Inhibition of Fatty Acid-Binding Protein 4 Attenuated Kidney Fibrosis by Mediating Macrophage-to-Myofibroblast Transition.
Inhibition of Fatty Acid-Binding Protein 4 Attenuated Kidney Fibrosis by Mediating Macrophage-to-Myofibroblast Transition.
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DOI：
10.3389/fimmu.2020.566535
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发表时间：
2020
影响因子：
7.3
通讯作者：
Fu P
中科院分区：
文献类型：
--
作者：
Feng Y;Guo F;Xia Z;Liu J;Mai H;Liang Y;Zhu G;Li Y;Bai L;Li L;Huang R;Shi M;Ma L;Fu P
巨噬细胞向肌成纤维细胞转化（MMT）过程是肾间质纤维化（RIF）的重要途径。脂肪酸结合蛋白4（FABP 4）通过促进梗阻性肾病的炎症反应而恶化RIF。然而，FABP 4在纤维化肾病中的临床意义仍有待确定，并且对MMT中的FABP 4信号传导知之甚少。收集慢性肾脏病患者的活检标本和FABP 4缺陷小鼠或FABP 4治疗小鼠的单侧输尿管梗阻（UUO）的肾脏，以研究FABP 4介导的RIF的MMT。我们进行了肾脏RNA-seq转录组和TGF-β1诱导的骨髓源性巨噬细胞（BMDM）测定，以确定FABP 4的机制。我们发现FABP 4表达与活检标本和UUO小鼠损伤肾脏中的RIF相关，其中FABP 4与MMT细胞共表达。在UUO小鼠中，FABP 4缺陷和高选择性FABP 4抑制剂BMS 309403治疗均抑制RIF。FABP 4消融还减弱了UUO诱导的MMT细胞数量和血清淀粉样蛋白A1（Saa 1）表达。siRNA介导的Saa 1基因敲低降低了体外MMT细胞的数量。总之，FABP 4是通过介导MMT导致RIF的重要因素，并且FABP 4的遗传/药理学抑制提供了治疗肾纤维化的新方法。
The macrophage-to-myofibroblast transition (MMT) process is an important pathway that contributing to renal interstitial fibrosis (RIF). Fatty acid–binding protein 4 (FABP4) deteriorated RIF via promoting inflammation in obstructive nephropathy. However, the clinical significance of FABP4 in fibrotic kidney disease remains to be determined and little is known of the FABP4 signaling in MMT. Biopsy specimens of chronic kidney disease patients and kidneys subjected to unilateral ureteral obstruction (UUO) of FABP4-deficient mice or FABP4 inhibitor-treated mice were collected for the investigation of FABP4 mediating MMT of RIF. We conducted kidney RNA-seq transcriptomes and TGF-β1-induced bone marrow–derived macrophage (BMDM) assays to determine the mechanisms of FABP4. We found that FABP4 expression correlated with RIF in biopsy specimens and the injured kidneys of UUO mice where FABP4 was co-expressed with MMT cells. In UUO mice, FABP4 deficiency and a highly selective FABP4 inhibitor BMS309403 treatment both suppressed RIF. FABP4 ablation also attenuated the UUO-induced number of MMT cells and serum amyloid A1 (Saa1) expression. The siRNA-mediated Saa1 knockdown decreased the number of MMT cells in vitro. In conclusion, FABP4 is an important factor contributing to RIF by mediating MMT, and genetic/pharmacological inhibition of FABP4 provides a novel approach for the treatment of kidney fibrosis.
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影响因子：
5.5
作者：
Nikolic-Paterson DJ;Wang S;Lan HY
通讯作者：
Lan HY
影响因子：
--
作者：
Wang S;Meng XM;Ng YY;Ma FY;Zhou S;Zhang Y;Yang C;Huang XR;Xiao J;Wang YY;Ka SM;Tang YJ;Chung AC;To KF;Nikolic-Paterson DJ;Lan HY
通讯作者：
Lan HY
影响因子：
19.6
作者：
Tang, Patrick Ming-Kuen;Zhou, Shuang;Lan, Hui-Yao
通讯作者：
Lan, Hui-Yao
影响因子：
3.7
作者：
Hill NR;Fatoba ST;Oke JL;Hirst JA;O'Callaghan CA;Lasserson DS;Hobbs FD
通讯作者：
Hobbs FD
影响因子：
--
作者：
Tanaka, Marenao;Furuhashi, Masato;Miura, Tetsuji
通讯作者：
Miura, Tetsuji