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High glucose induces podocyte ferroptosis through BAP1/SLC7A11 pathway
Ren Peiyao1,2, Man Xueli1, Sun Wenbo1
1Department of Nephrology, The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Traditional Chinese Medicine), Hangzhou, Zhejiang, 310000, PR China.
Heliyon
|January 16, 2025
Summary
High glucose accelerates ferroptosis in diabetic nephropathy by inhibiting cystine uptake in podocytes. This occurs through increased BAP1 expression, which downregulates SLC7A11 and promotes oxidative stress and cell death.
Area of Science:
- Nephrology
- Cell Biology
- Biochemistry
Background:
- Ferroptosis is a key factor in diabetic nephropathy (DN) development.
- The precise regulatory mechanisms of ferroptosis in DN are not fully understood.
Purpose of the Study:
- To elucidate the regulatory role of BAP1 in ferroptosis within podocytes under high glucose conditions.
- To investigate the impact of high glucose on SLC7A11 expression and its relation to ferroptosis in diabetic nephropathy.
Main Methods:
- MPC5 cells were cultured in high glucose (HG) to mimic diabetic conditions.
- Ferroptosis and oxidative stress markers (MDA, cystine uptake, ROS) were measured.
- BAP1 and SLC7A11 interactions were studied using wild-type and C91A mutant cells.
Main Results:
- High glucose exacerbated erastin-induced ferroptosis, reducing glutathione and increasing oxidative stress.
- HG suppressed SLC7A11 expression, while its overexpression restored cystine uptake and reduced oxidative stress.
- HG increased BAP1 levels; BAP1 silencing upregulated SLC7A11 and reduced ferroptosis.
Conclusions:
- High glucose inhibits podocyte cystine uptake by increasing BAP1 expression and affecting SLC7A11 deubiquitination.
- This leads to lipid peroxide accumulation and ferroptosis, contributing to diabetic nephropathy progression.
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