Zhao Huishou, Sun Dan, Wang Shan, Liu Yi, Zhao Xiaojuan, Tian Wenqi, Dou Xiuhong, Liu Jilong, Xu Jinyang, Peng Lu, Sun Shiren, Xia Yunlong, Xu Xiaoming, Wang Cheng, Wang Di, Zhao Guohong, Wang Xin, Weng Huanze, Ding Fengyue, Xing Pingping, Zhang Fuyang, Liu Shiyu, Yan Wenjun, Tao Ling
Department of Cardiology, Xijing Hospital, Fourth Military Medical University, Xi'an, China.
Department of Gynecology and Obstetrics, Tangdu Hospital, Fourth Military Medical University, Xi'an, China.
Nat Commun. 2025 Aug 25;16(1):7846. doi: 10.1038/s41467-025-62890-9.
Approximately 30-40% of patients with diabetes develop diabetic kidney disease (DKD). Identifying decisive factors for DKD initiation is crucial. Here, we observed that glomerular podocytes in male and female patients with DKD and db/db mice specifically displayed BCAA catabolic defects. Podocyte-specific PP2Cm (a key BCAA catabolism enzyme) knockout or exogenous BCAA supplementation induced DKD phenotypes including podocyte dysfunction/apoptosis, glomerular pathology, and proteinuria in high-fat (HF)-diet-fed male mice. Mechanistically, BCAAs promoted PKM2 depolymerization and inactivation in podocytes. Depolymerized PKM2 suppressed glucose oxidative phosphorylation (OXPHOS), diverting glucose metabolism towards serine biosynthesis and folate metabolism. Depolymerized PKM2 is also co-transported with DDIT3 into the nucleus, acting as a co-transcriptional factor to enhance DDIT3 transcriptional activity, which promotes Chac1 and Trib3 expression and directly inducing podocyte apoptosis. Thus, BCAA catabolic defects may be one of the missing factors that determine DKD initiation. Targeting BCAA catabolism or PKM2 activation is a promising DKD prevention strategy.
约30%-40%的糖尿病患者会发展为糖尿病肾病（DKD）。确定DKD发病的决定性因素至关重要。在此，我们观察到DKD男性和女性患者以及db/db小鼠的肾小球足细胞特异性表现出支链氨基酸（BCAA）分解代谢缺陷。足细胞特异性敲除PP2Cm（一种关键的BCAA分解代谢酶）或补充外源性BCAA会在高脂（HF）饮食喂养的雄性小鼠中诱导出DKD表型，包括足细胞功能障碍/凋亡、肾小球病理改变和蛋白尿。从机制上讲，BCAAs促进足细胞中丙酮酸激酶M2（PKM2）解聚和失活。解聚的PKM2抑制葡萄糖氧化磷酸化（OXPHOS），使葡萄糖代谢转向丝氨酸生物合成和叶酸代谢。解聚的PKM2还与DNA损伤诱导转录因子3（DDIT3）共同转运到细胞核中，作为一种共转录因子增强DDIT3的转录活性，从而促进含巯基抗氧化蛋白1（Chac1）和 Tribbles 同源物 3（Trib3）的表达并直接诱导足细胞凋亡。因此，BCAA分解代谢缺陷可能是决定DKD发病的缺失因素之一。针对BCAA分解代谢或PKM2激活是一种有前景的DKD预防策略。
