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

Abstract

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.

The Predictive Role of the Biomarker Kidney Molecule-1 (KIM-1) in Acute Kidney Injury (AKI) Cisplatin-Induced Nephrotoxicity

“…The latter are vital for both membrane structure maintenance and overall mitochondrial activity. As cisplatin levels increase, Bcl-2 is downregulated in response to p53 activation [87,88,89,90].…”

Recent Advances in Models, Mechanisms, Biomarkers, and Interventions in Cisplatin-Induced Acute Kidney Injury

“…Bcl family proteins are essential for maintenance of mitochondrial function and membrane integrity. There is a strong consensus that the anti-apoptotic mitochondrial protein, Bcl-2, is downregulated in response to cisplatin [40,44,70,75,76,78,79,83,84,88,89,104,105,106,107,108,109,110,111,112,113,114,115,116,117] through p53 activation [111,113,118]. One study, however, showed that Bcl-2 mRNA is increased after administration of cisplatin [119].…”

Inhibition of fibroblast growth factor-inducible 14 (Fn14) attenuates experimental tubulointerstitial fibrosis and profibrotic factor expression of proximal tubular epithelial cells

“…DAPT is a speci c inhibitor of the Notch1 signaling pathway (19). DAPT decreased the enhancement effect of TWEAK on the mRNA expression of pro brotic factors, collagen I, bronectin, and α-SMA, as well as Notch1/Jagged1 molecules in HK2 cells (Fig.…”