Branched-chain amino acids contribute to diabetic kidney disease progression via PKM2-mediated podocyte metabolic reprogramming and apoptosis

Huishou Zhao, Dan Sun, Shan Wang, Yi Liu, Xiaojuan Zhao, Wenqi Tian, Xiuhong Dou, Jilong Liu, Jinyang Xu, Lu Peng, Shiren Sun, Yunlong Xia, Xiaoming Xu, Cheng Wang, Di Wang, Guohong Zhao, Xin Wang, Huanze Weng, Fengyue Ding, Pingping Xing, Fuyang Zhang, Shiyu Liu, Wenjun Yan () and Ling Tao ()
Additional contact information
Huishou Zhao: Fourth Military Medical University
Dan Sun: Fourth Military Medical University
Shan Wang: Fourth Military Medical University
Yi Liu: Fourth Military Medical University
Xiaojuan Zhao: Fourth Military Medical University
Wenqi Tian: Fourth Military Medical University
Xiuhong Dou: Fourth Military Medical University
Jilong Liu: Fourth Military Medical University
Jinyang Xu: Fourth Military Medical University
Lu Peng: Fourth Military Medical University
Shiren Sun: Fourth Military Medical University
Yunlong Xia: Fourth Military Medical University
Xiaoming Xu: Fourth Military Medical University
Cheng Wang: Fourth Military Medical University
Di Wang: Fourth Military Medical University
Guohong Zhao: Fourth Military Medical University
Xin Wang: Fourth Military Medical University
Huanze Weng: Fourth Military Medical University
Fengyue Ding: Fourth Military Medical University
Pingping Xing: Fourth Military Medical University
Fuyang Zhang: Fourth Military Medical University
Shiyu Liu: Fourth Military Medical University
Wenjun Yan: Fourth Military Medical University
Ling Tao: Fourth Military Medical University

Nature Communications, 2025, vol. 16, issue 1, 1-20

Abstract: Abstract 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.

Date: 2025
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DOI: 10.1038/s41467-025-62890-9

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