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Deficiency of Growth Arrest and DNA Damage-Inducible 45 α -R-Loop Pathway and Kidney Injury in Diabetic Nephropathy
Xue Qi Li1, Jia Xiu Zhang1, Liang Li1
1Institute of Nephrology, Zhong da Hospital, School of Medicine, Southeast University, Nanjing, China.
Journal of the American Society of Nephrology : JASN
|March 18, 2025
Abstract
No abstract available in PubMed .
Insights
Growth arrest and DNA damage–inducible 45α (GADD45α) deficiency worsens diabetic nephropathy by affecting R-loops and STEAP4 transcription. Targeting this pathway may offer new therapies for diabetic kidney disease.
Area of Science:
- Nephrology
- Molecular Biology
- Epigenetics
Background:
- Diabetic nephropathy, a leading cause of kidney failure, arises from hyperglycemia-induced epigenetic dysregulation.
- Growth arrest and DNA damage–inducible 45α (GADD45α) and R-loops are implicated in diabetic nephropathy pathogenesis.
- This study investigates GADD45α's role in diabetic nephropathy via epigenetic modulation and R-loop interaction.
Purpose of the Study:
- To elucidate the function of GADD45α in diabetic nephropathy.
- To explore the interaction between GADD45α, R-loops, and epigenetic modifications in kidney cells.
- To identify potential therapeutic targets for diabetic nephropathy.
Main Methods:
- Established a diabetic mouse model using streptozotocin.
- Analyzed kidney histology and biochemical markers in wild-type, GADD45α knockout, and GADD45α-overexpressing mice.
- Utilized lentivirus for GADD45α overexpression in human kidney cells and high-glucose treatment for in vitro mechanistic studies.
Main Results:
- Reduced GADD45α expression correlated with kidney dysfunction in diabetic nephropathy.
- GADD45α knockout exacerbated kidney injury, while overexpression ameliorated it.
- GADD45α, via R-loops, recruits ten eleven translocation 1 to activate STEAP4 transcription, mitigating mitochondrial injury and oxidative stress.
Conclusions:
- GADD45α deficiency exacerbates diabetic nephropathy by inhibiting STEAP4 promoter demethylation through R-loop interaction.
- The GADD45α-R-loop pathway presents a promising therapeutic target for diabetic nephropathy.
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