Tacrolimus Protects Podocytes from Injury in Lupus Nephritis Partly by Stabilizing the Cytoskeleton and Inhibiting Podocyte Apoptosis.
Tacrolimus Protects Podocytes from Injury in Lupus Nephritis Partly by Stabilizing the Cytoskeleton and Inhibiting Podocyte Apoptosis.
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他克莫司部分通过稳定细胞骨架和抑制足细胞凋亡来保护狼疮性肾炎足细胞免受损伤
DOI：
10.1371/journal.pone.0132724
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发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Yu X
中科院分区：
文献类型：
--
作者：
Liao R;Liu Q;Zheng Z;Fan J;Peng W;Kong Q;He H;Yang S;Chen W;Tang X;Yu X
目的几项研究报道了他克莫司（TAC）可显著减少狼疮性肾炎（LN）患者和小鼠模型的蛋白尿。然而，这种影响的机制仍未确定。本研究探讨TAC保护足细胞免受损伤的机制，以确定保护肾功能的新靶点。方法给MRL/lpr小鼠灌胃TAC，剂量为0.1 mg/kg / d，连续8周。采集了尿液和血液样本。肾切片（2μm）采用苏木精-伊红（HE）、周期性酸-希夫碱（PAS）和马森三色染色。小鼠足细胞（MPC5）用TAC和/或TGF-β1处理48h。采用real-time PCR、Western blotting和/或免疫荧光法分别检测synaptopodin和Wilms ' tumor 1 (WT1) mRNA水平和蛋白表达。流式细胞术检测膜联蛋白v对细胞凋亡的影响。透射电镜观察足突细胞足突。采用免疫荧光法和共聚焦显微镜观察IgG和C3沉积情况。结果MRL/lpr疾病对照小鼠Synaptopodin表达显著降低，24小时蛋白尿、尿素氮、血清肌酐升高。然而，TAC可以减少蛋白尿，改善肾功能，减轻肾脏病理，恢复synaptopodin表达并保持足细胞数量。在MPC5细胞中，TGF-β1增强了足细胞中F-actin的损伤，而TAC则稳定了这种损伤。TAC还能减少TGF-β1诱导的足细胞凋亡，抑制MRL/lpr小鼠足突融合。此外，我们的结果还显示TAC抑制肾小球中IgG和C3的沉积。结论TAC通过稳定足细胞肌动蛋白骨架和抑制足细胞凋亡来保护足细胞免受损伤，从而减少尿蛋白，保护肾功能。
Objective Several studies have reported that tacrolimus (TAC) significantly reduced proteinuria in lupus nephritis (LN) patients and mouse models. However, the mechanism for this effect remains undetermined. This study explored the mechanism of how TAC protects podocytes from injury to identify new targets for protecting renal function. Methods MRL/lpr mice were given TAC at a dosage of 0.1 mg/kg per day by intragastric administration for 8 weeks. Urine and blood samples were collected. Kidney sections (2μm) were stained with hematoxylin-eosin (HE), periodic acid-Schiff base (PAS) and Masson's trichrome stain. Mouse podocyte cells (MPC5) were treated with TAC and/or TGF-β1 for 48h. The mRNA levels and protein expression of synaptopodin and Wilms’ tumor 1 (WT1) were determined by real-time PCR, Western blotting and/or immunofluorescence, respectively. Flow cytometry was used to detect cell apoptosis with annexin V. Podocyte foot processes were observed under transmission electron microscopy. IgG and C3 deposition were assessed with immunofluorescence assays and confocal microscopy. Results Synaptopodin expression significantly decreased in MRL/lpr disease control mice, accompanied by increases in 24-h proteinuria, blood urea nitrogen, and serum creatinine. TAC, however, reduced proteinuria, improved renal function, attenuated renal pathology, restored synaptopodin expression and preserved podocyte numbers. In MPC5 cells, TGF-β1 enhanced F-actin damage in podocytes and TAC stabilized it. TAC also decreased TGF-β1-induced podocyte apoptosis in vitro and inhibited foot process fusion in MRL/lpr mice. In addition, our results also showed TAC inhibited glomerular deposition of IgG and C3. Conclusion This study demonstrated that TAC reduced proteinuria and preserved renal function in LN through protecting podocytes from injury partly by stabilizing podocyte actin cytoskeleton and inhibiting podocyte apoptosis.
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影响因子：
5.1
作者：
Su, Jian;Li, Shi-Jun;Liu, Zhi-Hong
通讯作者：
Liu, Zhi-Hong
影响因子：
3.3
作者：
KINO, T;HATANAKA, H;OCHIAI, T
通讯作者：
OCHIAI, T
影响因子：
19.6
作者：
White, KE;Bilous, RW
通讯作者：
Bilous, RW
DOI：
10.1083/jcb.139.1.193
发表时间：
1997-10-06
期刊：
The Journal of cell biology
影响因子：
--
作者：
Mundel P;Heid HW;Mundel TM;Krüger M;Reiser J;Kriz W
通讯作者：
Kriz W
DOI：
10.1152/ajprenal.00438.2013
发表时间：
2014-01-01
影响因子：
4.2
作者：
Das, Ranjan;Xu, Shanhua;Park, Kyu-Sang
通讯作者：
Park, Kyu-Sang