Wu Yen-Wen, Chen Jaw-Wen, Lin Liang-Yu, Huang Jih-Hsin, Chang Chia-Chi, Chang Ting-Ting
Division of Cardiology, Cardiovascular Medical Center, Far Eastern Memorial Hospital, New Taipei City, Taiwan; School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan; Graduate Institute of Medicine, Yuan Ze University, Taoyuan City, Taiwan.
School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan; Department and Institute of Pharmacology, National Yang Ming Chiao Tung University, Taipei, Taiwan; Division of Cardiology and Cardiovascular Research Center, Taipei Medical University Hospital, Taipei, Taiwan; Cardiovascular Research Center, National Yang Ming Chiao Tung University, Taipei, Taiwan; Faucalty of Medicine, Colleague of Medicine, Taipei Medical University, Taipei, Taiwan.
Biochem Pharmacol. 2025 Jun;236:116899. doi: 10.1016/j.bcp.2025.116899. Epub 2025 Mar 31.
Diabetic kidney disease (DKD) is a common complication associated with diabetes mellitus (DM). Fatty acid binding protein (FABP) 4 is a small cytoplasmic lipid chaperone that is up-regulated in DKD. This study aims to elucidate whether FABP4 could play a critical role and serve as a potential therapeutic target in DKD. In a clinical observational study, DKD patients and non-DKD subjects were enrolled and their circulating FABP4 levels were analyzed. The renoprotective effects of FABP4 inhibition were evaluated in vivo and in vitro using db/db mice and high glucose-induced human kidney proximal tubular epithelial cells, respectively. Circulating FABP4 was up-regulated in clinical patients and mice with DKD. The inhibition of FABP4 with an orally administered inhibitor ameliorated insulin resistance and renal function in DKD mice, as evidenced by decreased systemic inflammation as well as improved serum creatinine and BUN levels, kidney weight to body weight ratio, and urine albumin-to-creatinine ratio. FABP4 inhibition also reduced renal tubular injury, fibrosis, and macrophage infiltration in DKD mice. Furthermore, FABP4 inhibition down-regulated the inflammatory, fibrotic, and cell apoptotic protein expressions in kidney tissues of DKD mice and in high glucose-induced renal proximal tubular epithelial cells. On the other hand, FABP4 directly caused cellular inflammation, fibrosis, and apoptosis via NF-κB activation in renal tubular epithelial cells. Altogether, FABP4 might induce renal inflammation and renal tubular epithelial cell damage during the pathological process of DKD. Future clinical studies may be required to validate whether FABP4 inhibition can serve as a novel therapeutic strategy for DKD.
糖尿病肾病（DKD）是糖尿病（DM）常见的并发症。脂肪酸结合蛋白（FABP）4是一种小的细胞质脂质伴侣蛋白，在DKD中表达上调。本研究旨在阐明FABP4在DKD中是否发挥关键作用并作为潜在的治疗靶点。在一项临床观察性研究中，纳入了DKD患者和非DKD受试者，并分析了他们循环中的FABP4水平。分别使用db/db小鼠和高糖诱导的人肾近端小管上皮细胞在体内和体外评估FABP4抑制的肾脏保护作用。临床患者和DKD小鼠循环中的FABP4上调。口服抑制剂抑制FABP4可改善DKD小鼠的胰岛素抵抗和肾功能，全身炎症减轻以及血清肌酐、尿素氮水平、肾重与体重比和尿白蛋白与肌酐比值改善证明了这一点。FABP4抑制还减少了DKD小鼠的肾小管损伤、纤维化和巨噬细胞浸润。此外，FABP4抑制下调了DKD小鼠肾组织和高糖诱导的肾近端小管上皮细胞中炎症、纤维化和细胞凋亡蛋白的表达。另一方面，FABP4通过激活肾小管上皮细胞中的NF-κB直接导致细胞炎症、纤维化和凋亡。总之，FABP4可能在DKD的病理过程中诱导肾脏炎症和肾小管上皮细胞损伤。未来可能需要进行临床研究来验证FABP4抑制是否可作为DKD的一种新的治疗策略。
