γ-secretase inhibitor DAPT mitigates cisplatin-induced acute kidney injury by suppressing Notch1 signaling.

Organ toxicity, including kidney injury, limits the use of cisplatin for the treatment of multiple human cancers. Hence, interventions to alleviate cisplatin-induced nephropathy are of benefit to cancer patients. Recent studies have demonstrated that pharmacological inhibition of the Notch signaling pathway enhances cisplatin efficacy against several cancer cells. However, whether augmentation of the anti-cancer effect of cisplatin by Notch inhibition comes at the cost of increased kidney injury is unclear. We show here that treatment of mice with cisplatin resulted in a significant increase in Notch ligand Delta-like 1 (Dll1) and Notch1 intracellular domain (N1ICD) protein expression levels in the kidneys. N-[N-(3,5-difluorophenacetyl)-L-alanyl]-S-phenylglycine t-butyl ester (DAPT), a γ-secretase inhibitor reversed cisplatin-induced increase in renal N1ICD expression and plasma or urinary levels of predictive biomarkers of acute kidney injury (AKI). DAPT also mitigated cisplatin-induced tubular injury and reduction in glomerular filtration rate. Real-time multiphoton microscopy revealed marked necrosis and peritubular vascular dysfunction in the kidneys of cisplatin-treated mice which were abrogated by DAPT. Cisplatin-induced Dll1/Notch1 signaling was recapitulated in a human proximal tubule epithelial cell line (HK-2). siRNA-mediated Dll1 knockdown and DAPT attenuated cisplatin-induced Notch1 cleavage and cytotoxicity in HK-2 cells. These data suggest that Dll1-mediated Notch1 signaling contributes to cisplatin-induced AKI. Hence, the Notch signaling pathway could be a potential therapeutic target to alleviate renal complications associated with cisplatin chemotherapy.