关蛋白14 - 3 - 3和突触足蛋白相互作用。FKBP 12的RNA沉默减少了培养的足细胞中14 - 3 - 3表达、F-肌动蛋白染色和突起形成。FKBP 12在阿霉素（ADR）肾病模型及ADR处理的足细胞中表达降低。ADR处理后足细胞突起形成变差。Tac治疗改善了这些下降。对正常细胞的Tac处理增加了突起中F-actin处FKBP 12的表达并增强了突起形成。Tac增强了FKBP 12与突触足蛋白的相互作用。这些观察结果表明，肌动蛋白细胞骨架上的FKBP 12参与了过程的维持，Tac治疗通过恢复肌动蛋白细胞骨架上的FKBP 12来改善足细胞损伤。
FKBP12 was identified as a binding protein of tacrolimus (Tac). Tac binds to FKBP12 and exhibits immunosuppressive effects in T cells. Although it is reported that Tac treatment directly ameliorates the dysfunction of the podocyte in nephrotic syndrome, the precise pharmacological mechanism of Tac is not well understood yet. It is also known that FKBP12 functions independently of Tac. However, the localization and the physiological function of FKBP12 are not well elucidated. In this study, we observed that FKBP12 is highly expressed in glomeruli, and the FKBP12 in glomeruli is restricted in podocytes. FKBP12 in cultured podocytes was expressed along the actin cytoskeleton and associated with filamentous actin (F‐actin). FKBP12 interacted with the actin‐associated proteins 14‐3‐3 and synaptopodin. RNA silencing for FKBP12 reduced 14‐3‐3 expression, F‐actin staining, and process formation in cultured podocytes. FKBP12 expression was decreased in the nephrotic model caused by adriamycin (ADR) and the cultured podocyte treated with ADR. The process formation was deteriorated in the podocytes treated with ADR. Tac treatment ameliorated these decreases. Tac treatment to the normal cells increased the expression of FKBP12 at F‐actin in processes and enhanced process formation. Tac enhanced the interaction of FKBP12 with synaptopodin. These observations suggested that FKBP12 at actin cytoskeleton participates in the maintenance of processes, and Tac treatment ameliorates podocyte injury by restoring FKBP12 at actin cytoskeleton.