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A KDM6A-KLF10 reinforcing feedback mechanism aggravates diabetic podocyte dysfunction
Chun-Liang Lin1,2,3,4,5, Yung-Chien Hsu1,4, Yu-Ting Huang1,4
1Departments of Nephrology, Chang Gung Memorial Hospital, Chiayi, Taiwan.
EMBO Molecular Medicine
|April 6, 2019
Summary
Diabetic nephropathy causes kidney disease. Researchers found KDM6A and KLF10 create a feedback loop that worsens podocyte dysfunction, leading to kidney injury. Targeting this loop may treat diabetic kidney disease.
Area of Science:
- Nephrology
- Molecular Biology
- Epigenetics
Background:
- Diabetic nephropathy is a major cause of end-stage renal disease.
- Podocyte (glomerular visceral epithelial cell) dysfunction is central to diabetic nephropathy, but underlying mechanisms are unclear.
Purpose of the Study:
- To elucidate the molecular mechanism of podocyte dysfunction in diabetic nephropathy.
- To investigate the role of KDM6A and its downstream target KLF10 in diabetic kidney injury.
Main Methods:
- Investigated the KDM6A-KLF10 interaction and its effect on podocyte-specific markers.
- Utilized mouse models with KDM6A or KLF10 inactivation to assess diabetes-induced kidney injury.
- Analyzed KDM6A and KLF10 levels in kidney tissues and urinary exosomes from human patients.
Main Results:
- Identified a positive feedback loop where KDM6A up-regulates KLF10, which in turn increases KDM6A expression.
- KLF10 represses podocyte markers like nephrin by recruiting Dnmt1 to the gene promoter.
- KDM6A or KLF10 inactivation significantly reduced proteinuria and kidney damage in diabetic mice; elevated levels were found in human patients.
Conclusions:
- The KDM6A-KLF10 feedback loop exacerbates diabetic podocyte dysfunction and kidney injury.
- Targeting the KDM6A-KLF10 pathway presents a potential therapeutic strategy for diabetic nephropathy.
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