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MicroRNA-709 Mediates Acute Tubular Injury through Effects on Mitochondrial Function
Yan Guo1,2, Jiajia Ni1, Shuang Chen1,2
1Department of Nephrology, State Key Laboratory of Reproductive Medicine, Children's Hospital of Nanjing Medical University, Nanjing, China.
Abstract:
Mitochondrial dysfunction has important roles in the pathogenesis of AKI, yet therapeutic approaches to improve mitochondrial function remain limited. In this study, we investigated the pathogenic role of microRNA-709 (miR-709) in mediating mitochondrial impairment and tubular cell death in AKI. In a cisplatin-induced AKI mouse model and in biopsy samples of human AKI kidney tissue, miR-709 was significantly upregulated in the proximal tubular cells (PTCs). The expression of miR-709 in the renal PTCs of patients with AKI correlated with the severity of kidney injury. In cultured mouse PTCs, overexpression of miR-709 markedly induced mitochondrial dysfunction and cell apoptosis, and inhibition of miR-709 ameliorated cisplatin-induced mitochondrial dysfunction and cell injury. Further analyses showed that mitochondrial transcriptional factor A (TFAM) is a target gene of miR-709, and genetic restoration of TFAM attenuated mitochondrial dysfunction and cell injury induced by cisplatin or miR-709 overexpression in vitro Moreover, antagonizing miR-709 with an miR-709 antagomir dramatically attenuated cisplatin-induced kidney injury and mitochondrial dysfunction in mice. Collectively, our results suggest that miR-709 has an important role in mediating cisplatin-induced AKI via negative regulation of TFAM and subsequent mitochondrial dysfunction. These findings reveal a pathogenic role of miR-709 in acute tubular injury and suggest a novel target for the treatment of AKI.
Insights
MicroRNA-709 (miR-709) exacerbates acute kidney injury (AKI) by impairing mitochondrial function and causing tubular cell death. Inhibiting miR-709 offers a potential therapeutic strategy for AKI treatment.
Area of Science:
- Nephrology
- Molecular Biology
- Mitochondrial Biology
Background:
- Mitochondrial dysfunction is a key factor in acute kidney injury (AKI) pathogenesis.
- Current therapies for improving mitochondrial function in AKI are limited.
- MicroRNAs (miRNAs) are increasingly recognized as critical regulators in kidney disease.
Purpose of the Study:
- To investigate the role of microRNA-709 (miR-709) in the development of AKI.
- To determine if miR-709 mediates mitochondrial impairment and tubular cell death in AKI.
- To explore miR-709 as a potential therapeutic target for AKI.
Main Methods:
- Utilized a cisplatin-induced AKI mouse model and human AKI kidney biopsy samples.
- Assessed miR-709 expression in proximal tubular cells (PTCs) using quantitative PCR.
- Performed in vitro studies with cultured mouse PTCs involving miR-709 overexpression/inhibition and TFAM manipulation.
- Administered miR-709 antagomirs in vivo to evaluate therapeutic effects in cisplatin-induced AKI.
Main Results:
- miR-709 was significantly upregulated in PTCs of mice and humans with AKI, correlating with injury severity.
- Overexpression of miR-709 induced mitochondrial dysfunction and apoptosis in cultured PTCs.
- Inhibition of miR-709 ameliorated cisplatin-induced mitochondrial dysfunction and cell injury.
- TFAM was identified as a direct target of miR-709; restoring TFAM attenuated injury.
- In vivo administration of miR-709 antagomirs protected against cisplatin-induced AKI and mitochondrial dysfunction.
Conclusions:
- miR-709 plays a critical pathogenic role in cisplatin-induced AKI by targeting TFAM and causing mitochondrial dysfunction.
- miR-709 is a significant contributor to acute tubular injury.
- Targeting miR-709 represents a novel therapeutic strategy for AKI.