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MiR-20a-5p alleviates kidney ischemia/reperfusion injury by targeting ACSL4-dependent ferroptosis
Lang Shi1, Zhixia Song2, Yuzhen Li1
1Department of Nephrology, Renmin Hospital of Wuhan University, Wuhan, Hubei Province, China.
Abstract:
Ischemia/reperfusion injury (IRI) is prone to occur after kidney transplantation, leading to delayed graft function (DGF). MicroRNAs play a crucial role in the pathogenesis of ischemia/reperfusion-induced acute kidney injury, and miR-20a-5p was found to be the most significantly upregulated gene in a DGF patient cohort. However, the roles of microRNAs in transplanted kidneys remain largely unknown. In this study, we found that miR-20a-5p was upregulated in the kidneys of acute kidney injury mice and in patients with DGF. We identified early growth response-1 as a critical upstream target and verified the binding of early growth response-1 to a predicted sequence in the promoter region of the miR-20a-5p gene. Functionally, the miR-20a-5p mimic attenuated IRI and postischemic renal fibrosis, whereas the miR-20a-5p inhibitor delivery aggravated IRI and fibrosis. Importantly, delivery of the miR-20a-5p mimic or inhibitor in the donor kidneys attenuated or aggravated renal loss and structural damage in cold storage transplantation injury. Furthermore, our study identified miR-20a-5p as a negative regulator of acyl-CoA synthetase long-chain family member 4 (ACSL4) by targeting the 3' untranslated region of ACSL4 mRNA, thereby inhibiting ACSL4-dependent ferroptosis. Our results suggest a potential therapeutic application of miR-20a-5p in kidney transplantation through the inhibition of ACSL4-dependent ferroptosis.
Insights
MicroRNA-20a-5p is upregulated in kidney injury and transplantation. It protects against ischemia/reperfusion injury and fibrosis by inhibiting ferroptosis, suggesting a therapeutic role in kidney transplantation.
Area of Science:
- Nephrology
- Molecular Biology
- Transplantation Immunology
Background:
- Ischemia/reperfusion injury (IRI) is a major cause of delayed graft function (DGF) after kidney transplantation.
- MicroRNAs are implicated in IRI-induced acute kidney injury, with miR-20a-5p notably upregulated in DGF patients.
Purpose of the Study:
- To investigate the role of miR-20a-5p in kidney IRI and transplantation.
- To elucidate the molecular mechanisms underlying miR-20a-5p's function in renal IRI and ferroptosis.
Main Methods:
- Analysis of miR-20a-5p expression in mouse models of kidney IRI and human DGF patients.
- Investigation of upstream regulation by early growth response-1 (EGR1).
- Functional studies using miR-20a-5p mimics and inhibitors in vitro and in vivo, including donor kidney treatment.
Main Results:
- miR-20a-5p was upregulated in kidneys affected by IRI and in DGF patients.
- EGR1 directly targets the miR-20a-5p promoter.
- miR-20a-5p mimicry attenuated IRI and fibrosis, while inhibition worsened outcomes; donor kidney treatment showed similar protective/detrimental effects.
- miR-20a-5p directly targets and downregulates ACSL4, inhibiting ferroptosis.
Conclusions:
- miR-20a-5p plays a protective role against kidney IRI and transplantation injury.
- The miR-20a-5p/ACSL4 axis regulates ferroptosis in the context of renal IRI.
- miR-20a-5p represents a potential therapeutic target for mitigating kidney IRI and improving transplantation outcomes.
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