Formononetin protects against cisplatin-induced acute kidney injury through activation of the PPARα/Nrf2/HO-1/NQO1 pathway

Acute kidney injury (AKI) is characterized by an abrupt deterioration of renal function. Formononetin (FOR) protects against cisplatin (CIS)-induced AKI, and it has various potential pharmacological and biological effects, including anti-inflammatory, antioxidative and anti-apoptotic effects. The current study investigated the role of FOR in CIS-induced AKI. Rats were treated with CIS to establish an AKI model, followed by treatment with FOR. HK-2 cells were treated with CIS, FOR, GW6471 [a peroxisome proliferator-activated receptor alpha (PPAR alpha) antagonist], eupatilin (a PPAR alpha agonist) and nuclear factor erythroid 2-related factor 2 (Nrf2) small interfering RNA (siNrf2), and cell proliferation and apoptosis were determined by MTT and flow cytometry assays. The mRNA and proteins levels of PPAR alpha, Nrf2, heme oxygenase-1 (HO-1) and NAD(P)H quinone dehydrogenase 1 (NQO1) were measured by reverse transcription-quantitative PCR and western blotting. The results demonstrated that FOR attenuated the histopathological changes, the levels of blood urea nitrogen, creatinine, TNF-alpha and IL-1 beta, and the MDA content and MPO activity, whereas it enhanced CAT activity in the AKI rat model. Furthermore, FOR and eupatilin promoted cell viability and CAT activity, and increased the levels of PPAR alpha, Nrf2 and HO-1 and NQO1, but suppressed apoptosis and MPO activity, and reduced the levels of MDA, TNF-alpha and IL-1 beta in CIS-treated HK-2 cells. Notably, the aforementioned effects were reversed by GW6471 treatment or siNrf2 transfection. In conclusion, FOR protects against CIS-induced AKI via activation of the PPAR alpha/Nrf2/HO-1/NQO1 pathway.

Automated summary

This study demonstrated that FOR protects against CIS-induced AKI through activation of the PPAR alpha/Nrf2/HO-1/NQO1 pathway. Additionally, FOR and eupatilin promote cell viability and antioxidant enzyme activity, while showing significant inhibitory effects on apoptosis and inflammatory factors in HK-2 cells.