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Potential role of microRNA-503 in Icariin-mediated prevention of high glucose-induced endoplasmic reticulum stress
Bao-Lin Su1, Liang-Liang Wang1, Liang-You Zhang1
1Department of Nephrology, The First Affiliated Hospital of Guangzhou University of Traditional Chinese Medicine, Guangzhou 510405, Guangdong Province, China.
Background:
Dysregulated microRNA (miRNA) is crucial in the progression of diabetic nephropathy (DN).
Aim:
To investigate the potential molecular mechanism of Icariin (ICA) in regulating endoplasmic reticulum (ER) stress-mediated apoptosis in high glucose (HG)-induced primary rat kidney cells (PRKs), with emphasis on the role of miR-503 and sirtuin 4 (SIRT4) in this process.
Methods:
Single intraperitoneal injection of streptozotocin (65 mg/kg) in Sprague-Dawley rats induce DN in the in vivo hyperglycemic model. Glucose-treated PRKs were used as an in vitro HG model. An immunofluorescence assay identified isolated PRKs. Cell Counting Kit-8 and flow cytometry analyzed the effect of ICA treatment on cell viability and apoptosis, respectively. Real-time quantitative polymerase chain reaction and western blot analyzed the levels of ER stress-related proteins. Dual luciferase analysis of miR-503 binding to downstream SIRT4 was performed.
Results:
ICA treatment alleviated the upregulated miR-503 expression in vivo (DN) and in vitro (HG). Mechanistically, ICA reduced HG-induced miR-503 overexpression, thereby counteracting its function in downregulating SIRT4 levels. ICA regulated the miR-503/SIRT4 axis and subsequent ER stress to alleviate HG-induced PRKs injury.
Conclusion:
ICA reduced HG-mediated inhibition of cell viability, promotion of apoptosis, and ER stress in PRKs. These effects involved regulation of the miR-503/SIRT4 axis. These findings indicate the potential of ICA to treat DN, and implicate miR-503 as a viable target for therapeutic interventions in DN.
Insights
Icariin (ICA) alleviates diabetic nephropathy (DN) by regulating the miR-503/sirtuin 4 (SIRT4) axis, reducing endoplasmic reticulum (ER) stress and apoptosis in kidney cells.
Area of Science:
- Nephrology
- Molecular Biology
- Pharmacology
Background:
- Dysregulated microRNA (miRNA) is a key factor in diabetic nephropathy (DN) progression.
- Endoplasmic reticulum (ER) stress contributes to apoptosis in high glucose (HG)-induced kidney injury.
Purpose of the Study:
- To elucidate the molecular mechanism of Icariin (ICA) in mitigating ER stress-mediated apoptosis in primary rat kidney cells (PRKs) under HG conditions.
- To investigate the role of the miR-503/sirtuin 4 (SIRT4) axis in ICA's therapeutic effects on DN.
Main Methods:
- Established in vivo (streptozotocin-induced DN) and in vitro (HG-treated PRKs) models.
- Assessed ICA's impact on cell viability and apoptosis using Cell Counting Kit-8 and flow cytometry.
- Quantified ER stress markers and analyzed the miR-503/SIRT4 interaction via real-time PCR, western blot, and dual luciferase assays.
Main Results:
- ICA treatment reduced elevated miR-503 expression in both in vivo and in vitro DN models.
- ICA counteracted HG-induced miR-503 overexpression, thereby preventing the downregulation of SIRT4.
- The miR-503/SIRT4 axis was identified as a key mediator in ICA's protective effects against HG-induced PRK injury and ER stress.
Conclusions:
- Icariin effectively improved cell viability and reduced apoptosis and ER stress in HG-exposed PRKs.
- ICA's therapeutic actions are linked to its modulation of the miR-503/SIRT4 axis.
- These findings highlight ICA's potential for DN treatment and miR-503 as a therapeutic target.
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