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Inhibition of miR-17~92 Cluster Ameliorates High Glucose-Induced Podocyte Damage
Xiaobao Fan1,2, Zhiming Hao1, Zhenjiang Li2
1Department of Rheumatology and Immunology, The First Affiliated Hospital of Medical College of Xi'an Jiaotong University, Xi'an City, Shaanxi Province 710061, China.
Abstract:
The loss and damage of podocytes is an early feature of diabetic nephropathy (DN). The miR-17∼92 cluster was dysregulated in diabetic and polycystic kidney disease patients, but its role in DN is unclear. Hence, an in vitro study on the high glucose- (HG-) treated mouse podocytes (MPC5) was designed to elucidate the effect of miR-17∼92 cluster downregulation on cell viability, apoptosis, inflammation, fibrosis, and podocyte function. The results suggested that the miR-17∼92 cluster members miR-17-5p, miR-18a, miR-19a, miR-19b, miR-20a, and miR-92a were upregulated in the renal biopsy tissue of DN patients and HG-treated MPC5. The downregulation of the miR-17∼92 cluster effectively suppressed the cell apoptosis, inflammation, fibrosis, and podocyte dysfunction in HG-stimulated MPC5 cells. The bioinformatics analysis and rescue experiments showed that ABCA1 (ATP-binding cassette transporter A1) is an effector of the miR-17~92 cluster. Silence of ABCA1 inhibited the protective effect of the miR-17∼92 cluster downregulation on podocyte damage. In summary, this research indicated that the downregulation of the miR-17∼92 cluster ameliorates HG-induced podocyte damage via targeting ABCA1.
Insights
Downregulating the miR-17∼92 cluster protects against high glucose-induced podocyte damage in diabetic nephropathy. This protective effect is mediated by targeting ABCA1 (ATP-binding cassette transporter A1).
Area of Science:
- Nephrology
- Molecular Biology
- Genetics
Background:
- Podocyte injury is a hallmark of diabetic nephropathy (DN).
- The miR-17∼92 cluster is implicated in other kidney diseases but its role in DN remains undefined.
- Understanding molecular mechanisms is crucial for developing DN therapies.
Purpose of the Study:
- To investigate the role of the miR-17∼92 cluster in high glucose-induced podocyte damage.
- To determine the effect of miR-17∼92 cluster downregulation on podocyte viability, apoptosis, inflammation, and fibrosis.
- To identify the downstream targets of the miR-17∼92 cluster in DN.
Main Methods:
- In vitro study using high glucose-treated mouse podocytes (MPC5).
- Analysis of miR-17∼92 cluster member expression in DN patient tissues and cell models.
- Assessment of cell viability, apoptosis, inflammation, and fibrosis markers.
- Bioinformatics analysis and rescue experiments to identify molecular targets.
Main Results:
- miR-17∼92 cluster members (miR-17-5p, miR-18a, miR-19a, miR-19b, miR-20a, miR-92a) were upregulated in DN tissues and HG-treated podocytes.
- Downregulation of the miR-17∼92 cluster significantly reduced apoptosis, inflammation, and fibrosis in HG-stimulated podocytes.
- ABCA1 (ATP-binding cassette transporter A1) was identified as a key effector of the miR-17∼92 cluster.
Conclusions:
- The miR-17∼92 cluster is upregulated in diabetic nephropathy and contributes to podocyte injury.
- Downregulation of the miR-17∼92 cluster exerts protective effects against high glucose-induced podocyte damage.
- The protective mechanism involves targeting ABCA1, highlighting a potential therapeutic pathway for DN.
