Pre-emptive pharmacological inhibition of fatty acid-binding protein 4 attenuates kidney fibrosis by reprogramming tubular lipid metabolism.
Pre-emptive pharmacological inhibition of fatty acid-binding protein 4 attenuates kidney fibrosis by reprogramming tubular lipid metabolism.
复制标题
脂肪酸结合蛋白 4 的先发性药理学抑制通过重新编程肾小管脂质代谢来减轻肾纤维化
DOI：
10.1038/s41419-021-03850-1
复制
发表时间：
2021-06-03
影响因子：
9
通讯作者：
Gao H
中科院分区：
文献类型：
--
作者：
Chen Y;Dai Y;Song K;Huang Y;Zhang L;Zhang C;Yan Q;Gao H
肾纤维化是慢性肾病（CKD）进展的标志，由肾小管损伤和脂质代谢失调引起。遗传废除脂肪酸结合蛋白4（FABP 4）是一种重要的脂质转运蛋白，已被报道可抑制肾间质纤维化。然而，化学抑制FABP 4在纤维化肾脏中的作用和潜在机制尚未得到充分证实。在这里，我们研究了FABP 4抑制剂BMS 309403对肾小管上皮细胞（TEC）脂质代谢和肾纤维化进展的影响。FABP 4的表达在肾纤维化过程中显著升高，并伴随着TECs内脂滴的积聚。用BMS 309403处理减轻了TEC的脂质沉积，以及单侧输尿管梗阻（UUO）参与的小鼠和TGF-β诱导的TEC中的间质纤维化反应。此外，BMS 309403给药通过调节过氧化物酶体增殖物激活受体γ（PPARγ）和恢复脂肪酸氧化（FAO）相关酶活性来增强TEC中的FAO;此外，BMS 309403显著降低纤维化肾脏中的细胞脂毒性，如内质网（ER）应激和细胞凋亡。综上所述，我们的结果表明，通过BMS 309403对FABP 4的预先药理学抑制重新平衡TEC中的异常脂质代谢并减弱肾纤维化的进展，因此可能具有治疗纤维化肾病的治疗潜力。
Kidney fibrosis is a hallmark of chronic kidney disease (CKD) progression that is caused by tubular injury and dysregulated lipid metabolism. Genetic abolition fatty acid-binding protein 4 (FABP4), a key lipid transporter, has been reported to suppress kidney interstitial fibrosis. However, the role and underlying mechanism of chemical inhibition of FABP4 in fibrotic kidney have not been well-documented. Here, we examined preemptive the effect of a FABP4 inhibitor, BMS309403, on lipid metabolism of tubular epithelial cells (TECs) and progression of kidney fibrosis. The expression of FABP4 was significantly elevated, concomitated with the accumulation of lipid droplets in TECs during kidney fibrosis. Treatment with BMS309403 alleviated lipid deposition of TECs, as well as interstitial fibrotic responses both in unilateral ureteral obstruction (UUO)-engaged mice and TGF-β-induced TECs. Moreover, BMS309403 administration enhanced fatty acid oxidation (FAO) in TECs by regulating peroxisome proliferator-activated receptor γ (PPARγ) and restoring FAO-related enzyme activities; In addition, BMS309403 markedly reduced cell lipotoxicity, such as endoplasmic reticulum (ER) stress and apoptosis in fibrotic kidney. Taken together, our results suggest that preemptive pharmacological inhibition of FABP4 by BMS309403 rebalances abnormal lipid metabolism in TECs and attenuates the progression of kidney fibrosis, thus may hold therapeutic potential for the treatment of fibrotic kidney diseases.
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DOI：
10.4137/cmc.s17067
发表时间：
2014
期刊：
Clinical Medicine Insights. Cardiology
影响因子：
--
作者：
Furuhashi M;Saitoh S;Shimamoto K;Miura T
通讯作者：
Miura T
FATP2 介导的肾小管脂质代谢重编程参与肾纤维化
影响因子：
9
作者：
Chen Y;Yan Q;Lv M;Song K;Dai Y;Huang Y;Zhang L;Zhang C;Gao H
通讯作者：
Gao H
影响因子：
19.6
作者：
Li, Z;Rodríguez-Iturbe, B;Vaziri, ND
通讯作者：
Vaziri, ND
影响因子：
7.3
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
通讯作者：
Fu P
影响因子：
7.3
作者：
Lee, Mary Y. K.;Li, Huiying;Vanhoutte, Paul M.
通讯作者：
Vanhoutte, Paul M.