Hyperglycemic stress aggravates diabetic retinopathy and nephropathy by promoting cilium disassembly via a deacetylation- and methylation-mediated regulatory mechanism
4 affiliations
- 1Center for Cell Structure and Function, College of Life Sciences, Shandong Normal University, Jinan, China
- 2Translational Medicine Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- 3Department of Genetics and Cell Biology, State Key Laboratory of Medicinal Chemical Biology, College of Life Sciences, Nankai University, Tianjin, China
- 4School of Life Sciences and Medicine, Shandong University of Technology, Zibo, China
Abstract
Primary cilia are essential microtubule-based sensory organelles, and their dysfunction has been increasingly linked to metabolic stress. However, the underlying molecular mechanisms remain poorly understood. Herein, we reveal that ciliary defects in retinal photoreceptors and renal tubules exacerbate tissue damage during the progression of diabetic complications. Under hyperglycemic stress, protein arginine methyltransferase 1 (PRMT1) and histone deacetylase 6 (HDAC6) are significantly upregulated in both retinal and renal tissues. Genetic ablation of either enzyme effectively preserves ciliary architecture and restores organ function in diabetic mice. Mechanistically, PRMT1 localizes to the basal body, where it interacts with and methylates HDAC6 at arginine 16, consequently enhancing HDAC6 stability. In turn, HDAC6 mediates the deacetylation of PRMT1 at lysine 128, which elevates PRMT1 protein levels. This mutual modification crosstalk establishes a pathological positive feedback loop that stabilizes a pro-disassembly complex at the basal body, thereby potentiating ciliary impairment and expediting the progression of diabetic complications. Pharmacological inhibition of the PRMT1-HDAC6 loop significantly attenuates the pathological features of both diabetic retinopathy and nephropathy. Collectively, our findings uncover a reciprocal regulatory mechanism mediated by deacetylation and arginine methylation that drives cilium disassembly under hyperglycemic stress, providing promising therapeutic targets for the treatment of metabolic ciliopathies.
Primary cilium dysfunction contributes to diabetic complications, but the mechanisms linking hyperglycemia to cilium loss remain unclear. This study shows PRMT1-HDAC6 crosstalk drives cilium disassembly, identifying a therapeutic target for metabolic ciliopathies.
Related
- HDA6-mediated histone deacetylation restricts premature tapetal PCD to maintain male fertility during early flowering in Arabidopsis
- Adenovirus Protein VI Mediates Membrane Disruption following Capsid Disassembly
- A two-step model of FtsZ-ring disassembly in Bacillus subtilis
- StSIRT1 regulates potato dormancy through deacetylation of peroxidase-like 3 at K37
- Loss of cohesin deacetylation through KDAC8 inactivation leads to altered cohesin complex expression and chromosomal instability
BibTeX
@article{ran2026hyperglycemic,
title = {{Hyperglycemic stress aggravates diabetic retinopathy and nephropathy by promoting cilium disassembly via a deacetylation- and methylation-mediated regulatory mechanism}},
author = {Jie Ran and Changfeng Wei and Yang Yang and Yufei Zhang and Guizhi Guo and Nan Ma and Long Yin and Hongjun Fan and Jingrui Li and Heng Guo and Renshuai Zhang and Runa Wang and Dengwen Li and Min Liu},
journal = {PLOS Biology},
year = {2026},
month = sep,
doi = {10.1371/journal.pbio.3003975},
url = {https://journals.plos.org/plosbiology/article?id=10.1371/journal.pbio.3003975},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Hyperglycemic stress aggravates diabetic retinopathy and nephropathy by promoting cilium disassembly via a deacetylation- and methylation-mediated regulatory mechanism
AU - Jie Ran
AU - Changfeng Wei
AU - Yang Yang
AU - Yufei Zhang
AU - Guizhi Guo
AU - Nan Ma
AU - Long Yin
AU - Hongjun Fan
AU - Jingrui Li
AU - Heng Guo
AU - Renshuai Zhang
AU - Runa Wang
AU - Dengwen Li
AU - Min Liu
PY - 2026
DA - 2026/09/03
JO - PLOS Biology
DO - 10.1371/journal.pbio.3003975
UR - https://journals.plos.org/plosbiology/article?id=10.1371/journal.pbio.3003975
AB - Primary cilia are essential microtubule-based sensory organelles, and their dysfunction has been increasingly linked to metabolic stress. However, the underlying molecular mechanisms remain poorly understood. Herein, we reveal that ciliary defects in retinal photoreceptors and renal tubules exacerbate tissue damage during the progression of diabetic complications. Under hyperglycemic stress, protein arginine methyltransferase 1 (PRMT1) and histone deacetylase 6 (HDAC6) are significantly upregulated in both retinal and renal tissues. Genetic ablation of either enzyme effectively preserves ciliary architecture and restores organ function in diabetic mice. Mechanistically, PRMT1 localizes to the basal body, where it interacts with and methylates HDAC6 at arginine 16, consequently enhancing HDAC6 stability. In turn, HDAC6 mediates the deacetylation of PRMT1 at lysine 128, which elevates PRMT1 protein levels. This mutual modification crosstalk establishes a pathological positive feedback loop that stabilizes a pro-disassembly complex at the basal body, thereby potentiating ciliary impairment and expediting the progression of diabetic complications. Pharmacological inhibition of the PRMT1-HDAC6 loop significantly attenuates the pathological features of both diabetic retinopathy and nephropathy. Collectively, our findings uncover a reciprocal regulatory mechanism mediated by deacetylation and arginine methylation that drives cilium disassembly under hyperglycemic stress, providing promising therapeutic targets for the treatment of metabolic ciliopathies. Primary cilium dysfunction contributes to diabetic complications, but the mechanisms linking hyperglycemia to cilium loss remain unclear. This study shows PRMT1-HDAC6 crosstalk drives cilium disassembly, identifying a therapeutic target for metabolic ciliopathies.
SN - 1545-7885
ER -