Prolonged glucagon exposure rewires lipid oxidation and drives diabetic kidney disease progression

Xingfeng Liu, Jingwen Chen, Shengying Gu, Yibing Chen, Ruiping Zhang, Qingce Zang, Ting Li, Hanwen Li, Dejin Lu, Shaocong Hou, Lijuan Kong, Qian Jiang, Caiyi Xing, Wenjia Fan, Yanjun Wan, Jiaqi Zhang, Linyuan Zhu, Chunxiao Ma, Qijin Zhao, Hai Yan, Zeper Abliz, Bing Cui () and Pingping Li ()
Additional contact information
Xingfeng Liu: Chinese Academy of Medical Sciences and Peking Union Medical College
Jingwen Chen: Chinese Academy of Medical Sciences and Peking Union Medical College
Shengying Gu: Chinese Academy of Medical Sciences and Peking Union Medical College
Yibing Chen: Chinese Academy of Medical Sciences and Peking Union Medical College
Ruiping Zhang: Chinese Academy of Medical Sciences and Peking Union Medical College
Qingce Zang: Chinese Academy of Medical Sciences and Peking Union Medical College
Ting Li: Chinese Academy of Medical Sciences and Peking Union Medical College
Hanwen Li: Chinese Academy of Medical Sciences and Peking Union Medical College
Dejin Lu: Chinese Academy of Medical Sciences and Peking Union Medical College
Shaocong Hou: Chinese Academy of Medical Sciences and Peking Union Medical College
Lijuan Kong: Chinese Academy of Medical Sciences and Peking Union Medical College
Qian Jiang: Chinese Academy of Medical Sciences and Peking Union Medical College
Caiyi Xing: Chinese Academy of Medical Sciences and Peking Union Medical College
Wenjia Fan: Chinese Academy of Medical Sciences and Peking Union Medical College
Yanjun Wan: Chinese Academy of Medical Sciences and Peking Union Medical College
Jiaqi Zhang: Chinese Academy of Medical Sciences and Peking Union Medical College
Linyuan Zhu: Chinese Academy of Medical Sciences and Peking Union Medical College
Chunxiao Ma: Chinese Academy of Medical Sciences and Peking Union Medical College
Qijin Zhao: Chinese Academy of Medical Sciences and Peking Union Medical College
Hai Yan: REMD Biotherapeutics Inc.
Zeper Abliz: Chinese Academy of Medical Sciences and Peking Union Medical College
Bing Cui: Chinese Academy of Medical Sciences and Peking Union Medical College
Pingping Li: Chinese Academy of Medical Sciences and Peking Union Medical College

Nature Communications, 2025, vol. 16, issue 1, 1-18

Abstract: Abstract Diabetic kidney disease (DKD) is the leading cause of end-stage kidney disease. Tubular abnormalities may precede glomerular pathology and indicate functional progression of DKD. Here, we find glucagon injection exacerbates lipid accumulation and renal injury, in addition to causing morphological changes in proximal tubules, podocytes, and mitochondria in the early phase of DKD in mice. However, the specific knockdown or knockout of Gcgr in renal tubular epithelial cells almost completely halts DKD development. In contrast to the effect of short-term glucagon stimulation, long-term glucagon exposure leads to the reversal of glucagon action (glucagon reversal) in proximal tubular epithelial cells (PTECs), which is characterized by reduced energy production and an increase in lipogenesis through Gcgr-PKA-Creb-mTORC1 pathway. Accordingly, anti-GCGR antibody treatment strongly blocks the pathogenesis of DKD induced by both type 2 and type 1 diabetes. Thus, our results highlight a previously unrecognized role of glucagon/Gcgr signaling in PTEC lipogenesis and DKD.

Date: 2025
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DOI: 10.1038/s41467-025-63529-5

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