Department of Nephrology, West China Hospital, Sichuan University, Chengdu, China.
Animal Experimental Center, West China Hospital, Sichuan University, Chengdu, China.
Int Immunopharmacol. 2024 Feb 15;128:111561. doi: 10.1016/j.intimp.2024.111561. Epub 2024 Jan 22.
Peritoneal fibrosis is a severe clinical complication associated with peritoneal dialysis (PD) and impacts its efficacy and patient outcomes. The process of mesothelial-mesenchymal transition (MMT) in peritoneal mesothelial cells plays a pivotal role in fibrogenesis, whereas metabolic reprogramming, characterized by excessive glycolysis, is essential in MMT development. No reliable therapies are available despite substantial progress made in understanding the mechanisms underlying peritoneal fibrosis. Protective effect of omega-3 polyunsaturated fatty acids (ω3 PUFAs) has been described in PD-induced peritoneal fibrosis, although the detailed mechanisms remain unknown. It is known that ω3 PUFAs bind to and activate the free fatty acid receptor 4 (FFAR4). However, the expression and role of FFAR4 in the peritoneum have not been investigated. Thus, we hypothesized that ω3 PUFAs would alleviate peritoneal fibrosis by inhibiting hyperglycolysis and MMT through FFAR4 activation. First, we determined FFAR4 expression in peritoneal mesothelium in humans and mice. FFAR4 expression was abnormally decreased in patients on PD and mice and HMrSV5 mesothelial cells exposed to PD fluid (PDF); this change was restored by the ω3 PUFAs (EPA and DHA). ω3 PUFAs significantly inhibited peritoneal hyperglycolysis, MMT, and fibrosis in PDF-treated mice and HMrSV5 mesothelial cells; these changes induced by ω3 PUFAs were blunted by treatment with the FFAR4 antagonist AH7614 and FFAR4 siRNA. Additionally, ω3 PUFAs induced FFAR4, Ca/calmodulin-dependent protein kinase kinase β (CaMKKβ), and AMPK and suppressed mTOR, leading to the inhibition of hyperglycolysis, demonstrating that the ω3 PUFAs-mediated FFAR4 activation ameliorated peritoneal fibrosis by inhibiting hyperglycolysis and MMT via CaMKKβ/AMPK/mTOR signaling. As natural FFAR4 agonists, ω3 PUFAs may be considered for the treatment of PD-associated peritoneal fibrosis.
腹膜纤维化是腹膜透析（PD）相关的一种严重临床并发症，会影响 PD 的疗效和患者预后。腹膜间皮细胞的上皮间质转化（EMT）过程在纤维化发生中起关键作用，而以过度糖酵解为特征的代谢重编程是 EMT 发展所必需的。尽管在理解腹膜纤维化的机制方面取得了很大进展，但仍然没有可靠的治疗方法。ω-3 多不饱和脂肪酸（ω3 PUFAs）在 PD 诱导的腹膜纤维化中具有保护作用，尽管其详细机制尚不清楚。已知 ω3 PUFAs 与游离脂肪酸受体 4（FFAR4）结合并激活它。然而，FFAR4 在腹膜中的表达和作用尚未被研究过。因此，我们假设 ω3 PUFAs 通过激活 FFAR4 来抑制高糖酵解和 EMT，从而减轻腹膜纤维化。首先，我们确定了人类和小鼠腹膜间皮中 FFAR4 的表达。在 PD 患者和 PD 液（PDF）处理的小鼠和 HMrSV5 间皮细胞中，FFAR4 的表达异常降低；这种变化可以通过 ω3 PUFAs（EPA 和 DHA）恢复。ω3 PUFAs 显著抑制 PDF 处理的小鼠和 HMrSV5 间皮细胞中的腹膜高糖酵解、EMT 和纤维化；ω3 PUFAs 诱导的这些变化可以被 FFAR4 拮抗剂 AH7614 和 FFAR4 siRNA 减弱。此外，ω3 PUFAs 诱导 FFAR4、钙/钙调蛋白依赖性蛋白激酶激酶 β（CaMKKβ）和 AMPK，并抑制 mTOR，导致高糖酵解抑制，表明 ω3 PUFAs 通过 CaMKKβ/AMPK/mTOR 信号通路抑制 EMT 和高糖酵解来改善腹膜纤维化。作为天然的 FFAR4 激动剂，ω3 PUFAs 可能被考虑用于治疗 PD 相关的腹膜纤维化。
