Department of Pharmacy, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, PR China.
Department of Pharmacy, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, PR China; National Clinical Research Center for Geriatric Disorders (XIANGYA), Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China.
Eur J Pharmacol. 2021 Feb 5;892:173755. doi: 10.1016/j.ejphar.2020.173755. Epub 2020 Nov 25.
CTRP6, a newly identified adiponectin analogue, has been shown to be involved in inflammation, diabetes and cardiovascular diseases. Recently, increasing evidence has shown that CTRP6 plays a critical role in fibrotic diseases, such as myocardial fibrosis and skin fibrosis. FAO, an important energy source for kidney proximal tubular cells, also participates in the process of fibrosis. Therefore, our study aimed to investigate the effect of CTRP6 on mediating FAO in kidney fibrosis and the underlying associated mechanism. Firstly, the activity of CTRP6 and the key enzymes of FAO (CPT1A, ACOX1) were tested in vivo and vitro. Next, the regulatory effect of CTRP6/AMPK on FAO was accessed in animal models and in cell lines. Additionally, we explored the effect of exogenous recombinant CTRP6 on renal tubular epithelial cell differentiation. Decreased CTRP6 and p-AMPK were detected in UUO-induced kidney fibrosis and in TGF-β1-treated HK-2 cells. We also observed that defective FAO occurred during kidney fibrosis. Moreover, the human CTRP6 peptide could inhibit the ECM deposition and promote the phosphorylation of AMPK by promoting FAO. However, the inhibitory effects of CTRP6 on TGF-β1-induced ECM deposition and the protective effects of CTRP6 on FAO could be abolished by compound C, a selective inhibitor of AMPK. Compound C also reversed the CTRP6-mediated upregulation of p-AMPK. The mediation of FAO by CTRP6 plays a key role in kidney fibrosis by regulating TGF-β1-induced renal tubular epithelial cell differentiation by promoting FAO, which is mediated via AMPK activation.
CTRP6，一种新发现的脂联素类似物，已被证明参与炎症、糖尿病和心血管疾病。最近，越来越多的证据表明，CTRP6 在纤维化疾病中发挥着关键作用，如心肌纤维化和皮肤纤维化。FAO，肾近端小管细胞的重要能量来源，也参与纤维化过程。因此，我们的研究旨在探讨 CTRP6 介导肾纤维化中 FAO 的作用及其潜在的相关机制。首先，在体内和体外检测了 CTRP6 的活性和 FAO 的关键酶（CPT1A、ACOX1）。接下来，在动物模型和细胞系中研究了 CTRP6/AMPK 对 FAO 的调节作用。此外，我们还探讨了外源性重组 CTRP6 对肾小管上皮细胞分化的影响。UUO 诱导的肾纤维化和 TGF-β1 处理的 HK-2 细胞中检测到 CTRP6 和 p-AMPK 减少。我们还观察到肾纤维化过程中发生了 FAO 缺陷。此外，人 CTRP6 肽可通过促进 FAO 抑制 ECM 沉积并促进 AMPK 的磷酸化，从而抑制 ECM 沉积。然而，CTRP6 对 TGF-β1 诱导的 ECM 沉积的抑制作用以及 CTRP6 对 FAO 的保护作用可被 AMPK 的选择性抑制剂化合物 C 所消除。化合物 C 还逆转了 CTRP6 介导的 p-AMPK 上调。CTRP6 通过促进 FAO 调节 TGF-β1 诱导的肾小管上皮细胞分化，在肾纤维化中发挥关键作用，其通过 AMPK 激活介导 FAO。
