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转化,导致肾脏纤维化。

IF 3.7 2区 医学 Q1 PHYSIOLOGY American Journal of Physiology-renal Physiology Pub Date : 2023-05-01 Epub Date: 2023-03-16 DOI:10.1152/ajprenal.00226.2022
Adaku C Ume, Tara Y Wenegieme, Jennae N Shelby, Chiagozie D B Paul-Onyia, Aston M J Waite, John K Kamau, Danielle N Adams, Keiichiro Susuki, Eric S Bennett, Hongmei Ren, Clintoria R Williams
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引用次数: 0

摘要

免疫抑制剂钙调蛋白抑制剂(CNIs)的使用受到不可逆肾损伤的限制,肾纤维化是其显著特征。钙调蛋白抑制剂会直接损害多种肾细胞类型。鉴于肾脏细胞群的多样性,更多的靶细胞类型和信号传导机制值得进一步研究。我们假设成纤维细胞通过转化生长因子-β(TGF-β)/Smad 信号轴促进 CNI 诱导的肾脏纤维化并传播异型坏死效应。为了验证这一点,耐肾损伤小鼠(C57BL/6)接受他克莫司(10 毫克/千克)或载体治疗 21 天。对肾损伤标志物和信号介质进行了评估。为了研究它们在肾损伤中的作用,小鼠肾脏成纤维细胞暴露于他克莫司(1 nM)或载体中 24 小时。经他克莫司处理的肾脏显示出肾脏纤维化的迹象。此外,α-平滑肌肌动蛋白表达明显增加,表明存在成纤维细胞活化。TGF-β 受体活化和下游 Smad2/3 信号也被上调。与体内研究结果一致,他克莫司处理的肾成纤维细胞表现出一种表型转换,即成纤维细胞向肌成纤维细胞的转变(FMT),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型胶原表达均明显增加。这些发现伴随着 TGF-β 信号的诱导。药物抑制 TGF-β 的下游效应因子 Smad3 可减轻他克莫司诱导的表型变化。总之,这些研究结果表明:1)他克莫司抑制了钙调素系/活化 T 细胞核因子轴,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记物的产生,这是 FMT 的显著特征;3)FMT 在他克莫司诱导的肾纤维化中有助于细胞外基质扩张。这些结果将肾成纤维细胞纳入了越来越多的 CNI 靶向细胞类型中,并确定肾脏 FMT 是一个通过 TGF-β 依赖性机制介导的过程。我们的研究不仅将肾成纤维细胞纳入了受 CNIs 负面影响的日益增多的细胞类型中,而且还确定了肾成纤维细胞向肌成纤维细胞的转化是一个通过 TGF-β 依赖性机制介导的过程。这一洞察力将指导未来的研究,调查抑制 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。
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Tacrolimus induces fibroblast-to-myofibroblast transition via a TGF-β-dependent mechanism to contribute to renal fibrosis.

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 that 1) 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; and 3) 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 & NOTEWORTHY Renal 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.

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来源期刊
CiteScore
8.40
自引率
7.10%
发文量
154
审稿时长
2-4 weeks
期刊介绍: The American Journal of Physiology - Renal Physiology publishes original manuscripts on timely topics in both basic science and clinical research. Published articles address a broad range of subjects relating to the kidney and urinary tract, and may involve human or animal models, individual cell types, and isolated membrane systems. Also covered are the pathophysiological basis of renal disease processes, regulation of body fluids, and clinical research that provides mechanistic insights. Studies of renal function may be conducted using a wide range of approaches, such as biochemistry, immunology, genetics, mathematical modeling, molecular biology, as well as physiological and clinical methodologies.
期刊最新文献
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