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MicroRNA21/HDAC4 mediates podocyte apoptosis under high glucose conditions by regulating the activation of FoxO1
Lanjun Fu1,2, Nan Yang1,2, Juan Jin1,2
1Department of Nephrology, the First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine), Hangzhou, 310006, Zhejiang, P.R. China.
Abstract:
Diabetic kidney disease (DKD), which lacks effective treatment, has become the leading cause of end-stage renal disease. Apoptosis of podocytes, as a vital mode of cell injury, plays an important role in the progression of DKD. MicroRNA-21 (miR-21) and Forkhead transcription Factor O1 (FoxO1) have been revealed to act in DKD, but the mechanisms remain elusive. Here, we investigated the special regulatory mechanism by which miR-21 activates FoxO1 in mouse podocytes induced by high glucose (HG). In vitro, after exposure to HG, podocyte apoptosis, miR-21, HDAC4, FoxO1/acetylate-FoxO1/phosphorylate-FoxO1, Bcl-2, and nephrin were examined. Then, we evaluated the vital effect of miR-21 in regulating podocyte apoptosis and identified the critical activator of FoxO1 by overexpression or inhibition of miR-21/HDAC4 via adenoviral transfer. The results showed that HG increased podocyte apoptosis, elevated the expression of miR-21, HDAC4, acetylate-FoxO1, and FoxO1, and reduced the expression of Bcl-2 and nephrin. In addition, overexpression or inhibition of miR-21 could affect the levels of HDAC4, acetylated FoxO1, FoxO1, Bcl-2, and nephrin. Finally, overexpression of HDAC4 decreased the acetylation of FoxO1 while increasing the phosphorylation of FoxO1, which resulted in a decline in Bcl-2 and nephrin. Therefore, these data indicated that miR-21/FoxO1 was a key pathway in regulating podocyte apoptosis under HG conditions. Furthermore, phosphorylation rather than acetylation was the critical activator of FoxO1.
Insights
MicroRNA-21 (miR-21) activates Forkhead transcription Factor O1 (FoxO1) through phosphorylation, not acetylation, to promote podocyte apoptosis in diabetic kidney disease. This miR-21/FoxO1 pathway is a key target for treating DKD.
Area of Science:
- Nephrology
- Molecular Biology
- Biochemistry
Background:
- Diabetic kidney disease (DKD) is a leading cause of end-stage renal disease with limited treatment options.
- Podocyte apoptosis is a critical factor in DKD progression.
- The roles of microRNA-21 (miR-21) and Forkhead transcription Factor O1 (FoxO1) in DKD are not fully understood.
Purpose of the Study:
- To investigate the regulatory mechanism of miR-21 activation of FoxO1 in high glucose-induced mouse podocytes.
- To determine the role of miR-21 in podocyte apoptosis.
- To identify the critical activator of FoxO1.
Main Methods:
- In vitro study using mouse podocytes exposed to high glucose.
- Examination of podocyte apoptosis, miR-21, HDAC4, FoxO1 (acetylated and phosphorylated forms), Bcl-2, and nephrin expression.
- Adenoviral transfer for overexpression or inhibition of miR-21 and HDAC4.
Main Results:
- High glucose induced podocyte apoptosis, increased miR-21, HDAC4, acetylated FoxO1, and FoxO1, while decreasing Bcl-2 and nephrin.
- miR-21 modulation affected HDAC4, acetylated FoxO1, FoxO1, Bcl-2, and nephrin levels.
- HDAC4 overexpression reduced FoxO1 acetylation, increased phosphorylation, and decreased Bcl-2 and nephrin.
Conclusions:
- The miR-21/FoxO1 pathway is crucial for regulating podocyte apoptosis in high glucose conditions.
- FoxO1 phosphorylation, not acetylation, is the critical activator in this process.
- Targeting the miR-21/FoxO1 pathway may offer a therapeutic strategy for DKD.
