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MiR‑140‑5p alleviates mouse liver ischemia/reperfusion injury by targeting CAPN1.

ABSTRACT: Ischemia/reperfusion (I/R)‑induced liver injury remains a primary concern in liver transplantation and hepatectomy. Previous studies have indicated that microRNAs (miRs) are involved in multiple pathophysiological processes, including liver I/R. miR‑140‑5p reportedly inhibits inflammatory responses and apoptosis in several diseases; however, the role of miR‑140‑5p in liver I/R remains unknown. The present study aimed to investigate the potential role and mechanism of miR‑140‑5p on liver I/R injury. Mouse liver I/R and mouse AML12 cell hypoxia/reoxygenation (H/R) models were established. miR‑140‑5p mimics, inhibitor or agonists were used to overexpress or inhibit miR‑140‑5p in vitro and in vivo. Reverse transcription‑quantitative polymerase chain reaction was used to detect miR‑140‑5p expression. Liver and cell injury were evaluated using several biochemical assays. The association between miR‑140‑5p and calpain‑1 (CAPN1) was confirmed using a dual‑luciferase reporter assay. The results revealed that miR‑140‑5p expression was decreased in the mouse model of liver I/R injury and AML12 cells subjected to H/R, while overexpressed miR‑140‑5p reduced liver injury in vivo and cell injury in vitro. In addition, CAPN1 was determined to be a target of miR‑140‑5p; overexpressed CAPN1 abrogated the effect of miR‑140‑5p on H/R‑induced cell injury. The present study indicated that miR‑140‑5p protected against liver I/R by targeting CAPN1, which may provide a novel therapeutic target for liver I/R injury.

SUBMITTER: Yu Q

PROVIDER: S-EPMC8335737 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BACKGROUND:Ischemic stroke is a deadly disease that poses a serious threat to human life. Superoxide dismutase 3 (SOD3, ECSOD) is the main antioxidant enzyme that removes superoxide anions from cells. This study aimed to investigate the effect of SOD3 overexpression on cerebral ischemia-reperfusion injury in rats. METHODS:GV230-EGFP-ECSOD, the recombinant SOD3-overexpressed vector, was constructed by genetic engineering technology, and mesenchymal stem cells (MSCs) were infected with lentiviral packaging. In animal experiment, cerebral ischemia-reperfusion injury model rats were successfully established. ECSOD-MSCs are the MSCs that successfully transfected with SOD3 overexpression vector. The animals were injected with ECSOD-MSCs (ECSOD-MSC group), normal MSCs (MSCs group), PBS (PBS group), and not do any processing (Model group) via the tail vein. Then MRI was used to detect the infarct volume of rats, modified Neurological Severity Scores (mNSS), and immunohistochemistry were used to evaluate the expression of neurological function and apoptosis-related genes in rats. RESULTS:Western blot analysis revealed that the SOD3 was highly expressed in MSCs. Animal experiments showed that the transplantation of ECSOD-MSCs significantly reduced the infarct volume of ischemic stroke rats (p < 0.05), significantly improved neurological function in rats (p < 0.05), and found proapoptotic gene, Bax, expression was significantly decreased (p < 0.05), the expression of anti-apoptotic gene, Bcl-2, was significantly increased (p < 0.05). The highly expressed SOD3 has no correction with brain infarct volume, and the highly expressed SOD3 has a positive correlation with cell apoptosis. It is speculated that overexpression of SOD3 affects the expression of Bax and Bcl-2, and improves apoptosis to alleviate ischemic stroke. CONCLUSION:Our results indicated that MSCs transfected with SOD3 can effectively alleviate cerebral ischemia-reperfusion injury in rats.

Project description:BackgroundKidney ischemia-reperfusion (I/R) injury is an independent risk factor for delayed graft function after kidney transplantation with long-term graft survival deterioration. Previously, we found that the upregulated expression of miR-17-5p exerts a protective effect in kidney I/R injury, but the mechanism has not been clearly studied.MethodsA kidney I/R injury model was induced in adult C57BL/6 male mice (20-22 g) by clamping both kidney pedicles for 30 min. The miR-17-5p agomir complex was injected into mice 24 h before surgery via the tail vein at a total injection volume of 10 µL/g body weight. The mice were euthanized on post-I/R injury day 2, and kidney function, apoptosis, autophagy, and related molecules were then detected. Human kidney-2 (HK-2) cells, which underwent hypoxia/reoxygenation, were treated with the miR-17-5p agomir, miR-17-5p antagomir, and small interfering ribonucleic acids (siRNAs). Cell viability, apoptosis, autophagy, and molecules were also examined.ResultsAutophagy, miR-17-5p expression, and kidney function damage were significantly more increased in the I/R group than in the sham group. In the cultured HK-2 cells underwent hypoxia/reoxygenation, the miR-17-5p agomir directly inhibited the expression of phosphatase and tensin homolog deleted on chromosome 10 (PTEN) and Bcl-2 like protein 11 (BIM), and attenuated apoptosis and autophagy. Further, miR-17-5p inhibited autophagy by activating the protein kinase B (Akt)/Beclin1 pathway, which was suppressed by siRNAs. Additionally, the administration of miR-17-5p agomir greatly improved kidney function in the I/R mice group by inhibiting autophagy and apoptosis.ConclusionsThese findings suggest a new possible therapeutic strategy for the prevention and treatment of kidney I/R injury. The upregulation of miR-17-5p expression appears to inhibit apoptosis and autophagy by suppressing PTEN and BIM expression, which in turn upregulates downstream Akt/Beclin1 expression.

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MiR‑140‑5p alleviates mouse liver ischemia/reperfusion injury by targeting CAPN1.

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