Kif26b contributes to the progression of interstitial fibrosis via migration and myofibroblast differentiation in renal fibroblast
Kif26b contributes to the progression of interstitial fibrosis via migration and myofibroblast differentiation in renal fibroblast
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DOI：
10.1096/fj.202200355r
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发表时间：
2022-11-01
期刊：
影响因子：
4.8
通讯作者：
Wada，Takashi
中科院分区：
文献类型：
--
作者：
Yamamura，Yuta;Iwata，Yasunori;Wada，Takashi
驱动蛋白家族成员26 b（Kif 26 b）是肾脏发育所必需的，其在小鼠中的缺失导致肾脏发育不全。然而，这种基因在成人环境中的作用仍然难以捉摸。因此，本研究旨在探讨Kif 26在肾纤维化进展中的作用。使用Kif 26 b杂合小鼠和野生型小鼠建立腺嘌呤给药肾纤维化模型。并对肾纤维化的发生机制进行了探讨。采用体外培养的肾成纤维细胞模型研究Kif 26 b的潜在通路和功能，并通过腺嘌呤干预保护Kif 26 b杂合子小鼠免于肾纤维化。Kif 26 b杂合子小鼠肾脏结缔组织生长因子（CTGF）表达和肌成纤维细胞积聚减少。在Kif 26 b杂合子小鼠中，与Kif 26 b蛋白C末端结合的非肌肉肌球蛋白重链II（NMHCII）的表达也受到抑制。体外研究显示，通过转染靶向肾成纤维细胞（RFB）Kif 26的siRNA，CTGF、α-平滑肌肌动蛋白和肌球蛋白重链9（Myh 9）的表达降低。用Kif 26 b表达载体转染的RFBs，这些基因的表达比未转染的细胞更高。最后，Kif 26 b抑制和NMHCII阻断导致肾成纤维细胞迁移和胶原凝胶收缩能力降低。总之，在肾纤维化模型中，Kif 26 b通过Myh 9的迁移和肌成纤维细胞分化促进间质纤维化的进展。适时阻断该通路可能是治疗肾纤维化的一种方法。
Kinesin family member 26b(Kif26b) is essential for kidney development, and its deletion in mice leads to kidney agenesis. However, the roles of this gene in adult settings remain elusive. Thus, this study aims to investigate the role ofKif26bin the progression of renal fibrosis. A renal fibrosis model with adenine administration usingKif26bheterozygous mice and wild‐type mice was established. Renal fibrosis and the underlying mechanism were investigated. The underlying pathways and functions ofKif26bwere evaluated in an in vitro model using primary renal fibroblasts.Kif26bheterozygous mice were protected from renal fibrosis with adenine administration. Renal expressions of connective tissue growth factor (CTGF) and myofibroblast accumulation were reduced inKif26bheterozygous mice. The expression of nonmuscle myosin heavy chain II (NMHCII), which binds to the C‐terminus of Kif26b protein, was also suppressed inKif26bheterozygous mice. The in vitro study revealed reduced expressions ofCTGF,α‐smooth muscle actin, andmyosin heavy chain 9(Myh9) via transfection with siRNAs targetingKif26bin renal fibroblasts (RFB). RFBs, which were transfected by the expression vector ofKif26b, demonstrated higher expressions of these genes than non‐transfected cells. Finally,Kif26bsuppression and NMHCII blockage led to reduced abilities of migration and collagen gel contraction in renal fibroblasts. Taken together,Kif26bcontributes to the progression of interstitial fibrosis via migration and myofibroblast differentiation through Myh9 in the renal fibrosis model. Blockage of this pathway at appropriate timing might be a therapeutic approach for renal fibrosis.