Tacrolimus induces fibroblast-to-myofibroblast transition via a TGF-β-dependent mechanism to contribute to renal fibrosis.
Tacrolimus induces fibroblast-to-myofibroblast transition via a TGF-β-dependent mechanism to contribute to renal fibrosis.
复制标题
他克莫司通过 TGF-β 依赖性机制诱导成纤维细胞向肌成纤维细胞的转变，从而促进肾纤维化。
DOI：
10.1152/ajprenal.00226.2022
复制
发表时间：
2023
期刊：
影响因子：
--
通讯作者：
Williams,ClintoriaR
中科院分区：
文献类型：
--
作者：
Ume,AdakuC;Wenegieme,TaraY;Shelby,JennaeN;Paul-Onyia,ChiagozieDB;Waite3rd,AstonMJ;Kamau,JohnK;Adams,DanielleN;Susuki,Keiichiro;Bennett,EricS;Ren,Hongmei;Williams,ClintoriaR
免疫抑制剂钙调磷酸酶抑制剂（CNI）的使用受到不可逆肾损伤的限制，其特征是肾纤维化。CNI直接损害许多肾细胞类型。考虑到不同的肾细胞群，其他靶细胞类型和信号传导机制需要进一步研究。我们假设成纤维细胞参与CNI诱导的肾纤维化，并通过转化生长因子-β（TGF-β）/Smad信号轴传播促纤维化作用。为了测试这一点，肾损伤抗性小鼠（C57 BL/6）接受他克莫司（10 mg/kg）或溶剂21天。评估肾损伤标志物和信号传导介质。为了研究其在肾损伤中的作用，将小鼠肾成纤维细胞暴露于他克莫司（1 nM）或溶剂24 h。除了下游信号传导事件之外，还评估了形态学和功能变化。他克莫司处理的肾脏显示肾纤维化的证据。此外，α-平滑肌肌动蛋白表达显著增加，表明存在成纤维细胞活化。TGF-β受体活化和下游Smad 2/3信号传导也上调。与体内结果一致，他克莫司处理的肾成纤维细胞显示出称为成纤维细胞至肌成纤维细胞转化（FMT）的表型转换，因为α-平滑肌肌动蛋白、肌动蛋白应力纤维、细胞运动性和IV型胶原蛋白表达显著增加。这些发现伴随着TGF-β信号传导的伴随诱导。下游TGF-β效应子Smad 3的药理学抑制减弱了他克莫司诱导的表型变化。总的来说，这些发现表明：1）他克莫司抑制活化T细胞轴的钙调神经磷酸酶/核因子，同时诱导肾成纤维细胞中TGF-β1配体分泌和受体活化;2）异常TGF-β受体活化刺激Smad介导的肌成纤维细胞标志物的产生，这是FMT的显著特征; 3）FMT有助于他克莫司诱导的肾纤维化中细胞外基质的扩增。这些结果将肾成纤维细胞纳入越来越多的CNI靶向细胞类型的列表中，并将肾FMT确定为通过TGF-β依赖性机制介导的过程。新&值得注意的是肾纤维化是不可逆肾损伤的一个有害特征，仍然是长期钙调磷酸酶抑制剂（CNI）免疫抑制治疗的一个险恶后果。我们的研究不仅将肾成纤维细胞纳入越来越多的受CNI负面影响的细胞类型列表中，而且还将肾成纤维细胞向肌成纤维细胞的转化确定为通过TGF-β依赖性机制介导的过程。这一见解将指导未来的研究，研究抑制TGF-β信号传导以维持CNI介导的免疫抑制的可行性，同时最终保护肾脏健康。
Use of immunosuppressant calcineurin inhibitors (CNIs) is limited by irreversible kidney damage, hallmarked by renal fibrosis. CNIs directly damage many renal cell types. Given the diverse renal cell populations, additional targeted cell types and signaling mechanisms warrant further investigation. We hypothesized that fibroblasts contribute to CNI-induced renal fibrosis and propagate profibrotic effects via the transforming growth factor-β (TGF-β)/Smad signaling axis. To test this, kidney damage-resistant mice (C57BL/6) received tacrolimus (10 mg/kg) or vehicle for 21 days. Renal damage markers and signaling mediators were assessed. To investigate their role in renal damage, mouse renal fibroblasts were exposed to tacrolimus (1 nM) or vehicle for 24 h. Morphological and functional changes in addition to downstream signaling events were assessed. Tacrolimus-treated kidneys displayed evidence of renal fibrosis. Moreover, α-smooth muscle actin expression was significantly increased, suggesting the presence of fibroblast activation. TGF-β receptor activation and downstream Smad2/3 signaling were also upregulated. Consistent with in vivo findings, tacrolimus-treated renal fibroblasts displayed a phenotypic switch known as fibroblast-to-myofibroblast transition (FMT), as α-smooth muscle actin, actin stress fibers, cell motility, and collagen type IV expression were significantly increased. These findings were accompanied by concomitant induction of TGF-β signaling. Pharmacological inhibition of the downstream TGF-β effector Smad3 attenuated tacrolimus-induced phenotypic changes. Collectively, these findings suggest that1) tacrolimus inhibits the calcineurin/nuclear factor of activated T cells axis while inducing TGF-β1 ligand secretion and receptor activation in renal fibroblasts;2) aberrant TGF-β receptor activation stimulates Smad-mediated production of myofibroblast markers, notable features of FMT; and3) FMT contributes to extracellular matrix expansion in tacrolimus-induced renal fibrosis. These results incorporate renal fibroblasts into the growing list of CNI-targeted cell types and identify renal FMT as a process mediated via a TGF-β-dependent mechanism.NEW & NOTEWORTHYRenal fibrosis, a detrimental feature of irreversible kidney damage, remains a sinister consequence of long-term calcineurin inhibitor (CNI) immunosuppressive therapy. Our study not only incorporates renal fibroblasts into the growing list of cell types negatively impacted by CNIs but also identifies renal fibroblast-to-myofibroblast transition as a process mediated via a TGF-β-dependent mechanism. This insight will direct future studies investigating the feasibility of inhibiting TGF-β signaling to maintain CNI-mediated immunosuppression while ultimately preserving kidney health.
登录
查看更多内容
幼年关节炎中的 HLA 抗原
DOI：
--
发表时间：
1983
期刊：
影响因子：
--
作者：
Ø. Førre;J. Dobloug;H. Hoyeraal;E. Thorsby
通讯作者：
E. Thorsby
HLA-DQ α 多态性：寡核苷酸探针表征第一和第二结构域对电泳变体的贡献。
影响因子：
2.7
作者：
Nepom,BS;Schwarz,DA;Johnston,JV;Radka,SF
通讯作者：
Radka,SF
患有幼年关节炎的黑人和白人患者的 HLA 抗原：与类风湿因子、隐藏类风湿因子、抗核抗体和免疫复合物水平的关联。
DOI：
--
发表时间：
1984
期刊：
The Journal of rheumatology
影响因子：
--
作者：
Moore,TL;Oldfather,JW;Osborn,TG;Dorner,RW;Sheridan,PW;Weiss,TD;Zuckner,J;Rodey,GE
通讯作者：
Rodey,GE
人类和鼠 T 细胞受体 β 基因家族的保守组织
影响因子：
64.8
作者：
E. Lai;P. Concannon;L. Hood
通讯作者：
L. Hood
多发性硬化症的易感位点与 T 细胞受体 β 链复合物有关
影响因子：
64.5
作者：
E. Seboun;M. Robinson;T. Doolittle;T. Ciulla;T. Kindt;S. Hauser
通讯作者：
S. Hauser