Renal IGFBP6 Interacts With THBS1 to Drive Renal Cellular Senescence and Fibrosis
Epithelial dedifferentiation and myofibroblast activation are critical drivers of chronic kidney disease (CKD) progression. Elevated levels of IGFBP6 have been linked to decreased renal function in CKD patients, but its precise role and underlying mechanisms remain unclear. In this study, we observed significantly increased IGFBP6 expression in the kidney tissues of both renal fibrosis patients and animal models. Global or tubule-specific IGFBP6 knockout attenuated renal cellular senescence and fibrosis development in mice. In vitro, IGFBP6 deficiency preserved epithelial cell phenotype and inhibited fibroblast activation. Additionally, anti-IGFBP6 treatment demonstrated promising therapeutic effects in alleviating renal cellular senescence and fibrosis. Mechanistically, IGFBP6, acting as an adaptor protein, could bind to thrombospondin 1 (THBS1) and prevent its ubiquitination-mediated degradation, thereby activating the THBS1-CD47 cellular pathway in epithelial cells, which contributed to renal cellular senescence and fibrosis. Notably, both genetic and neutralizing antibody-mediated inhibition of IGFBP6 alleviated renal cellular senescence and fibrosis, suggesting that the IGFBP6/THBS1/CD47 axis represents a potential therapeutic target for chronic kidney injury.
Authors
- Xiaowei Hu (ORCID: https://orcid.org/0000-0002-0778-2848)
- X Z Li
- Run-run Shan
- Ju-tao Yu (ORCID: https://orcid.org/0000-0002-8888-9881)
- Jiagen Wen (ORCID: https://orcid.org/0000-0002-4375-6567)
- Chao Hou (ORCID: https://orcid.org/0000-0003-3855-1660)
- Xiao‐Yu Shen
- Xiao‐Ming Meng (ORCID: https://orcid.org/0000-0002-1166-561X)
- Changgeng Xu (ORCID: https://orcid.org/0000-0003-4935-6932)
- Yu‐Jie Liu (ORCID: https://orcid.org/0000-0002-4985-1565)
- Tian Zhao (ORCID: https://orcid.org/0000-0001-6456-9763)
- Zi Wang (ORCID: https://orcid.org/0000-0002-3953-0493)
- Di Zhang (ORCID: https://orcid.org/0000-0003-4309-8098)
- Mingming Liu (ORCID: https://orcid.org/0000-0002-6750-5068)
- Yuqing Wang (ORCID: https://orcid.org/0009-0006-5852-5418)
- Rui Hou (ORCID: https://orcid.org/0000-0002-6950-2290)
- Yuhang Dong
- Yi-Xiang Wang (ORCID: https://orcid.org/0000-0002-4021-4228)
- S Huang
- S X Sun
- Juan Jin
- Jie Wei
- Ya‐Xin Ru
- Jian‐min You
- Wei Wang
- Fei Zhang (ORCID: https://orcid.org/0000-0002-4830-1174)
- Chao Li
Institutions
- University of Science and Technology of China (CN)
- Xinjiang Medical University (CN)
- China Pharmaceutical University (CN)
- Chinese University of Hong Kong (HK)
- Anhui Medical University (CN)
- Fifth Affiliated Hospital of Xinjiang Medical University (CN)
- Wuhan Union Hospital (CN)
- First Affiliated Hospital of Anhui Medical University (CN)
- Anhui Provincial Children's Hospital (CN)
- Second Affiliated Hospital of Anhui Medical University (CN)
- Ministry of Education (KN)
- Huazhong University of Science and Technology (CN)
- Nanjing University (CN)
- University of Hong Kong (HK)
Publication Details
- Journal
- Advanced Science
- Published
- 2026-05-22
- DOI
- https://doi.org/10.1002/advs.75802
- Primary Topic
- Chronic Kidney Disease and Diabetes
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- National Natural Science Foundation of China