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Targeting Oct2 and P53: Formononetin prevents cisplatin-induced acute kidney injury
Di Huang1, Chuangyuan Wang2, Yingjie Duan3
1Department of Clinical Pharmacology, College of Pharmacy, Dalian Medical University, Dalian, China.
Abstract:
Nephrotoxicity is one of major side effects of cisplatin in chemotherapy. Therefore, there is an urgent medical need to develop drugs that may protect kidney from toxicity. In previous study, we found that it showed the protective effects of formononetin against apoptosis by upregulating Nrf2. In this study, we investigated the renoprotective effect of formononetin against cisplatin-induced AKI and tried to elucidate the possible mechanisms. The amelioration of renal function, histopathological changes, and apoptosis in tubular cells was observed after formononetin treatment. Formononetin decreased expression of organic cation transporter 2 (Oct2) and increased the expressions of multidrug resistance-associated proteins (Mrps), which might result in a decrease accumulation of cisplatin in tubular cells after AKI. 5-Bromo-2-deoxyuridine (BrdU) and Ki-67 staining assay indicated that formononetin could promote the renal tubular cells proliferation after cisplatin nephrotoxicity. Moreover, formononetin regulated cyclins and pro-apoptotic proteins to involve the regulation of cell cycle. Furthermore, formononetin decreased p53 expression via promoting the overexpression of murine double minute 2 (MDM2) and MDMX. Taken together, formononetin provided protective effects by promoting proliferation of surviving renal tubular cells and inhibiting apoptosis after cisplatin-induced AKI.
Insights
Formononetin protects kidneys from cisplatin damage by reducing cell death and promoting the proliferation of surviving kidney cells. This natural compound also influences cisplatin accumulation and regulates cell cycle proteins, offering a potential therapeutic strategy against chemotherapy-induced kidney injury.
Area of Science:
- Pharmacology
- Nephrology
- Cell Biology
Background:
- Cisplatin chemotherapy can cause significant kidney toxicity (nephrotoxicity).
- There is a critical need for therapeutic agents to protect kidneys during cisplatin treatment.
- Formononetin has previously shown protective effects against apoptosis by upregulating Nrf2.
Purpose of the Study:
- To investigate the renoprotective effects of formononetin against cisplatin-induced acute kidney injury (AKI).
- To elucidate the underlying mechanisms of formononetin's protective action in the kidneys.
Main Methods:
- Formononetin treatment was administered to assess its impact on cisplatin-induced AKI.
- Evaluated renal function, histopathological changes, and tubular cell apoptosis.
- Assessed expression levels of organic cation transporter 2 (Oct2), multidrug resistance-associated proteins (Mrps), and cell proliferation markers (BrdU, Ki-67).
- Analyzed the regulation of cyclins, pro-apoptotic proteins, p53, MDM2, and MDMX.
Main Results:
- Formononetin treatment ameliorated renal function and histopathological damage, reducing tubular cell apoptosis.
- Formononetin decreased Oct2 expression and increased Mrp expression, potentially reducing cisplatin accumulation in tubular cells.
- Formononetin promoted renal tubular cell proliferation and regulated proteins involved in cell cycle control and apoptosis.
- Formononetin decreased p53 expression by promoting MDM2 and MDMX overexpression.
Conclusions:
- Formononetin exhibits significant renoprotective effects against cisplatin-induced AKI.
- The protective mechanisms involve promoting the proliferation of surviving renal tubular cells and inhibiting apoptosis.
- Formononetin influences cisplatin transport and modulates key cell cycle and apoptosis regulatory pathways.