Inhibition of Plk1 Attenuates Cisplatin-Induced AKI via Upregulation of PERK/P-eIF2α Pathway

Background: Acute kidney injury(AKI) is a common and serious clinical complication and lacks effective treatment except renal replacement therapy. PLK1 is an important cell cycle regulator with no study reported in AKI. In current study, we investigated the effect of Plk1 inhibition by BI6727 or knock down of Plk1 by siRNA in cisplatin induced AKI in mice or in cultured renal tubular epithelial cells. Methods: AKI was induced in C57BL/6J mice by administration of cisplatin at dose of 25mg/kg(i.p.) . Plk1 inhibitor BI6727 (7.5mg/kg)was given 6hrs prior to cisplatin injection. All Mice were executed 72hrs after cisplatin injection. Mice blood and kidney tissues were collected for histology or protein anaylsis. Renal proximal tubular epithelial cell line TKPT was pretreated with BI6727 or transfected with Plk1-shRNA, then cisplatin was added for 24hrs and cells were collected for apoptosis detection by flow cytometry. Results: In BI6727 treated mice, increased serum creatinine caused by cisplatin was reduced by 65%. PAS staining showed tubular injury score was about 47% less. Protein expression of Kim1 and NGAL were reduced by 56% and 81%. mRNA of TNF-α and IL-6 were reduced by 85% and 77%. Tunnel staining showed about 46.1% less apoptotic cells. In cultured TKPT cells, BI6727 treatment reduced the apoptotic cells by 58% and knock-down of Plk1 reduced the apoptotic cells by 46.8% compared to cisplatin treated cells. Further, we found BI6727 upregulated PERK/P-eIF2α pathway, which is the central mechanism of the integrated stress response(ISR). Under conditions of stress, activation of the ISR inhibits protein translation and preserves energy for essential functions to support cell survival. Conclusion: Inhibition of Plk1 by BI6727 protects against cisplatin-induced acute kidney injury. This effect is mediated by upregulation of PERK/P-eIF2α pathway. Our research suggests a pathogenic role of Plk1 in promoting AKI. Plk1 may be a potential target for AKI treatment. Funding: Government Support – Non-U.S.