Yang Chieh-Lun, Yang Wen-Hsing, Gao Zhanhui, Liu Sijia, Wei Wei, Duan Fenfen, Chen Haiyan, Lou Jizhuang
Department of Nephrology, Nanjing Benq Medical Center, The Affiliated Benq Hospital of Nanjing Medical University, Jiangsu, No. 71, Hexi Street, Jianye District, Nanjing, 210019, People's Republic of China.
Department of Nursing, New York City College of Technology, Brooklyn, NY, 11201, USA.
Probiotics Antimicrob Proteins. 2025 Mar 20. doi: 10.1007/s12602-025-10516-3.
Chronic kidney disease (CKD) is anticipated to be the fifth cause of global death by 2040 due to the lack of therapeutic tools currently. Lactobacillus paracasei (L. paracasei) isolated from artisanal fermented beverages has been implicated to have health-promoting properties. This study was designed to investigate the effects of L. paracasei on the mechanisms underlying renal injury regulation during CKD. A mouse CKD model was developed by 5/6 nephrectomy, and a fibrotic cell model was induced on human kidney-2 (HK-2) cells using TGF-β1. L. paracasei alleviated renal injury in CKD mice and TGF-β1-induced inflammatory and fibrotic injury in HK-2 cells. L. paracasei exerted in vitro and in vivo benefits by inducing lysine-specific demethylase 3A (KDM3A), and the knockdown of KDM3A markedly attenuated the therapeutic benefit of L. paracasei. KDM3A activated vacuole membrane protein 1 (VMP1) by removing the H3K9me1/2 modification on its promoter. L. paracasei activated autophagy to mitigate renal damage, which was compromised by the autophagy inhibitor 3-MA, allowing renal damage to intensify. Taken together, L. paracasei activates KDM3A expression and further activates VMP1 expression by removing inhibitory H3K9me1/2 modification on the VMP1 promoter to alleviate CKD by activating autophagy in renal tubular epithelial cells.
由于目前缺乏治疗手段，预计到2040年慢性肾脏病（CKD）将成为全球第五大死因。从手工发酵饮料中分离出的副干酪乳杆菌（L. paracasei）被认为具有促进健康的特性。本研究旨在探讨副干酪乳杆菌对CKD期间肾损伤调节机制的影响。通过5/6肾切除术建立小鼠CKD模型，并使用转化生长因子-β1（TGF-β1）在人肾-2（HK-2）细胞上诱导纤维化细胞模型。副干酪乳杆菌减轻了CKD小鼠的肾损伤以及TGF-β1诱导的HK-2细胞炎症和纤维化损伤。副干酪乳杆菌通过诱导赖氨酸特异性去甲基化酶3A（KDM3A）在体外和体内发挥有益作用，而KDM3A的敲低显著减弱了副干酪乳杆菌的治疗效果。KDM3A通过去除液泡膜蛋白1（VMP1）启动子上的H3K9me1/2修饰来激活VMP1。副干酪乳杆菌激活自噬以减轻肾损伤，而自噬抑制剂3-甲基腺嘌呤（3-MA）会损害这种作用，从而使肾损伤加剧。综上所述，副干酪乳杆菌通过去除VMP1启动子上的抑制性H3K9me1/2修饰来激活KDM3A表达并进一步激活VMP1表达，从而通过激活肾小管上皮细胞自噬来减轻CKD。
