Division of Nephrology, Nanfang Hospital, Southern Medical University, State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Nephrology, 1838 North Guangzhou Ave, Guangzhou 510515, P. R. China.
Division of Nephrology, The Second Affiliated Hospital of Guangzhou Medical University, Changgang East Road, Guangzhou 510260, P.R. China.
Theranostics. 2023 Aug 15;13(13):4482-4496. doi: 10.7150/thno.84921. eCollection 2023.
Peritoneal dialysis (PD) is limited by gradual fibrotic remodeling in the peritoneum, a process involving profibrotic response of mesothelial cells. However, the role of fatty acid oxidation (FAO) and carnitine palmitoyltransferase 1A (CPT1A) in this process remains unexplored. FAO and CPT1A expression were characterized in mesothelial cells from patients on long-term PD and from a mouse model of PD using multiple experimental methods, including single-cell sequencing, seahorse assay, real-time quantitative PCR, Western blot, and immunofluorescence staining. Overexpression of CPT1A was achieved in a human mesothelial cell line and in primary mouse mesothelial cells. Finally, genetic and pharmacological manipulations of CPT1A were performed in a mouse model of PD. Herein, FAO and CPT1A expression were reduced in mesothelial cells from patients on long-term PD, which negatively correlated with expression of fibrogenic markers in these cells. This was corroborated in PD mice, as well as in mouse and human mesothelial cells incubated with transforming growth factor (TGF) β1. CPT1A overexpression in mesothelial cells, which prevented TGFβ1-induced suppression of mitochondrial respiration, restored cellular ATP levels and downregulated the expression of fibrogenic markers. Furthermore, restoration of FAO by overexpressing CPT1A in PD mice reversed profibrotic phenotype in mesothelial cells and reduced fibrotic lesions in the peritoneum. Treatment with the CPT1A activator C75 induced similar therapeutic benefit in PD mice. In contrast, inhibition of FAO with a CPT1 inhibitor caused more severe fibrosis in PD mice. A defective FAO is responsible for the profibrotic response of mesothelial cells and thus the peritoneal fibrogenesis. This aberrant metabolic state could be improved by modulating CPT1A in mesothelial cells, suggesting FAO enhancement in mesothelial cells is a potential treatment of peritoneal fibrosis.
腹膜透析（PD）受到腹膜逐渐纤维化重塑的限制，这一过程涉及间皮细胞的促纤维化反应。然而，脂肪酸氧化（FAO）和肉毒碱棕榈酰转移酶 1A（CPT1A）在这一过程中的作用仍未被探索。采用多种实验方法，包括单细胞测序、 Seahorse 检测、实时定量 PCR、Western blot 和免疫荧光染色，对长期 PD 患者和 PD 小鼠模型中的间皮细胞进行了 FAO 和 CPT1A 表达特征的研究。在人源间皮细胞系和原代鼠间皮细胞中实现了 CPT1A 的过表达。最后，在 PD 小鼠模型中进行了 CPT1A 的基因和药物操作。在此，长期 PD 患者间皮细胞中的 FAO 和 CPT1A 表达减少，这与这些细胞中纤维生成标记物的表达呈负相关。这在 PD 小鼠以及用转化生长因子（TGF）β1孵育的鼠源和人源间皮细胞中得到了证实。CPT1A 在间皮细胞中的过表达，可防止 TGFβ1 诱导的线粒体呼吸抑制，恢复细胞内 ATP 水平，并下调纤维生成标记物的表达。此外，在 PD 小鼠中通过过表达 CPT1A 恢复 FAO 可逆转间皮细胞的促纤维化表型，并减少腹膜中的纤维化病变。在 PD 小鼠中用 CPT1A 激活剂 C75 治疗可产生类似的治疗效果。相比之下，用 CPT1 抑制剂抑制 FAO 会导致 PD 小鼠的纤维化更严重。FAO 的缺陷导致间皮细胞的促纤维化反应，从而导致腹膜纤维化。通过调节间皮细胞中的 CPT1A 可以改善这种异常代谢状态，这表明增强间皮细胞中的 FAO 是治疗腹膜纤维化的一种潜在方法。
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